<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/NCT03036228</url>
  </required_header>
  <id_info>
    <org_study_id>MASTIFF</org_study_id>
    <nct_id>NCT03036228</nct_id>
  </id_info>
  <brief_title>MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class</brief_title>
  <acronym>MASTIFF</acronym>
  <official_title>MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Thomas Helleday Foundation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Thomas Helleday Foundation</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary Objective&#xD;
&#xD;
      • To determine the safety and tolerability of Karonudib (TH1579) in escalating doses for the&#xD;
      treatment of patients with advanced solid malignant tumours.&#xD;
&#xD;
      Secondary Objective&#xD;
&#xD;
        -  To define DLT and MTD.&#xD;
&#xD;
        -  To determine a recommended phase 2 dose (RP2D) and schedule.&#xD;
&#xD;
        -  To determine the pharmacokinetics of Karonudib.&#xD;
&#xD;
        -  To determine preliminary signs of clinical efficacy of Karonudib.&#xD;
&#xD;
        -  To determine overall survival.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 14, 2017</start_date>
  <completion_date type="Anticipated">June 30, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2021</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>Sequential Assignment</intervention_model>
    <intervention_model_description>13 different dose cohorts with escalating doses are planned.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety and tolerability of Karonudib (TH1579) will be evaluated.</measure>
    <time_frame>28 days, first treatment cycle for the patient.</time_frame>
    <description>Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD). DLTs will be assessed during first cycle of therapy, week 1-4 based on Haematological toxicity and Non-haematological toxicity.&#xD;
MTD: The highest dose of Karonudib that does not cause unacceptable side effects is defined as the MTD.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To determine the pharmacokinetics of Karonudib.</measure>
    <time_frame>28 days, first treatment cycle for the patient</time_frame>
    <description>Peak Plasma Concentration, Cmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To determine the pharmacokinetics of Karonudib.</measure>
    <time_frame>28 days, first treatment cycle for the patient</time_frame>
    <description>Tmax, time is the time to reach Cmax (Peak Plasma Concentration)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To determine the pharmacokinetics of Karonudib.</measure>
    <time_frame>28 days, first treatment cycle for the patient</time_frame>
    <description>biological half-life (plasma T1/2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To determine the pharmacokinetics of Karonudib.</measure>
    <time_frame>28 days, first treatment cycle for the patient</time_frame>
    <description>Area under the Curve (AUC)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To determine preliminary signs of clinical efficacy of Karonudib.</measure>
    <time_frame>54 days, two treatment cycles for the patient</time_frame>
    <description>RECIST 1.1</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">35</enrollment>
  <condition>Cancer</condition>
  <arm_group>
    <arm_group_label>Dose escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Karonudib is an oral inhibitor of MTH1 and will be supplied as an oral solution or tablets to be taken BID. Each cycle is defined as 28 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Karonudib</intervention_name>
    <description>Dose escalation of administration with Karonudib.</description>
    <arm_group_label>Dose escalation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent.&#xD;
&#xD;
          2. Age at least 18 years (there is no upper age limit but patients must be judged to have&#xD;
             a &quot;biologic&quot; age of 75 years or less).&#xD;
&#xD;
          3. Histological or cytological confirmation of cancer (imaging/AFP are sufficient for&#xD;
             patients with HCC according to international standards).&#xD;
&#xD;
          4. The patient has received standard of care treatments and has progressive disease with&#xD;
             only experimental therapies as further treatment options.&#xD;
&#xD;
          5. Life expectancy of at least 12 weeks (as per investigators clinical assessment).&#xD;
&#xD;
          6. ECOG PFS 0 or 1.&#xD;
&#xD;
          7. Patients must have measurable disease based on RECIST 1.1 criteria or evaluable&#xD;
             metastatic disease.&#xD;
&#xD;
          8. Adequate bone marrow, hepatic and renal function defined as:&#xD;
&#xD;
               1. Haemoglobin ≥ 95 g/L (blood transfusion not less than 21 days prior to&#xD;
                  screening).&#xD;
&#xD;
               2. Absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥100 x 109/L.&#xD;
&#xD;
               3. Total bilirubin &lt; 1.5 x ULN (does not apply to patients with Gilberts Syndrome).&#xD;
&#xD;
               4. AST and ALT ≤ 1.5 x ULN (or ≤ 3 x ULN in the presence of liver metastases).&#xD;
&#xD;
               5. Serum creatinine not over ≤ ULN (if serum creatinine is between 1 and 1.5 x ULN,&#xD;
                  patients may be eligible provided that the calculated GFR is at least 50 ml/min&#xD;
                  using Cockcroft-Gault method).&#xD;
&#xD;
               6. Albumin greater than or equal to 23 g/L.&#xD;
&#xD;
          9. Subject must be able to take oral medication.&#xD;
&#xD;
         10. Negative pregnancy test according to CTFG guidance 2014 for females of child-producing&#xD;
             potential.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age less than 18 years.&#xD;
&#xD;
          2. Less than 4 weeks since stopping previous systemic cancer treatment.&#xD;
&#xD;
          3. Less than 3 weeks since stopping palliative radiotherapy.&#xD;
&#xD;
          4. Less than 3 weeks after minor surgery.&#xD;
&#xD;
          5. Less than 6 months since a clinically significant cardiovascular event such as&#xD;
             myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke or TIA.&#xD;
&#xD;
          6. Congestive heart failure NYHA class ≥ II.&#xD;
&#xD;
          7. History of arrhythmias or arrhythmias discovered during the screening period (apart&#xD;
             from atrial fibrillation without ventricular tachycardia and premature extra beats).&#xD;
&#xD;
          8. Patients requiring anti-arrhythmic drugs.&#xD;
&#xD;
          9. QTc interval &gt;450 ms at baseline.&#xD;
&#xD;
         10. Use of fentanyl (must be stopped at least 1 week prior to initiation of Karonudib).&#xD;
&#xD;
         11. Use of anti-oxidants vitamins and acetylcysteine (must be stopped within 48 hours of&#xD;
             starting treatment with Karonudib).&#xD;
&#xD;
         12. Use of antidepressant medications which are substrate for CYP2D6 (must be stopped at&#xD;
             least 3 weeks prior to starting treatment with Karonudib).&#xD;
&#xD;
         13. Any severe acute or chronic medical condition that places the patient at increased&#xD;
             risk or interferes with the interpretation of study results.&#xD;
&#xD;
         14. Leptomeningeal metastases (patient with previously treated brain metastases are&#xD;
             eligible provided that there is no evidence of disease progression for a minimum of 8&#xD;
             weeks prior to inclusion - in these cases a CNS MR is required within the screening&#xD;
             period).&#xD;
&#xD;
         15. Known acute or chronic infection with hepatitis B or C.&#xD;
&#xD;
         16. Known HIV infection.&#xD;
&#xD;
         17. Pregnant or breast-feeding women.&#xD;
&#xD;
         18. Patients with reproductive potential not implementing accepted and effective means of&#xD;
             contraception.&#xD;
&#xD;
         19. Participation in any other clinical trial within the previous 4 weeks.&#xD;
&#xD;
         20. Unable to comply with study procedures.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Teresa Sandvall, MSc</last_name>
    <role>Study Director</role>
    <affiliation>Oxcia</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Teresa Sandvall, MSc</last_name>
    <email>teresa.sandvall@oxcia.se</email>
  </overall_contact>
  <location>
    <facility>
      <name>Karolinska University Hospital</name>
      <address>
        <city>Stockholm</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jeffrey Yachnin, MD, PhD</last_name>
    </contact>
    <investigator>
      <last_name>Jeffrey Yachnin, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>January 13, 2017</study_first_submitted>
  <study_first_submitted_qc>January 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 30, 2017</study_first_posted>
  <last_update_submitted>February 3, 2021</last_update_submitted>
  <last_update_submitted_qc>February 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 4, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Solid tumours</keyword>
  <!-- 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/NCT03036228
org study id: MASTIFF
nct id: NCT03036228
lead sponsor: 
has dmc: Yes
Primary Objective

