<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03306420</url>
  </required_header>
  <id_info>
    <org_study_id>MS201408-0005</org_study_id>
    <nct_id>NCT03306420</nct_id>
  </id_info>
  <brief_title>First-in-Human Study of MS201408-0005A as Single Agent and in Combinations</brief_title>
  <official_title>Phase I, First-in-Human, Open-Label, Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of MS201408-0005A as Single Agent and Sequentially in Combinations With MS201408-0005C or MS201408-0005B in Subjects With Metastatic or Locally Advanced Unresectable Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>EMD Serono Research &amp; Development Institute, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck KGaA, Darmstadt, Germany</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>EMD Serono</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase I, open-label study to determine the safety, tolerability, pharmacokinetic&#xD;
      (PK), pharmacodynamics (PD), and preliminary antitumor activity of MS201408-0005A as single&#xD;
      agent (Part IA only) and in combination with MS201408-0005C or MS201408-0005B (Part IB, Part&#xD;
      IC).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The study was terminated early due to lackluster pharmacodynamic data that showed no&#xD;
    significant reduction of plasma kynurenine at steady state of M4112.&#xD;
  </why_stopped>
  <start_date type="Actual">October 3, 2017</start_date>
  <completion_date type="Actual">January 14, 2019</completion_date>
  <primary_completion_date type="Actual">January 14, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part 1A Dose Escalation: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) as Per National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03</measure>
    <time_frame>Cycle 1 (Each Cycle is of 28 days)</time_frame>
    <description>DLTs was assessed as per NCI CTCAE v 4.03. DLT defined as any Grade greater than or equal (&gt;=) 3 nonhematological AE or Immune-related adverse event (irAE) assessed by Investigator or Sponsor during first Cycle (first 28 days) of study treatment. Asymptomatic Grade &gt;= 3 lipase or amylase elevation not associated with clinical manifestations of pancreatitis. Any TEAE observed in subsequent cycle. Any Grade 4 neutropenia of &gt;= 5 days duration, Grade &gt;= 3 febrile neutropenia, Grade 3 hemoglobin decrease despite blood transfusion or erythroid growth factor. Grade 4 hemoglobin decrease assessed as related to study drug. Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. Any Grade &gt;= 3 clinical signs and symptoms related to increased QTc.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1A Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Who Experienced a Treatment Related Adverse Events (TRAE) According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03</measure>
    <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
    <description>An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment related AE was defined as having a &quot;Possible&quot; or &quot;Related&quot; relationship to study treatment, as assessed by the Investigator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters</measure>
    <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
    <description>The laboratory measurements included hematology, biochemistry and hormonal tests. Number of participants with any clinically significant abnormalities in laboratory measurements were reported. Clinical significance was determined by the investigator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Vital Signs</measure>
    <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
    <description>Vital signs assessment included blood pressure, pulse rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1A Dose Escalation: Number of Participants With On-Treatment Shift in Eastern Cooperative Oncology Performance Status (ECOG PS) Score From 0 to 1</measure>
    <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
    <description>ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 4, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Number of participants with on-treatment shift in ECOG PS Score from 0 to 1 were reported.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1A Dose Escalation: Number of Participants With Clinically Significant Change From Baseline in Physical Examination Abnormalities</measure>
    <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
    <description>A complete physical examination (including, general appearance, skin, pulmonary, cardiovascular, gastrointestinal, external genitourinary only as medically relevant, lymphatic, neurologic and musculoskeletal systems, head/neck, extremities, eyes, ears, nose, throat, and cognitive status) was performed. Number of participants with clinical significant change from baseline in physical examination abnormalities were reported. Clinical significance was determined by the investigator.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post Dose AUC(0-8h) of M4112</measure>
    <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
    <description>Area under the drug concentration-time curve from 0 to 8 h post dosing for M4112. AUC0-8 was calculated according to the mixed log-linear trapezoidal rule.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of M4112</measure>
    <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
    <description>Pharmacokinetic PK parameter Cmax was obtained directly from the plasma concentration versus time curve.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Time to Reach Maximum Plasma Concentration (Tmax) of M4112</measure>
    <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
    <description>Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (AUC0-8/Dose) of M4112</measure>
    <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
    <description>Dose normalized was calculated as area under the plasma concentration-time curve from time zero to 8 h postdose divided by dose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4112</measure>
    <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
    <description>Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (Racc[AUC0-8h]) of M4112</measure>
    <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
    <description>Accumulation ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 hours After Administration (Racc[AUC0-8h]) of M4112 was reported. Racc(AUC0-8h) calculated as AUC0-8h, on Cycle 1 Day 15 divided by AUC0-8h on Cycle 1 Day 1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part IA Dose Escalation: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4112</measure>
    <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
    <description>Accumulation ratio for Cmax was calculated as Cmax, Cycle 1 Day 15 divided by Cmax, Cycle 1 Day 1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Pre-dose Observed Plasma Concentration (Cpre) of M4112</measure>
    <time_frame>Pre-dose on Days 8, 15 (Cycle 1) and Day 1 (Cycle 2) (Each Cycle is 28 days)</time_frame>
    <description>Maximum pre-dose observed plasma concentration was reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Dose Normalized Pre-dose Observed Plasma Concentration (Cpre/Dose) of M4112</measure>
    <time_frame>Pre-dose on Days 8, 15 (Cycle 1) and Day 1 (Cycle 2) (Each Cycle is 28 days)</time_frame>
    <description>Dose normalized pre-dose observed plasma concentration (Cpre/dose) of M4112 was reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Slope of Concentration-QTc (cQTc) Regression of M4112</measure>
    <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
    <description>Time-matched, replicate ECGs and PK samples collected in the dose-escalation phase and planned to analyze QTC response using slope analysis of exposure/response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Number of Participants With Best Overall Response (BOR)</measure>
    <time_frame>From first dose of study drug administration until PD, assessed up to 15.4 months</time_frame>
    <description>BOR was determined according to Response Evaluation Criteria in Solid Tumors version1.1(RECIST 1.1).Best response obtained among all tumor assessment visits after the date of first study drug administration until documented disease progression. BOR rate is defined as the number of participants with BOR was either confirmed complete response (CR) partial response (PR), stable disease (SD) and progressive disease (PD) relative to the number of participants belonging to the study of interest. CR:Disappearance of all target lesions; PR:At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; PD:At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; SD:Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Duration of Response</measure>
    <time_frame>From first dose of study drug administration until PD, assessed up to 15.4 months</time_frame>
    <description>Duration of response defined as time from first documentation of objective response complete response (CR) or partial response (PR) whichever is first recorded) to date of first documentation of objective progression of disease or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of longest diameter (SLD) of all lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Disease Control Rate</measure>
    <time_frame>From first dose of study drug administration until PD, assessed up to 15.4 months</time_frame>
    <description>Disease control was defined as percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt; 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. Percentage of participants with disease control were reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Time to Tumor Response</measure>
    <time_frame>From first dose of study drug administration until PD, assessed up to 15.4 months</time_frame>
    <description>Tumor response was defined as the presence of at least 1 confirmed complete response (CR) or confirmed partial response (PR) as judged by RECIST version 1.1. CR was defined for target lesions (TLs) as the disappearance of all lesions, and for non-target lesions (NTLs) as the disappearance of all non-target non-measurable lesions and/or normalization of serum levels of tumor markers. PR was defined for TLs as at least a 30 percent (%) decrease from baseline (BL) in the sum of longest diameter (SLD) of TLs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1A Dose Escalation: Progression Free Survival Time (PFS)</measure>
    <time_frame>From first dose of study drug administration until PD, assessed up to 15.4 months</time_frame>
    <description>Progression free survival time defined as time from start date to the date of the first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates.</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Metastatic or Locally Advanced Unresectable Solid Tumors</condition>
  <arm_group>
    <arm_group_label>Part IA Dose Escalation: M4112 100 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part IA Dose Escalation: M4112 200 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part IA Dose Escalation: M4112 400 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part IA Dose Escalation: M4112 600 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part IA Dose Escalation: M4112 800 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>M4112</intervention_name>
    <description>All participants who received M4112 100,200,400,600 and 800 mg twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
    <arm_group_label>Part IA Dose Escalation: M4112 100 mg</arm_group_label>
    <arm_group_label>Part IA Dose Escalation: M4112 200 mg</arm_group_label>
    <arm_group_label>Part IA Dose Escalation: M4112 400 mg</arm_group_label>
    <arm_group_label>Part IA Dose Escalation: M4112 600 mg</arm_group_label>
    <arm_group_label>Part IA Dose Escalation: M4112 800 mg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects with histologically or cytologically proven advanced or metastatic solid&#xD;
             malignancies for whom no effective standard therapy exists or has failed or subjects&#xD;
             who are intolerant to established therapy known to provide clinical benefit for their&#xD;
             condition (dose escalation cohorts; Part I).&#xD;
&#xD;
          -  An eastern cooperative oncology group performance status (ECOG PS) of 0 to 1 at&#xD;
             screening and adequate hematological, renal and hepatic function as defined by&#xD;
             protocol specified criteria.&#xD;
&#xD;
          -  Other protocol defined inclusion criteria could apply.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Intolerance to immune checkpoint inhibitor therapy as defined by the occurrence of an&#xD;
             adverse drug reaction requiring drug discontinuation (dose escalation cohorts),&#xD;
             concurrent anticancer treatment or immunosuppressive agents.&#xD;
&#xD;
          -  Prior organ transplantation including allogeneic stem cell transplantation, brain&#xD;
             metastases (except those meeting certain protocol specified criteria which are&#xD;
             acceptable), significant acute or chronic infections, a history of&#xD;
             cardiovascular/cerebrovascular disease.&#xD;
&#xD;
          -  Current significant cardiac conduction abnormalities and hypokalemia as specified in&#xD;
             the protocol.&#xD;
&#xD;
          -  Warfarin or other Vitamin K antagonists treatment, strong inhibitors or inducers of&#xD;
             cytochrome P450 (CYP)3A4, and drugs with a narrow therapeutic index, which are&#xD;
             predominantly metabolized by CYP3A4 and drugs known to have a high risk to prolong QTc&#xD;
             as per label.&#xD;
&#xD;
          -  Pregnancy or lactation.&#xD;
&#xD;
          -  Severe hypersensitivity reactions to monoclonal antibodies, known hypersensitivity to&#xD;
             the investigational medicinal products or to one or more of the excipients, autoimmune&#xD;
             diseases (inflammatory bowel diseases, interstitial lung disease, or pulmonary&#xD;
             fibrosis), and live vaccines within 28 days prior to study entry.&#xD;
&#xD;
          -  Pneumonitis and history of pneumonitis.&#xD;
&#xD;
          -  Other protocol defined exclusion criteria could apply.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Medical Responsible</last_name>
    <role>Study Director</role>
    <affiliation>EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Yale Cancer Center</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of TX M.D. Anderson Cancer Center-Investigational Cancer Therapeutics Partner</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>South Texas Accelerated Research Therapeutics (START)</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>October 5, 2017</study_first_submitted>
  <study_first_submitted_qc>October 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 11, 2017</study_first_posted>
  <results_first_submitted>December 16, 2019</results_first_submitted>
  <results_first_submitted_qc>January 27, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">February 6, 2020</results_first_posted>
  <last_update_submitted>January 27, 2020</last_update_submitted>
  <last_update_submitted_qc>January 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 6, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>MS201408-0005A</keyword>
  <keyword>MS201408-0005B</keyword>
  <keyword>MS201408-0005C</keyword>
  <keyword>First-in-Human</keyword>
  <keyword>Advanced solid tumors</keyword>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 7, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/20/NCT03306420/SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>September 8, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/20/NCT03306420/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>First Participant First Visit: 03-Oct-2017 Last Participant Last Visit: 14-Jan-2019.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Part 1A Dose Escalation: M4112 100 mg</title>
          <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="P2">
          <title>Part 1A Dose Escalation: M4112 200 mg</title>
          <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="P3">
          <title>Part 1A Dose Escalation: M4112 400 mg</title>
          <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="P4">
          <title>Part 1A Dose Escalation: M4112 600 mg</title>
          <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="P5">
          <title>Part 1A Dose Escalation: M4112 800 mg</title>
          <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="3"/>
                <participants group_id="P5" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="3"/>
                <participants group_id="P5" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Part 1A Dose Escalation: M4112 100 mg</title>
          <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="B2">
          <title>Part 1A Dose Escalation: M4112 200 mg</title>
          <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="B3">
          <title>Part 1A Dose Escalation: M4112 400 mg</title>
          <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="B4">
          <title>Part 1A Dose Escalation: M4112 600 mg</title>
          <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="B5">
          <title>Part 1A Dose Escalation: M4112 800 mg</title>
          <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="B6">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="3"/>
            <count group_id="B4" value="3"/>
            <count group_id="B5" value="3"/>
            <count group_id="B6" value="15"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="60.7" spread="14.84"/>
                    <measurement group_id="B2" value="54.7" spread="8.33"/>
                    <measurement group_id="B3" value="43.0" spread="9.54"/>
                    <measurement group_id="B4" value="67.7" spread="7.51"/>
                    <measurement group_id="B5" value="62.3" spread="14.84"/>
                    <measurement group_id="B6" value="57.7" spread="13.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="3"/>
                    <measurement group_id="B6" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="3"/>
                    <measurement group_id="B6" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="2"/>
                    <measurement group_id="B6" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Part 1A Dose Escalation: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) as Per National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03</title>
        <description>DLTs was assessed as per NCI CTCAE v 4.03. DLT defined as any Grade greater than or equal (&gt;=) 3 nonhematological AE or Immune-related adverse event (irAE) assessed by Investigator or Sponsor during first Cycle (first 28 days) of study treatment. Asymptomatic Grade &gt;= 3 lipase or amylase elevation not associated with clinical manifestations of pancreatitis. Any TEAE observed in subsequent cycle. Any Grade 4 neutropenia of &gt;= 5 days duration, Grade &gt;= 3 febrile neutropenia, Grade 3 hemoglobin decrease despite blood transfusion or erythroid growth factor. Grade 4 hemoglobin decrease assessed as related to study drug. Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. Any Grade &gt;= 3 clinical signs and symptoms related to increased QTc.</description>
        <time_frame>Cycle 1 (Each Cycle is of 28 days)</time_frame>
        <population>DLT analysis set included all participants treated in dose escalation cohorts who do not miss greater than (&gt;) 5 planned total daily doses of M4112 in the first cycle (first 28 days) of the dose escalation part for other than DLT.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) as Per National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03</title>
          <description>DLTs was assessed as per NCI CTCAE v 4.03. DLT defined as any Grade greater than or equal (&gt;=) 3 nonhematological AE or Immune-related adverse event (irAE) assessed by Investigator or Sponsor during first Cycle (first 28 days) of study treatment. Asymptomatic Grade &gt;= 3 lipase or amylase elevation not associated with clinical manifestations of pancreatitis. Any TEAE observed in subsequent cycle. Any Grade 4 neutropenia of &gt;= 5 days duration, Grade &gt;= 3 febrile neutropenia, Grade 3 hemoglobin decrease despite blood transfusion or erythroid growth factor. Grade 4 hemoglobin decrease assessed as related to study drug. Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. Any Grade &gt;= 3 clinical signs and symptoms related to increased QTc.</description>
          <population>DLT analysis set included all participants treated in dose escalation cohorts who do not miss greater than (&gt;) 5 planned total daily doses of M4112 in the first cycle (first 28 days) of the dose escalation part for other than DLT.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part 1A Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Who Experienced a Treatment Related Adverse Events (TRAE) According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03</title>
        <description>An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment related AE was defined as having a &quot;Possible&quot; or &quot;Related&quot; relationship to study treatment, as assessed by the Investigator.</description>
        <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
        <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Who Experienced a Treatment Related Adverse Events (TRAE) According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03</title>
          <description>An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment related AE was defined as having a &quot;Possible&quot; or &quot;Related&quot; relationship to study treatment, as assessed by the Investigator.</description>
          <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Any TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="3"/>
                    <measurement group_id="O4" value="3"/>
                    <measurement group_id="O5" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Any Related TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="3"/>
                    <measurement group_id="O5" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters</title>
        <description>The laboratory measurements included hematology, biochemistry and hormonal tests. Number of participants with any clinically significant abnormalities in laboratory measurements were reported. Clinical significance was determined by the investigator.</description>
        <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
        <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters</title>
          <description>The laboratory measurements included hematology, biochemistry and hormonal tests. Number of participants with any clinically significant abnormalities in laboratory measurements were reported. Clinical significance was determined by the investigator.</description>
          <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Vital Signs</title>
        <description>Vital signs assessment included blood pressure, pulse rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.</description>
        <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
        <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Vital Signs</title>
          <description>Vital signs assessment included blood pressure, pulse rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.</description>
          <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part 1A Dose Escalation: Number of Participants With On-Treatment Shift in Eastern Cooperative Oncology Performance Status (ECOG PS) Score From 0 to 1</title>
        <description>ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 4, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Number of participants with on-treatment shift in ECOG PS Score from 0 to 1 were reported.</description>
        <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
        <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Number of Participants With On-Treatment Shift in Eastern Cooperative Oncology Performance Status (ECOG PS) Score From 0 to 1</title>
          <description>ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 4, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Number of participants with on-treatment shift in ECOG PS Score from 0 to 1 were reported.</description>
          <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part 1A Dose Escalation: Number of Participants With Clinically Significant Change From Baseline in Physical Examination Abnormalities</title>
        <description>A complete physical examination (including, general appearance, skin, pulmonary, cardiovascular, gastrointestinal, external genitourinary only as medically relevant, lymphatic, neurologic and musculoskeletal systems, head/neck, extremities, eyes, ears, nose, throat, and cognitive status) was performed. Number of participants with clinical significant change from baseline in physical examination abnormalities were reported. Clinical significance was determined by the investigator.</description>
        <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
        <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Number of Participants With Clinically Significant Change From Baseline in Physical Examination Abnormalities</title>
          <description>A complete physical examination (including, general appearance, skin, pulmonary, cardiovascular, gastrointestinal, external genitourinary only as medically relevant, lymphatic, neurologic and musculoskeletal systems, head/neck, extremities, eyes, ears, nose, throat, and cognitive status) was performed. Number of participants with clinical significant change from baseline in physical examination abnormalities were reported. Clinical significance was determined by the investigator.</description>
          <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post Dose AUC(0-8h) of M4112</title>
        <description>Area under the drug concentration-time curve from 0 to 8 h post dosing for M4112. AUC0-8 was calculated according to the mixed log-linear trapezoidal rule.</description>
        <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
        <population>Pharmacokinetic (PK) analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post Dose AUC(0-8h) of M4112</title>
          <description>Area under the drug concentration-time curve from 0 to 8 h post dosing for M4112. AUC0-8 was calculated according to the mixed log-linear trapezoidal rule.</description>
          <population>Pharmacokinetic (PK) analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
          <units>nanogram*hour per milliliter (ng*h/mL)</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3550" spread="14.4"/>
                    <measurement group_id="O2" value="8740" spread="13.6"/>
                    <measurement group_id="O3" value="27700" spread="21.4"/>
                    <measurement group_id="O4" value="50400" spread="7.7"/>
                    <measurement group_id="O5" value="14600" spread="85.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 1 Day 15</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4790" spread="25.4"/>
                    <measurement group_id="O2" value="7580" spread="11.5"/>
                    <measurement group_id="O3" value="31500" spread="28.8"/>
                    <measurement group_id="O4" value="59500" spread="12.7"/>
                    <measurement group_id="O5" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 93200 ng*h/mL.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of M4112</title>
        <description>Pharmacokinetic PK parameter Cmax was obtained directly from the plasma concentration versus time curve.</description>
        <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
        <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of M4112</title>
          <description>Pharmacokinetic PK parameter Cmax was obtained directly from the plasma concentration versus time curve.</description>
          <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
          <units>nanogram per milliliter (ng/mL)</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="806" spread="9.9"/>
                    <measurement group_id="O2" value="2110" spread="13.6"/>
                    <measurement group_id="O3" value="7670" spread="39.6"/>
                    <measurement group_id="O4" value="11700" spread="24.6"/>
                    <measurement group_id="O5" value="2770" spread="83.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 1 Day 15</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="975" spread="34.9"/>
                    <measurement group_id="O2" value="1720" spread="20.5"/>
                    <measurement group_id="O3" value="6560" spread="27.4"/>
                    <measurement group_id="O4" value="12100" spread="2.2"/>
                    <measurement group_id="O5" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 21100 ng/mL.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Time to Reach Maximum Plasma Concentration (Tmax) of M4112</title>
        <description>Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.</description>
        <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
        <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Time to Reach Maximum Plasma Concentration (Tmax) of M4112</title>
          <description>Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.</description>
          <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
          <units>Hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.08" lower_limit="1.08" upper_limit="2.12"/>
                    <measurement group_id="O2" value="2.10" lower_limit="2.07" upper_limit="3.08"/>
                    <measurement group_id="O3" value="1.08" lower_limit="1.07" upper_limit="1.08"/>
                    <measurement group_id="O4" value="1.00" lower_limit="0.97" upper_limit="1.07"/>
                    <measurement group_id="O5" value="2.08" lower_limit="2.07" upper_limit="4.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 1 Day 15</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.08" lower_limit="2.12" upper_limit="4.13"/>
                    <measurement group_id="O2" value="2.10" lower_limit="1.00" upper_limit="6.08"/>
                    <measurement group_id="O3" value="1.08" lower_limit="0.50" upper_limit="3.00"/>
                    <measurement group_id="O4" value="1.03" lower_limit="0.93" upper_limit="2.17"/>
                    <measurement group_id="O5" value="NA" lower_limit="2.00" upper_limit="2.00">Median was not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 2.00 hours.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (AUC0-8/Dose) of M4112</title>
        <description>Dose normalized was calculated as area under the plasma concentration-time curve from time zero to 8 h postdose divided by dose.</description>
        <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
        <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (AUC0-8/Dose) of M4112</title>
          <description>Dose normalized was calculated as area under the plasma concentration-time curve from time zero to 8 h postdose divided by dose.</description>
          <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
          <units>ng*h/mL/mg</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35.5" spread="14.4"/>
                    <measurement group_id="O2" value="43.7" spread="13.6"/>
                    <measurement group_id="O3" value="69.1" spread="21.4"/>
                    <measurement group_id="O4" value="84.0" spread="7.7"/>
                    <measurement group_id="O5" value="18.2" spread="85.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 1 Day 15</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47.9" spread="25.4"/>
                    <measurement group_id="O2" value="37.9" spread="11.5"/>
                    <measurement group_id="O3" value="78.8" spread="28.8"/>
                    <measurement group_id="O4" value="99.2" spread="12.7"/>
                    <measurement group_id="O5" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 116 ng*h/mL/mg.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4112</title>
        <description>Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose.</description>
        <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
        <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4112</title>
          <description>Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose.</description>
          <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
          <units>ng/mL/mg</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.06" spread="9.9"/>
                    <measurement group_id="O2" value="10.5" spread="13.6"/>
                    <measurement group_id="O3" value="19.2" spread="39.6"/>
                    <measurement group_id="O4" value="19.6" spread="24.6"/>
                    <measurement group_id="O5" value="3.47" spread="83.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 1 Day 15</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.75" spread="34.9"/>
                    <measurement group_id="O2" value="8.58" spread="20.5"/>
                    <measurement group_id="O3" value="16.4" spread="27.4"/>
                    <measurement group_id="O4" value="20.2" spread="2.2"/>
                    <measurement group_id="O5" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 26.4 ng/mL/mg.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (Racc[AUC0-8h]) of M4112</title>
        <description>Accumulation ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 hours After Administration (Racc[AUC0-8h]) of M4112 was reported. Racc(AUC0-8h) calculated as AUC0-8h, on Cycle 1 Day 15 divided by AUC0-8h on Cycle 1 Day 1.</description>
        <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
        <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;Number of Participants Analyzed&quot; signifies those participants who were evaluable for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (Racc[AUC0-8h]) of M4112</title>
          <description>Accumulation ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 hours After Administration (Racc[AUC0-8h]) of M4112 was reported. Racc(AUC0-8h) calculated as AUC0-8h, on Cycle 1 Day 15 divided by AUC0-8h on Cycle 1 Day 1.</description>
          <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;Number of Participants Analyzed&quot; signifies those participants who were evaluable for this outcome measure.</population>
          <units>Ratio</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.35" spread="11.4"/>
                    <measurement group_id="O2" value="0.868" spread="15.3"/>
                    <measurement group_id="O3" value="1.14" spread="50.1"/>
                    <measurement group_id="O4" value="1.18" spread="9.4"/>
                    <measurement group_id="O5" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 4.67.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part IA Dose Escalation: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4112</title>
        <description>Accumulation ratio for Cmax was calculated as Cmax, Cycle 1 Day 15 divided by Cmax, Cycle 1 Day 1.</description>
        <time_frame>Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)</time_frame>
        <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;Number of Participants Analyzed&quot; signifies those participants who were evaluable for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part IA Dose Escalation: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4112</title>
          <description>Accumulation ratio for Cmax was calculated as Cmax, Cycle 1 Day 15 divided by Cmax, Cycle 1 Day 1.</description>
          <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;Number of Participants Analyzed&quot; signifies those participants who were evaluable for this outcome measure.</population>
          <units>Ratio</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.21" spread="24.8"/>
                    <measurement group_id="O2" value="0.815" spread="7.0"/>
                    <measurement group_id="O3" value="0.856" spread="66.8"/>
                    <measurement group_id="O4" value="1.03" spread="23.0"/>
                    <measurement group_id="O5" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants Individual value was 5.26.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Pre-dose Observed Plasma Concentration (Cpre) of M4112</title>
        <description>Maximum pre-dose observed plasma concentration was reported.</description>
        <time_frame>Pre-dose on Days 8, 15 (Cycle 1) and Day 1 (Cycle 2) (Each Cycle is 28 days)</time_frame>
        <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Pre-dose Observed Plasma Concentration (Cpre) of M4112</title>
          <description>Maximum pre-dose observed plasma concentration was reported.</description>
          <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 Day 8</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="156" spread="58.2"/>
                    <measurement group_id="O2" value="96.5" spread="85.0"/>
                    <measurement group_id="O3" value="1240" spread="51.6"/>
                    <measurement group_id="O4" value="4410" spread="54.5"/>
                    <measurement group_id="O5" value="5200" spread="105.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 1 Day 15</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="221" spread="20.5"/>
                    <measurement group_id="O2" value="199" spread="53.9"/>
                    <measurement group_id="O3" value="1630" spread="45.7"/>
                    <measurement group_id="O4" value="3380" spread="42.4"/>
                    <measurement group_id="O5" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 9810 ng/mL.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 2 Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="2"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="2"/>
                    <count group_id="O5" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="128" spread="67.7"/>
                    <measurement group_id="O2" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual values were 83.3 and 85.2 ng/mL.</measurement>
                    <measurement group_id="O3" value="957" spread="72.1"/>
                    <measurement group_id="O4" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual values were 1910 and 2560 ng/mL.</measurement>
                    <measurement group_id="O5" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 8560 ng/mL.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Dose Normalized Pre-dose Observed Plasma Concentration (Cpre/Dose) of M4112</title>
        <description>Dose normalized pre-dose observed plasma concentration (Cpre/dose) of M4112 was reported.</description>
        <time_frame>Pre-dose on Days 8, 15 (Cycle 1) and Day 1 (Cycle 2) (Each Cycle is 28 days)</time_frame>
        <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Dose Normalized Pre-dose Observed Plasma Concentration (Cpre/Dose) of M4112</title>
          <description>Dose normalized pre-dose observed plasma concentration (Cpre/dose) of M4112 was reported.</description>
          <population>PK analysis set included all participants who received M4112 and for whom at least 1 dose of M4112 and must have sufficient M4112 plasma concentration data to enable the calculation of at least 1 PK parameter. Here &quot;number analyzed&quot; signifies those participants who were evaluable for this outcome measure at given time points.</population>
          <units>ng/mL/mg</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 Day 8</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.56" spread="58.2"/>
                    <measurement group_id="O2" value="0.482" spread="85.0"/>
                    <measurement group_id="O3" value="3.11" spread="51.6"/>
                    <measurement group_id="O4" value="7.35" spread="54.5"/>
                    <measurement group_id="O5" value="6.50" spread="105.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 1 Day 15</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="3"/>
                    <count group_id="O5" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.21" spread="20.5"/>
                    <measurement group_id="O2" value="0.997" spread="53.9"/>
                    <measurement group_id="O3" value="4.08" spread="45.7"/>
                    <measurement group_id="O4" value="5.63" spread="42.4"/>
                    <measurement group_id="O5" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 12.3 ng/mL/mg.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 2 Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="2"/>
                    <count group_id="O3" value="3"/>
                    <count group_id="O4" value="2"/>
                    <count group_id="O5" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.28" spread="67.7"/>
                    <measurement group_id="O2" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual values were 0.417 and 0.426 ng/mL/mg.</measurement>
                    <measurement group_id="O3" value="2.39" spread="72.1"/>
                    <measurement group_id="O4" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual values were 3.18 and 4.27 ng/mL/mg.</measurement>
                    <measurement group_id="O5" value="NA" spread="NA">Geometric Mean and Geometric Coefficient of Variation were not calculated as it was pre-specified not to calculate the Descriptive statistics if less than 3 number of participants. Individual value was 10.7 ng/mL/mg.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Slope of Concentration-QTc (cQTc) Regression of M4112</title>
