Clinical trial NCT03261947: 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
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, Metastatic Colorectal Cancer, and Other Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Pancreatic Cancer
Colorectal Cancer
Esophageal Neoplasms
Carcinoma, Non-small-cell Lung
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2017-08-25
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: Pancreatic Arm Now Closed.

The drug being tested in this study is called TAK-931. TAK-931 blocks function of a specific protein called CDC7 kinase in the human body. TAK-931 is being tested in participants with metastatic cancer (colorectal, pancreatic, sqNSCLC and sqEC) in the United States and Japan and also in the participants with any type of metastatic cancer with no standard therapeutic alternative in the United States only. This study will look at the safety, tolerability and pharmacokinetics of TAK-931.

The study will enroll approximately 160 participants. Participants will be enrolled in 5 cohorts: 1) Western safety cohort, to be enrolled in the United States only, will include non-Japanese participants with metastatic solid tumors and no standard therapeutic alternative, 2) Metastatic pancreatic cancer cohort, 3) Metastatic colorectal cancer cohort, 4) Metastatic sqNSCLC cohort, and 5) Metastatic sqEC cohort. All participants will receive:

• TAK-931 50 mg (2x25 mg or 5x10 mg) capsules

All participants will be asked to take one 50 mg (2x25 mg or 5x10 mg) capsule at the same time of the day every day for 14 days, followed by 7 days break in 21-day cycles throughout the study.

This multi-center trial will be conducted in the United States and Japan. The overall time to participate in this study is approximately 24 months. Participants will make multiple visits to the clinic. Participants in both Western cohort and disease specific cohorts will be followed for progression-free survival every 12 weeks after the last dose of the study drug until the occurrence of disease progression, loss to follow up, consent withdrawal, death, start of subsequent antineoplastic therapy, study termination, or until 6 months after discontinuation of the study treatment, whichever occurs first. Once disease progression is confirmed, participants in the disease-specific cohorts will be followed for overall survival every 12 weeks until death, loss to follow up, consent withdrawal, study termination, or transfer of a participant to a long term safety study, single participant investigational new drug application, or similar program after the last dose of the study drug.

Eligibility criteria: Inclusion Criteria:

1. Adult male or female participants aged \>=20 years (Japan) or \>=18 years (United States).
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, OR participants with pathologically confirmed locally advanced or metastatic sqEC that has progressed after at least a first line of standard systemic therapy for metastatic disease. First-line participants can be enrolled if a platinum doublet is contraindicated or refused by the participants, OR pathologically confirmed locally advanced or metastatic sqNSCLC that has progressed after at least 2 lines of standard systemic therapy for 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 greater than (\>) 50% as measured by ECHO or 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).
   * New York Heart Association Class III 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 (example, pericardial effusion or restrictive cardiomyopathy).
   * Baseline prolongation of the QT interval corrected for heart rate (HR) using Fridericia's formula \[QT interval corrected for heart rate using Fridericia's formula (QTcF); example, repeated demonstration of QTcF interval \>480 millisecond (ms), history of congenital long QT syndrome, or torsades de pointes\].
5. 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. Participants with known microsatellite instability-high (MSI-H) genotype or known wild type tumor protein 53 (TP53) per local testing.
11. Western Safety Cohort Only: Participants with Japanese heredity.

Primary outcomes:
measure: Percentage of Participants With Dose Limiting Toxicities (DLTs) in Western Safety Cohort
timeFrame: Cycle 1 (each cycle = 21 days)
measure: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), TEAEs Leading to Dose Modifications and TEAEs Leading to Treatment Discontinuation in Western Safety Cohort
timeFrame: From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
measure: Disease Control Rate (DCR) in Tumor-Specific Cohorts
timeFrame: From first dose up to end of treatment (Up to approximately 14 months)
Secondary outcomes:
measure: Cmax: Maximum Observed Plasma Concentration for TAK-931
timeFrame: Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-931
timeFrame: Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
measure: AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose for TAK-931
timeFrame: Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
measure: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-931
timeFrame: Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
measure: CLr: Renal Clearance of TAK-931
timeFrame: Cycle 1 (each cycle = 21 days) Day 1 pre-dose and at multiple timepoints (up to 8 hours urine sampling) post-dose
measure: t1/2z: Terminal Disposition Phase Half-life for TAK-931
timeFrame: Cycle 1 (each cycle = 21 days) Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
measure: CLss/F: Steady-state Apparent Oral Clearance for TAK-931
timeFrame: Cycle 1 (each cycle = 21 days) Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
measure: Rac(AUC): Accumulation Ratio Based on AUC Over the Dosing Interval (AUCτ) for TAK-931
timeFrame: Cycle 1 (each cycle = 21 days) Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
measure: Overall Response Rate (CR and PR)
timeFrame: From first dose up to end of treatment (Up to approximately 14 months)
measure: Duration of Response (DOR)
timeFrame: From first documented response until disease progression or end of treatment, whichever occurs first (Up to 14 months)
measure: Progression Free Survival (PFS)
timeFrame: From date of randomization until disease progression or death, whichever occurs first (Up to approximately 34 months)
measure: Overall Survival (OS) in the Tumor-Specific Cohorts
timeFrame: Up to approximately 43 months
measure: Percentage of Participants With Grade >=3 TEAEs, SAEs, TEAEs Leading to Dose Modifications, and TEAEs Leading to Treatment Discontinuation in Tumor-Specific Cohorts
timeFrame: From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
measure: Percentage of Participants With Clinically Significant Changes in Laboratory Values, Reported as Adverse Events in Tumor-Specific Cohorts
timeFrame: From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
measure: Percentage of Participants With Clinically Significant Changes in Vital Sign Measurements, Reported as Adverse Events in Tumor-Specific Cohorts
timeFrame: From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
Other outcomes:
Locations:
city: Denver
country: United States
facility: Sarah Cannon Research Institute Oncology Research Consortium
state: Colorado
city: Sarasota
country: United States
facility: Sarah Cannon Research Institute
state: Florida
city: Minneapolis
country: United States
facility: Allina Health Virginia Piper Cancer Institute
state: Minnesota
city: Saint Louis
country: United States
facility: Siteman Cancer Center
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Nashville
country: United States
facility: SCRI - Tennessee Oncology - Nashville - Southern Hills Clinic
state: Tennessee
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: