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A Study to Evaluate the Safety, Tolerability, and Activity of TAK-931 in Participants With Metastatic Pancreatic Cancer, Metastatic Colorectal Cancer, and Other Advanced Solid Tumors

NCT03261947

Description:

The purpose of this study is to confirm the safety and tolerability of TAK-931 in a cohort of Western participants with metastatic solid tumors and to evaluate the anti-tumor activity of TAK-931 in participants with metastatic pancreatic cancer, colorectal cancer (CRC), squamous esophageal cancer (sqEC), and squamous non-small-cell lung cancer (sqNSCLC).

Related Conditions:
  • Colorectal Adenocarcinoma
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Safety, Tolerability, and Activity of TAK-931 in Participants With Metastatic Pancreatic Cancer or Metastatic Colorectal Cancer
  • Official Title: An Open-Label, Phase 2, Parallel Arm Study to Evaluate the Safety, Tolerability, and Activity of TAK-931 Single Agent in Patients With Metastatic Pancreatic Cancer or Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: TAK-931-2001
  • SECONDARY ID: U1111-1192-7975
  • NCT ID: NCT03261947

Conditions

  • Metastatic Pancreatic Cancer
  • Colorectal Cancer

Interventions

DrugSynonymsArms
TAK-931TAK-931

Purpose

The purpose of this study is to confirm the safety and tolerability of TAK-931 in a cohort of Western participants with metastatic solid tumors and to evaluate the anti-tumor activity of TAK-931 in participants with metastatic pancreatic cancer and colorectal cancer (CRC).

Detailed Description

      The drug being tested in this study is called TAK-931. TAK-931 blocks the function of a
      specific protein in the body called CDC7 kinase. TAK-931 is being tested in participants with
      metastatic pancreatic cancer or metastatic colorectal cancer plus a cohort of US patients
      with metastatic cancer with no other standard therapeutic alternative. This study will look
      at safety, tolerability and pharmacokinetics of TAK-931 in people who take TAK-931.

      The study will enroll approximately 88 patients. Participants will be enrolled in 3 cohorts:
      1) Western safety cohort to be enrolled in the US only which will include non-Japanese
      participants who have metastatic solid tumors with no standard therapeutic alternative, 2)
      Participants with metastatic pancreatic cancer 3) Participants with metastatic colorectal
      cancer. All participants will receive:

      • TAK-931 50 mg

      All participants will be asked to take one capsule at the same time each day throughout the
      study.

      This multi-center trial will be conducted in United States and Japan. The overall time to
      participate in this study is approximately 24 months. Participants will make multiple visits
      to the clinic, and participants in both Western cohort and disease specific cohort will be
      followed-up for up to 12 weeks for progression-free survival. Once disease progression is
      confirmed, participants in disease-specific cohort will be followed for overall survival for
      up to 12 weeks after last dose of study drug.
    

Trial Arms

NameTypeDescriptionInterventions
TAK-931ExperimentalTAK-931 50 mg, capsules, orally, once daily for 14 days, followed by 7-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 1 year).
  • TAK-931

Eligibility Criteria

        Inclusion Criteria:

          1. Adult male or female patients aged ≥20 years (Japan) or ≥18 years (US).

          2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          3. Has pathologically confirmed metastatic pancreatic adenocarcinoma that has progressed
             after, at least, a first line of standard systemic chemotherapy for the metastatic
             disease, OR participants with pathologically confirmed metastatic adenocarcinoma of
             the colon or rectum who have progressed to at least 2 lines of standard systemic
             chemotherapy for the metastatic disease.

          4. For the Western safety cohort only: participants with locally advanced or metastatic
             solid tumor for whom no standard treatment with an established survival benefit is
             available or if the participant refuses other standard therapy.

          5. For disease-specific cohort participants: measurable disease per RECIST v. 1.1

          6. Left ventricular ejection fraction >50% as measured by echocardiogram (ECHO) or
             multiple gated acquisition (MUGA) scan within 4 weeks before receiving the first dose
             of study drug.

          7. Recovered to Grade 1 or baseline from all toxic effects of previous therapy (except
             alopecia or neuropathy).

          8. Suitable venous access for the study-required blood sampling.

          9. For the Western safety cohort only: willingness to undergo serial skin tissue
             biopsies.

         10. For disease-specific cohort participants: Must have an archival (banked) tumor sample
             or agree to have a new (fresh) tumor biopsy during the screening period. If a new
             tumor sample is needed, the disease should be accessible for a nonsignificant risk
             biopsy procedure (those occurring outside the brain, lung/mediastinum, and pancreas,
             or obtained with endoscopic procedures not extending beyond the stomach or bowel). For
             participants in the Western safety cohort, this biopsy is optional.

        Exclusion Criteria:

          1. Participants who require continuous use of proton pump inhibitors (PPIs) or
             histamine-2 (H2) receptor antagonists and participants who are taking PPIs within 5
             days before the first dose of study drug.

          2. Treatment with clinically significant enzyme inducers, such as phenytoin,
             carbamazepine, phenobarbital, rifampin, rifabutin, rifapentine, or Saint John's wort
             within 14 days before the first dose of study drug.

          3. Treatment with any systemic anticancer treatment (including investigational products)
             within 30 days or 5 half-lives, whichever is shorter, before the first dose of study
             drug.

          4. History of any of the following within the last 3 months before administration of the
             first dose of study drug:

               -  Ischemic myocardial event including angina requiring therapy and artery
                  revascularization procedures, myocardial infarction, and unstable symptomatic
                  ischemic heart disease.

               -  Ischemic cerebrovascular event, including transient ischemic attack and artery,
                  revascularization procedures.

               -  Significant, uncontrolled cardiac arrhythmia (including atrial
                  flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).

               -  Current use of rate control drugs for arrhythmias or to control cardiac frequency
                  (including β-blockers [e.g., metoprolol], acetylcholine, digoxin, and
                  nondihydropyridine calcium channel blockers [e.g., diltiazem and verapamil).
                  Patients will not be excluded if these drugs are used for other indications other
                  than arrhythmia control.

               -  Placement of a pacemaker for control of cardiac rhythm.

               -  New York Heart Association Class II to IV heart failure.

               -  Any other cardiac condition that, in the opinion of the investigator, could pose
                  an additional risk for participation in the study (e.g., pericardial effusion or
                  restrictive cardiomyopathy).

               -  Baseline prolongation of the QT interval corrected for HR using Fridericia's
                  formula (QTcF; e.g., repeated demonstration of QTcF interval >480 ms, history of
                  congenital long QT syndrome, or torsades de pointes).

          5. Participants with any of the following blood pressure (BP) conditions:

               -  History of orthostatic hypotension or syncope that required medical intervention.

               -  Orthostatic hypotension is defined as a 20-mmHg decrease in systolic BP and/or a
                  10-mmHg decrease in diastolic BP within 2 to 5 minutes of quiet standing
                  immediately after 5 minutes of supine rest.

               -  Postural orthostatic tachycardia syndrome or postural tachycardia syndrome
                  (defined as an increase in HR of >30 beats per minute over baseline after 10
                  minutes of quiet standing).

               -  Hypertension that is unstable or not controlled by medication.

          6. History of uncontrolled brain metastasis unless:

               -  Previously treated with surgery, whole-brain radiation, or stereotactic
                  radiosurgery, and

               -  Stable disease (SD) for ≥30 days, without steroid use (or stable steroid dose
                  established for ≥14 days before the first dose of TAK-931).

          7. Known history of human immunodeficiency virus infection.

          8. Known hepatitis B virus (HBV) surface antigen seropositive or detectable hepatitis C
             virus (HCV) infection viral load. Note: Participants who have positive HBV core
             antibody or HBV surface antigen antibody can be enrolled but must have an undetectable
             HBV viral load.

          9. Prior treatment with radiation therapy involving ≥25% of the hematopoietically active
             bone marrow within 3 months before the first dose of study drug.

         10. Western Safety Cohort Only: Participants with Japanese heredity.

         11. Colorectal cancer (CRC) Cohort Only: Participants with known microsatellite
             instability-high (MSI-H) genotype.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with Dose Limiting Toxicities (DLTs) in Western Safety Cohort
Time Frame:Baseline up to 1 year
Safety Issue:
Description:DLT includes: Non-febrile Grade 4 neutropenia, Febrile neutropenia: Grade ≥3 neutropenia, Grade 4 thrombocytopenia, grade ≥3 thrombocytopenia of any duration accompanied by grade 2 bleeding or requiring transfusion, delay in the initiation of cycle 2 by more than 14 days due to a lack of adequate recovery of treatment-related hematological or nonhematologic toxicities, grade 2 ejection fraction decreased by echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan, Grade 4 laboratory abnormalities, other grade 2 nonhematologic toxicities that are considered by the investigator to be related to study drug and dose-limiting, participants receiving <50% of doses (<7 doses) of the planned TAK-931 dosing in cycle 1 due to study drug-related AEs, grade ≥3 nonhematologic toxicity with the few exceptions: Grade 3 arthralgia/ myalgia, fatigue, laboratory abnormalities, nausea and/or emesis or diarrhea.

Secondary Outcome Measures

Measure:Cmax: Maximum Observed Plasma Concentration for TAK-931
Time Frame:Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
Safety Issue:
Description:
Measure:Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-931
Time Frame:Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
Safety Issue:
Description:
Measure:AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose for TAK-931
Time Frame:Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
Safety Issue:
Description:
Measure:AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-931
Time Frame:Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
Safety Issue:
Description:
Measure:CLr: Renal Clearance of TAK-931
Time Frame:Day 1 pre-dose and at multiple timepoints (up to 24 hours) post-dose
Safety Issue:
Description:CLr is a measure of apparent clearance of the drug from the urine. The clearance is the rate at which waste substances are cleared from the blood.
Measure:t1/2z: Terminal disposition phase half-life
Time Frame:Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
Safety Issue:
Description:
Measure:CLss/F: Steady-state Apparent Oral Clearance
Time Frame:Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
Safety Issue:
Description:CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided by AUC expressed in liters/hour (L/hr).
Measure:Rac(AUC): Accumulation Ratio Based on AUC Over the Dosing Interval (AUCτ)
Time Frame:Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
Safety Issue:
Description:
Measure:Overall Response Rate (Complete Response [CR] and Partial response [PR])
Time Frame:Baseline up to 1 year
Safety Issue:
Description:Overall Response rate is defined as the sum of percentage of participants with complete response rate and partial response rate. Response and progression was evaluated in this study Per RECIST V1.1 where CR is defined as disappearance of all lesions, PR is defined as at least a 30% decrease in the sum of the LD of lesions, taking as reference the baseline sum LD. PD is defined as at least a 20% increase in the sum of the LD of lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Measure:Duration of Response (DOR)
Time Frame:Baseline up to 1 year
Safety Issue:
Description:DOR is defined as the time from the date of first documentation of a CR or PR to the date of first documentation of tumor progression. Per RECIST V1.1, CR is defined as disappearance of all lesions, PR is defined as at least a 30% decrease in the sum of the LD of lesions, taking as reference the baseline sum LD. PD is defined as at least a 20% increase in the sum of the LD of lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Measure:Progression Free Survival (PFS)
Time Frame:From randomization until disease progression or death whichever occurs first (up to 1 year)
Safety Issue:
Description:PFS is defined as time from start of study treatment to first documentation of disease progression. Per RECIST V1.1, PD is defined as at least a 20% increase in the sum of the LD of lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Measure:Overall Survival (OS)
Time Frame:Baseline up to 1 year
Safety Issue:
Description:OS is the time from start of study treatment to date of death due to any cause.
Measure:Percentage of Participants with TEAEs in the Tumor-Specific Cohorts
Time Frame:Baseline up to 1 year
Safety Issue:
Description:Percentage of participants with Grade ≥3 TEAEs, SAEs, TEAEs leading to treatment discontinuation or dose modifications, and clinically significant changes in laboratory values and vital sign measurements in the tumor-specific cohorts will be reported. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. A SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • Drug therapy

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