<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/NCT02189174</url>
  </required_header>
  <id_info>
    <org_study_id>CCLR457X2101</org_study_id>
    <nct_id>NCT02189174</nct_id>
  </id_info>
  <brief_title>Study of CLR457 Administered Orally in Adult Patients With Advanced Solid Malignancies</brief_title>
  <official_title>A Phase I/II Multicenter, Open-label Study of CLR457, Administered Orally in Adult Patients With Advanced Solid Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To estimate the maximum tolerated dose (MTD) or recommended dose for phase II (RP2D) of&#xD;
      CLR457 and to investigate the anti-tumor activity of CLR457&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Novartis decided to terminate the study considering safety and tolerability concerns and&#xD;
    limited clinical activity with CLR457 study drug administered once daily (qd).&#xD;
  </why_stopped>
  <start_date type="Actual">August 7, 2014</start_date>
  <completion_date type="Actual">November 12, 2015</completion_date>
  <primary_completion_date type="Actual">November 12, 2015</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Phase ll part of the study was not conducted as Novartis decided to terminate the study considering safety and tolerability concerns and limited clinical activity.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of DLT</measure>
    <time_frame>First 28 days of dosing</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective response rate (ORR) as per RECIST v1.1</measure>
    <time_frame>Baseline, every 8 weeks until discontinuation for an expected average of 4 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Adverse Events (AEs) and Serious Advers Events (SAEs)</measure>
    <time_frame>Continously throughout the study until 30 days after treatment discontinuation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of AEs and SAEs and dose reductions and interruptions</measure>
    <time_frame>Continously throughout the study until 30 days after treatment discontinuation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR)</measure>
    <time_frame>Baseline, every 8 weeks until discontinuation for an expected average of 4 months</time_frame>
    <description>per RECIST v1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>Baseline, every 8 weeks until discontinuation for an expected average of 4 months</time_frame>
    <description>per RECIST v1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Best overall response (BOR)</measure>
    <time_frame>Baseline and every 8 weeks for an expected average of 4 months</time_frame>
    <description>per RECIST v1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration and Pharmacokinetics (PK) parameters of CLR457</measure>
    <time_frame>During phase I: Baseline; Cycle 1 (C1) Day 1 (D1), 2, 8, 15, 16 and 22; Cycle 2 Day 1, 2, from Cycle 3 to cycle 6 on Day 1 During Phase II: Baseline; Cycle 1 Day 1, 2, 8, 15, 16 and 22</time_frame>
    <description>Parameters including but not limited to Cmax, Cmin, AUCinf, AUCtlast, AUCtau and T1/2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline in glucose metabolism markers (fasting glucose and insulin)</measure>
    <time_frame>For Phase I and II C1D1, C1D2, C1D15, C1D16 and for Phase I only C2D1 and C2D2</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pre- and post- treatment immunohistochemistry of PI3K pathway molecules in newly obtained paired tumor samples</measure>
    <time_frame>Baseline, C2D1</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">31</enrollment>
  <condition>Advanced Solid Tumor</condition>
  <arm_group>
    <arm_group_label>CLR457</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CLR457</intervention_name>
    <arm_group_label>CLR457</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent must be obtained prior to any screening procedures&#xD;
&#xD;
          -  Phase I: Patients with advanced/metastatic solid tumors, with measurable or&#xD;
             non-measurable disease as determined by modified RECIST version 1.1 who have&#xD;
             progressed despite standard therapy or be intolerant of standard therapy, or for whom&#xD;
             no standard therapy exists, who have tumors harboring one of the following: confirmed&#xD;
             PIK3CA mutation or amplification, PTEN loss of function, EGFR mutation, cMET&#xD;
             activation and/or HER2 overexpression. Endometrial carcinoma will not be selected for&#xD;
             any molecular status.&#xD;
&#xD;
          -  Phase II: Patients with advanced/metastatic solid tumors, with at least one measurable&#xD;
             lesion as determined by modified RECIST version 1.1, who progressed despite standard&#xD;
             therapy or be intolerant of standard therapy, or for whom no standard therapy exists,&#xD;
             fitting in one of the following groups: Group 1: patients with PIK3CA mutated or&#xD;
             amplified ER positive (ER+) breast cancer ; Group 2: patients with endometrial&#xD;
             carcinoma (not selected for any molecular status); Group 3: patients with solid tumors&#xD;
             (with the exception of PIK3CA mutant/amplified ER+ breast cancer and endometrial&#xD;
             carcinoma) harboring PIK3CA mutation or amplification/any PTEN status; Group 4:&#xD;
             patients with solid tumors (with the exception of endometrial carcinoma) harboring&#xD;
             PTEN loss of function/ PIK3CA wild type; Group 5: non-small cell lung cancer harboring&#xD;
             cMET activation and/or EGFR mutation. Up to 3 lines of chemotherapy allowed in&#xD;
             advanced/metastatic setting.&#xD;
&#xD;
          -  ECOG Performance Status ≤ 2.&#xD;
&#xD;
          -  Availability of a representative formalin fixed paraffin embedded tumor tissue sample.&#xD;
             If archival tumor sample is not available, a newly obtained tumor sample needs to be&#xD;
             submitted instead.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Brain metastasis unless treated and neurologically stable&#xD;
&#xD;
          -  Patient having out of range laboratory values defined as:&#xD;
&#xD;
        Hepatic and renal function:&#xD;
&#xD;
          -  Serum total Bilirubin ≥ 1.5 x ULN (upper limit of normal) or aspartate&#xD;
             aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2.5 x ULN&#xD;
&#xD;
          -  For patients with tumor involvement of the liver AST or ALT &gt; 5 x ULN&#xD;
&#xD;
          -  For patients with Gilbert's syndrome total bilirubin &gt; 2.5 x ULN&#xD;
&#xD;
          -  Serum creatinine &gt; 1.5 x ULN and/or measured or calculated creatinine clearance &lt; 75%&#xD;
             LLN (lower limit of normal)&#xD;
&#xD;
        Bone marrow function:&#xD;
&#xD;
          -  Platelets &lt; 100 x 109/L&#xD;
&#xD;
          -  Hemoglobin (Hgb) &lt; 9 g/dL&#xD;
&#xD;
          -  Absolute Neutrophil Count (ANC) &lt; 1.5 x 109/L&#xD;
&#xD;
        Cardiac function:&#xD;
&#xD;
          -  Clinically significant and/or uncontrolled heart disease such as congestive heart&#xD;
             failure (CHF) requiring treatment (NYH grade ≥2), hypertension or arrhythmia&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF) &lt; 45% as determined by MUGA scan or ECHO&#xD;
&#xD;
          -  QTcF &gt;480 msec on screening ECG or congenital long QT syndrome&#xD;
&#xD;
          -  Acute myocardial infarction (AMI) or unstable angina pectoris &lt; 3 months prior to&#xD;
             study entry&#xD;
&#xD;
               -  Peripheral neuropathy CTCAE Grade ≥2&#xD;
&#xD;
               -  History of pancreatitis of any grade&#xD;
&#xD;
               -  Patients with diabetes mellitus requiring insulin treatment and/or with clinical&#xD;
                  signs or with Fasting Plasma Glucose (FPG) ≥ 140 mg/dL / 7.8 mmol/L&#xD;
&#xD;
               -  Patients receiving treatment with medications that are known to be 1) strong&#xD;
                  inhibitors or inducers of CYP3A4/5; 2) CYP2C9 substrate with narrow therapeutic&#xD;
                  index; 3) QT prolonging agents; 4) proton pump inhibitors unless these&#xD;
                  medications can be discontinued at least a week prior to start of treatment.&#xD;
&#xD;
        Other protocol-defined inclusion/exclusion criteria may 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>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital SC-9</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering SC-4</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10017</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tennessee Oncology SC</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1X6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Kashiwa</city>
        <state>Chiba</state>
        <zip>277 8577</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Singapore</city>
        <zip>169610</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Barcelona</city>
        <state>Catalunya</state>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>Japan</country>
    <country>Singapore</country>
    <country>Spain</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Australia</country>
    <country>Austria</country>
    <country>France</country>
    <country>Hong Kong</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Switzerland</country>
  </removed_countries>
  <verification_date>December 2021</verification_date>
  <study_first_submitted>July 7, 2014</study_first_submitted>
  <study_first_submitted_qc>July 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 14, 2014</study_first_posted>
  <last_update_submitted>December 2, 2021</last_update_submitted>
  <last_update_submitted_qc>December 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Solid tumor,</keyword>
  <keyword>breast cancer,</keyword>
  <keyword>lung cancer,</keyword>
  <keyword>endometrial cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02189174
org study id: CCLR457X2101
nct id: NCT02189174
lead sponsor: 
has dmc: No
To estimate the maximum tolerated dose (MTD) or recommended dose for phase II (RP2D) of
      CLR457 and to investigate the anti-tumor activity of CLR457
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Phase ll part of the study was not conducted as Novartis decided to terminate the study considering safety and tolerability concerns and limited clinical activity.
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of DLT
time frame: First 28 days of dosing
measure: Objective response rate (ORR) as per RECIST v1.1
time frame: Baseline, every 8 weeks until discontinuation for an expected average of 4 months
measure: Incidence of Adverse Events (AEs) and Serious Advers Events (SAEs)
time frame: Continously throughout the study until 30 days after treatment discontinuation
measure: Severity of AEs and SAEs and dose reductions and interruptions
time frame: Continously throughout the study until 30 days after treatment discontinuation
measure: Duration of response (DOR)
time frame: Baseline, every 8 weeks until discontinuation for an expected average of 4 months
description: per RECIST v1.1
measure: Progression free survival (PFS)
time frame: Baseline, every 8 weeks until discontinuation for an expected average of 4 months
description: per RECIST v1.1
measure: Best overall response (BOR)
time frame: Baseline and every 8 weeks for an expected average of 4 months
description: per RECIST v1.1
measure: Plasma concentration and Pharmacokinetics (PK) parameters of CLR457
time frame: During phase I: Baseline; Cycle 1 (C1) Day 1 (D1), 2, 8, 15, 16 and 22; Cycle 2 Day 1, 2, from Cycle 3 to cycle 6 on Day 1 During Phase II: Baseline; Cycle 1 Day 1, 2, 8, 15, 16 and 22
description: Parameters including but not limited to Cmax, Cmin, AUCinf, AUCtlast, AUCtau and T1/2
measure: Changes from baseline in glucose metabolism markers (fasting glucose and insulin)
time frame: For Phase I and II C1D1, C1D2, C1D15, C1D16 and for Phase I only C2D1 and C2D2
measure: Pre- and post- treatment immunohistochemistry of PI3K pathway molecules in newly obtained paired tumor samples
time frame: Baseline, C2D1
arm group label: CLR457
arm group type: Experimental
intervention type: Drug
intervention name: CLR457
arm group label: CLR457
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
country: Japan
country: Singapore
country: Spain
country: United States
country: Australia
country: Austria
country: France
country: Hong Kong
country: Israel
country: Italy
country: Switzerland
responsible party type: Sponsor
mesh term: Neoplasms