        <description>Time-matched, replicate ECGs and PK samples collected in the dose-escalation phase and planned to analyze QTC response using slope analysis of exposure/response.</description>
        <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
        <population>Data was not collected as the study was prematurely terminated due to lackluster pharmacodynamic data.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Slope of Concentration-QTc (cQTc) Regression of M4112</title>
          <description>Time-matched, replicate ECGs and PK samples collected in the dose-escalation phase and planned to analyze QTC response using slope analysis of exposure/response.</description>
          <population>Data was not collected as the study was prematurely terminated due to lackluster pharmacodynamic data.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Number of Participants With Best Overall Response (BOR)</title>
        <description>BOR was determined according to Response Evaluation Criteria in Solid Tumors version1.1(RECIST 1.1).Best response obtained among all tumor assessment visits after the date of first study drug administration until documented disease progression. BOR rate is defined as the number of participants with BOR was either confirmed complete response (CR) partial response (PR), stable disease (SD) and progressive disease (PD) relative to the number of participants belonging to the study of interest. CR:Disappearance of all target lesions; PR:At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; PD:At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; SD:Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.</description>
        <time_frame>From first dose of study drug administration until PD, assessed up to 15.4 months</time_frame>
        <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment. Here &quot;Number of participants analyzed&quot; signifies those participants who were evaluable for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Number of Participants With Best Overall Response (BOR)</title>
          <description>BOR was determined according to Response Evaluation Criteria in Solid Tumors version1.1(RECIST 1.1).Best response obtained among all tumor assessment visits after the date of first study drug administration until documented disease progression. BOR rate is defined as the number of participants with BOR was either confirmed complete response (CR) partial response (PR), stable disease (SD) and progressive disease (PD) relative to the number of participants belonging to the study of interest. CR:Disappearance of all target lesions; PR:At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; PD:At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; SD:Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.</description>
          <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment. Here &quot;Number of participants analyzed&quot; signifies those participants who were evaluable for this outcome measure.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stable Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="3"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Progressive Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Duration of Response</title>
        <description>Duration of response defined as time from first documentation of objective response complete response (CR) or partial response (PR) whichever is first recorded) to date of first documentation of objective progression of disease or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of longest diameter (SLD) of all lesions.</description>
        <time_frame>From first dose of study drug administration until PD, assessed up to 15.4 months</time_frame>
        <population>Data was not collected as the study was prematurely terminated due to lackluster pharmacodynamic data.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Duration of Response</title>
          <description>Duration of response defined as time from first documentation of objective response complete response (CR) or partial response (PR) whichever is first recorded) to date of first documentation of objective progression of disease or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of longest diameter (SLD) of all lesions.</description>
          <population>Data was not collected as the study was prematurely terminated due to lackluster pharmacodynamic data.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Disease Control Rate</title>
        <description>Disease control was defined as percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt; 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. Percentage of participants with disease control were reported.</description>
        <time_frame>From first dose of study drug administration until PD, assessed up to 15.4 months</time_frame>
        <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Disease Control Rate</title>
          <description>Disease control was defined as percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt; 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. Percentage of participants with disease control were reported.</description>
          <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
          <units>Percentage of Participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="66.7" lower_limit="9.4" upper_limit="99.2"/>
                    <measurement group_id="O2" value="100" lower_limit="29.2" upper_limit="100.0"/>
                    <measurement group_id="O3" value="100" lower_limit="29.2" upper_limit="100.0"/>
                    <measurement group_id="O4" value="33.3" lower_limit="0.8" upper_limit="90.6"/>
                    <measurement group_id="O5" value="0.0" lower_limit="0.0" upper_limit="70.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Time to Tumor Response</title>
        <description>Tumor response was defined as the presence of at least 1 confirmed complete response (CR) or confirmed partial response (PR) as judged by RECIST version 1.1. CR was defined for target lesions (TLs) as the disappearance of all lesions, and for non-target lesions (NTLs) as the disappearance of all non-target non-measurable lesions and/or normalization of serum levels of tumor markers. PR was defined for TLs as at least a 30 percent (%) decrease from baseline (BL) in the sum of longest diameter (SLD) of TLs.</description>
        <time_frame>From first dose of study drug administration until PD, assessed up to 15.4 months</time_frame>
        <population>Data was not collected as the study was prematurely terminated due to lackluster pharmacodynamic data.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Time to Tumor Response</title>
          <description>Tumor response was defined as the presence of at least 1 confirmed complete response (CR) or confirmed partial response (PR) as judged by RECIST version 1.1. CR was defined for target lesions (TLs) as the disappearance of all lesions, and for non-target lesions (NTLs) as the disappearance of all non-target non-measurable lesions and/or normalization of serum levels of tumor markers. PR was defined for TLs as at least a 30 percent (%) decrease from baseline (BL) in the sum of longest diameter (SLD) of TLs.</description>
          <population>Data was not collected as the study was prematurely terminated due to lackluster pharmacodynamic data.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1A Dose Escalation: Progression Free Survival Time (PFS)</title>
        <description>Progression free survival time defined as time from start date to the date of the first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates.</description>
        <time_frame>From first dose of study drug administration until PD, assessed up to 15.4 months</time_frame>
        <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1A Dose Escalation: M4112 100 mg</title>
            <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O2">
            <title>Part 1A Dose Escalation: M4112 200 mg</title>
            <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O3">
            <title>Part 1A Dose Escalation: M4112 400 mg</title>
            <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O4">
            <title>Part 1A Dose Escalation: M4112 600 mg</title>
            <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
          <group group_id="O5">
            <title>Part 1A Dose Escalation: M4112 800 mg</title>
            <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1A Dose Escalation: Progression Free Survival Time (PFS)</title>
          <description>Progression free survival time defined as time from start date to the date of the first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates.</description>
          <population>The safety analysis set included all participants who had received at least 1 dose of the study treatment.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.7" lower_limit="1.9" upper_limit="8.1"/>
                    <measurement group_id="O2" value="5.5" lower_limit="3.9" upper_limit="5.5"/>
                    <measurement group_id="O3" value="NA" lower_limit="2.1" upper_limit="10.2">The Median was not reached due to higher number (&gt;50%) of censored participants.</measurement>
                    <measurement group_id="O4" value="1.8" lower_limit="1.1" upper_limit="3.7"/>
                    <measurement group_id="O5" value="1.2" lower_limit="0.0" upper_limit="1.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Baseline up to safety follow-up visit, assessed up to 15.4 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Part 1A Dose Escalation: M4112 100 mg</title>
          <description>Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="E2">
          <title>Part 1A Dose Escalation: M4112 200 mg</title>
          <description>Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="E3">
          <title>Part 1A Dose Escalation: M4112 400 mg</title>
          <description>Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="E4">
          <title>Part 1A Dose Escalation: M4112 600 mg</title>
          <description>Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
        <group group_id="E5">
          <title>Part 1A Dose Escalation: M4112 800 mg</title>
          <description>Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA version 21.1</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermatitis allergic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA version 21.1</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Anaemia of malignant disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Ileus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Amylase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Blood creatine phosphokinase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Blood urea increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Electrocardiogram QT prolonged</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Red blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Weight increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypercalcaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hyperphosphataemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Tumour pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysaesthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Azotaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Urinary tract obstruction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Urinary tract pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dry throat</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Pharyngeal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Rhinitis allergic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysaesthesia syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Rash erythematous</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Rash generalised</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hot flush</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Part IB and Part IC for this study were never initiated as the study was terminated early due to lackluster pharmacodynamic data that showed no significant reduction of plasma kynurenine at steady state at a range of tested dose levels of M4112.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Communication Center</name_or_title>
      <organization>Merck KGaA, Darmstadt, Germany</organization>
      <phone>+49-6151-72-5200</phone>
      <email>service@emdgroup.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03306420
org study id: MS201408-0005
nct id: NCT03306420
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This is a Phase I, open-label study to determine the safety, tolerability, pharmacokinetic
      (PK), pharmacodynamics (PD), and preliminary antitumor activity of MS201408-0005A as single
      agent (Part IA only) and in combination with MS201408-0005C or MS201408-0005B (Part IB, Part
      IC).
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Part 1A Dose Escalation: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) as Per National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03
time frame: Cycle 1 (Each Cycle is of 28 days)
description: DLTs was assessed as per NCI CTCAE v 4.03. DLT defined as any Grade greater than or equal (>=) 3 nonhematological AE or Immune-related adverse event (irAE) assessed by Investigator or Sponsor during first Cycle (first 28 days) of study treatment. Asymptomatic Grade >= 3 lipase or amylase elevation not associated with clinical manifestations of pancreatitis. Any TEAE observed in subsequent cycle. Any Grade 4 neutropenia of >= 5 days duration, Grade >= 3 febrile neutropenia, Grade 3 hemoglobin decrease despite blood transfusion or erythroid growth factor. Grade 4 hemoglobin decrease assessed as related to study drug. Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. Any Grade >= 3 clinical signs and symptoms related to increased QTc.
measure: Part 1A Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Who Experienced a Treatment Related Adverse Events (TRAE) According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03
time frame: Baseline up to safety follow-up visit, assessed up to 15.4 months
description: An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment related AE was defined as having a "Possible" or "Related" relationship to study treatment, as assessed by the Investigator.
measure: Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
time frame: Baseline up to safety follow-up visit, assessed up to 15.4 months
description: The laboratory measurements included hematology, biochemistry and hormonal tests. Number of participants with any clinically significant abnormalities in laboratory measurements were reported. Clinical significance was determined by the investigator.
measure: Part 1A Dose Escalation: Number of Participants With Clinically Significant Abnormalities in Vital Signs
time frame: Baseline up to safety follow-up visit, assessed up to 15.4 months
description: Vital signs assessment included blood pressure, pulse rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.
measure: Part 1A Dose Escalation: Number of Participants With On-Treatment Shift in Eastern Cooperative Oncology Performance Status (ECOG PS) Score From 0 to 1
time frame: Baseline up to safety follow-up visit, assessed up to 15.4 months
description: ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 4, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Number of participants with on-treatment shift in ECOG PS Score from 0 to 1 were reported.
measure: Part 1A Dose Escalation: Number of Participants With Clinically Significant Change From Baseline in Physical Examination Abnormalities
time frame: Baseline up to safety follow-up visit, assessed up to 15.4 months
description: A complete physical examination (including, general appearance, skin, pulmonary, cardiovascular, gastrointestinal, external genitourinary only as medically relevant, lymphatic, neurologic and musculoskeletal systems, head/neck, extremities, eyes, ears, nose, throat, and cognitive status) was performed. Number of participants with clinical significant change from baseline in physical examination abnormalities were reported. Clinical significance was determined by the investigator.
measure: Part 1A Dose Escalation: Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post Dose AUC(0-8h) of M4112
time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
description: Area under the drug concentration-time curve from 0 to 8 h post dosing for M4112. AUC0-8 was calculated according to the mixed log-linear trapezoidal rule.