      • To determine the safety and tolerability of Karonudib (TH1579) in escalating doses for the
      treatment of patients with advanced solid malignant tumours.

      Secondary Objective

        -  To define DLT and MTD.

        -  To determine a recommended phase 2 dose (RP2D) and schedule.

        -  To determine the pharmacokinetics of Karonudib.

        -  To determine preliminary signs of clinical efficacy of Karonudib.

        -  To determine overall survival.
allocation: N/A
intervention model: Sequential Assignment
intervention model description: 13 different dose cohorts with escalating doses are planned.
primary purpose: Treatment
masking: None (Open Label)
measure: Safety and tolerability of Karonudib (TH1579) will be evaluated.
time frame: 28 days, first treatment cycle for the patient.
description: Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD). DLTs will be assessed during first cycle of therapy, week 1-4 based on Haematological toxicity and Non-haematological toxicity.
MTD: The highest dose of Karonudib that does not cause unacceptable side effects is defined as the MTD.
measure: To determine the pharmacokinetics of Karonudib.
time frame: 28 days, first treatment cycle for the patient
description: Peak Plasma Concentration, Cmax
measure: To determine the pharmacokinetics of Karonudib.
time frame: 28 days, first treatment cycle for the patient
description: Tmax, time is the time to reach Cmax (Peak Plasma Concentration)
measure: To determine the pharmacokinetics of Karonudib.
time frame: 28 days, first treatment cycle for the patient
description: biological half-life (plasma T1/2)
measure: To determine the pharmacokinetics of Karonudib.
time frame: 28 days, first treatment cycle for the patient
description: Area under the Curve (AUC)
measure: To determine preliminary signs of clinical efficacy of Karonudib.
time frame: 54 days, two treatment cycles for the patient
description: RECIST 1.1
arm group label: Dose escalation
arm group type: Experimental
description: Karonudib is an oral inhibitor of MTH1 and will be supplied as an oral solution or tablets to be taken BID. Each cycle is defined as 28 days.
intervention type: Drug
intervention name: Karonudib
description: Dose escalation of administration with Karonudib.
arm group label: Dose escalation
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Teresa Sandvall, MSc
role: Study Director
affiliation: Oxcia
last name: Teresa Sandvall, MSc
email: teresa.sandvall@oxcia.se
facility: 
status: Recruiting
contact: 
investigator: 
country: Sweden
responsible party type: Sponsor