measure: Part 1A Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of M4112
time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
description: Pharmacokinetic PK parameter Cmax was obtained directly from the plasma concentration versus time curve.
measure: Part 1A Dose Escalation: Time to Reach Maximum Plasma Concentration (Tmax) of M4112
time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
description: Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
measure: Part 1A Dose Escalation: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (AUC0-8/Dose) of M4112
time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
description: Dose normalized was calculated as area under the plasma concentration-time curve from time zero to 8 h postdose divided by dose.
measure: Part 1A Dose Escalation: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4112
time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
description: Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose.
measure: Part 1A Dose Escalation: Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hour Post-dose (Racc[AUC0-8h]) of M4112
time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
description: Accumulation ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to 8 hours After Administration (Racc[AUC0-8h]) of M4112 was reported. Racc(AUC0-8h) calculated as AUC0-8h, on Cycle 1 Day 15 divided by AUC0-8h on Cycle 1 Day 1.
measure: Part IA Dose Escalation: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4112
time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 h post-dose on Day 1 and 15 of Cycle 1 (Each Cycle is for 28 days)
description: Accumulation ratio for Cmax was calculated as Cmax, Cycle 1 Day 15 divided by Cmax, Cycle 1 Day 1.
measure: Part 1A Dose Escalation: Pre-dose Observed Plasma Concentration (Cpre) of M4112
time frame: Pre-dose on Days 8, 15 (Cycle 1) and Day 1 (Cycle 2) (Each Cycle is 28 days)
description: Maximum pre-dose observed plasma concentration was reported.
measure: Part 1A Dose Escalation: Dose Normalized Pre-dose Observed Plasma Concentration (Cpre/Dose) of M4112
time frame: Pre-dose on Days 8, 15 (Cycle 1) and Day 1 (Cycle 2) (Each Cycle is 28 days)
description: Dose normalized pre-dose observed plasma concentration (Cpre/dose) of M4112 was reported.
measure: Part 1A Dose Escalation: Slope of Concentration-QTc (cQTc) Regression of M4112
time frame: Baseline up to safety follow-up visit, assessed up to 15.4 months
description: Time-matched, replicate ECGs and PK samples collected in the dose-escalation phase and planned to analyze QTC response using slope analysis of exposure/response.
measure: Part 1A Dose Escalation: Number of Participants With Best Overall Response (BOR)
time frame: From first dose of study drug administration until PD, assessed up to 15.4 months
description: BOR was determined according to Response Evaluation Criteria in Solid Tumors version1.1(RECIST 1.1).Best response obtained among all tumor assessment visits after the date of first study drug administration until documented disease progression. BOR rate is defined as the number of participants with BOR was either confirmed complete response (CR) partial response (PR), stable disease (SD) and progressive disease (PD) relative to the number of participants belonging to the study of interest. CR:Disappearance of all target lesions; PR:At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; PD:At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; SD:Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
measure: Part 1A Dose Escalation: Duration of Response
time frame: From first dose of study drug administration until PD, assessed up to 15.4 months
description: Duration of response defined as time from first documentation of objective response complete response (CR) or partial response (PR) whichever is first recorded) to date of first documentation of objective progression of disease or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of longest diameter (SLD) of all lesions.
measure: Part 1A Dose Escalation: Disease Control Rate
time frame: From first dose of study drug administration until PD, assessed up to 15.4 months
description: Disease control was defined as percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. Percentage of participants with disease control were reported.
measure: Part 1A Dose Escalation: Time to Tumor Response
time frame: From first dose of study drug administration until PD, assessed up to 15.4 months
description: Tumor response was defined as the presence of at least 1 confirmed complete response (CR) or confirmed partial response (PR) as judged by RECIST version 1.1. CR was defined for target lesions (TLs) as the disappearance of all lesions, and for non-target lesions (NTLs) as the disappearance of all non-target non-measurable lesions and/or normalization of serum levels of tumor markers. PR was defined for TLs as at least a 30 percent (%) decrease from baseline (BL) in the sum of longest diameter (SLD) of TLs.
measure: Part 1A Dose Escalation: Progression Free Survival Time (PFS)
time frame: From first dose of study drug administration until PD, assessed up to 15.4 months
description: Progression free survival time defined as time from start date to the date of the first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates.
arm group label: Part IA Dose Escalation: M4112 100 mg
arm group type: Experimental
description: Participants received an oral dose of 100 milligrams (mg) M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
arm group label: Part IA Dose Escalation: M4112 200 mg
arm group type: Experimental
description: Participants received an oral dose of 200 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
arm group label: Part IA Dose Escalation: M4112 400 mg
arm group type: Experimental
description: Participants received an oral dose of 400 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
arm group label: Part IA Dose Escalation: M4112 600 mg
arm group type: Experimental
description: Participants received an oral dose of 600 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
arm group label: Part IA Dose Escalation: M4112 800 mg
arm group type: Experimental
description: Participants received an oral dose of 800 mg M4112 twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
intervention type: Drug
intervention name: M4112
description: All participants who received M4112 100,200,400,600 and 800 mg twice daily in 28-day cycles, starting from Day 1 of each cycle until confirmed disease progression or unacceptable toxicity (up to 15 Months).
arm group label: Part IA Dose Escalation: M4112 100 mg
arm group label: Part IA Dose Escalation: M4112 200 mg
arm group label: Part IA Dose Escalation: M4112 400 mg
arm group label: Part IA Dose Escalation: M4112 600 mg
arm group label: Part IA Dose Escalation: M4112 800 mg
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Medical Responsible
role: Study Director
affiliation: EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Part IB and Part IC for this study were never initiated as the study was terminated early due to lackluster pharmacodynamic data that showed no significant reduction of plasma kynurenine at steady state at a range of tested dose levels of M4112.
point of contact: 