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

• ClinicalTrials.gov Identifier: NCT03261947
• Recruitment Status: Completed
• First Posted: August 25, 2017
• Last Update Posted: October 5, 2020
• Sponsor: Millennium Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Takeda ( Millennium Pharmaceuticals, Inc. )

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Metastatic Pancreatic Cancer; Colorectal Cancer; Esophageal Neoplasms; Carcinoma, Non-small-cell Lung	Drug: TAK-931	Phase 2

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 capsules

All participants will be asked to take one 50 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 101 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: October 25, 2017
• Actual Primary Completion Date: August 24, 2020
• Actual Study Completion Date: August 24, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: TAK-931; TAK-931 50 milligram (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).	Drug: TAK-931; 50 mg capsules

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants with Dose Limiting Toxicities (DLTs) in Western Safety Cohort [ Time Frame: Baseline up to 1 year ]
   DLT includes: Non-febrile Grade 4 neutropenia, Febrile neutropenia: Grade greater than or equal to (>=) 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 less than (<) 50 percent (%) of doses (<7 doses) of the planned TAK-931 dosing in cycle 1 due to study drug-related adverse events (AEs), grade >=3 nonhematologic toxicity with the few exceptions: Grade 3 arthralgia/ myalgia, fatigue, laboratory abnormalities, nausea and/or emesis or diarrhea.
2. 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 [ Time Frame: Baseline up to 1 year ]
   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.
3. Disease Control Rate (DCR) [ Time Frame: Baseline up to 1 year ]
   DCR is defined as percentage of participants with complete response (CR), partial response (PR) plus stable disease (SD) >=6 weeks from treatment initiation. Response and progression is evaluated in this study using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V 1.1) for lesions: CR is defined as disappearance of all lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of lesions, taking as reference the baseline sum LD. Progressive disease (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 Stable disease (SD) is defined as 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.

Secondary Outcome Measures :

1. Cmax: Maximum Observed Plasma Concentration for TAK-931 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose ]
2. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-931 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose ]
3. AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose for TAK-931 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose ]
4. AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-931 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose ]
5. CLr: Renal Clearance of TAK-931 [ Time Frame: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hours) post-dose ]
   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.
6. t1/2z: Terminal disposition phase half-life [ Time Frame: Cycle 1 Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose ]
7. CLss/F: Steady-state Apparent Oral Clearance [ Time Frame: Cycle 1 Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose ]
   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).
8. Rac(AUC): Accumulation Ratio Based on AUC Over the Dosing Interval (AUCτ) [ Time Frame: Cycle 1 Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose ]
9. Overall Response Rate (CR and PR) [ Time Frame: Baseline up to 1 year ]
   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.
10. Duration of Response (DOR) [ Time Frame: Baseline up to 1 year ]
    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.
11. Progression Free Survival (PFS) [ Time Frame: From randomization until disease progression or death whichever occurs first (up to 1 year) ]
    PFS is defined as time from start of study treatment to first documentation of disease progression or death due to any cause, whichever occurs first 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.
12. Overall Survival (OS) [ Time Frame: Baseline up to 1 year ]
    OS is the time from start of study treatment to date of death due to any cause.
13. Percentage of Participants with TEAEs in the Tumor-Specific Cohorts [ Time Frame: Baseline up to 1 year ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 reate (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.

Contacts and Locations

Locations

United States, Colorado

Sarah Cannon Research Institute Oncology Research Consortium

Denver, Colorado, United States, 80218

United States, Florida

Sarah Cannon Research Institute

Sarasota, Florida, United States, 34232

United States, Minnesota

Allina Health Virginia Piper Cancer Institute

Minneapolis, Minnesota, United States, 55404

United States, Missouri

Siteman Cancer Center

Saint Louis, Missouri, United States, 63110

United States, Nevada

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, United States, 89119

United States, Oklahoma

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States, 73104

United States, Tennessee

SCRI - Tennessee Oncology - Nashville - Southern Hills Clinic

Nashville, Tennessee, United States, 37203

United States, Washington

Virginia Mason Medical Center

Seattle, Washington, United States, 98101-2756

Japan

National Cancer Center Hospital East

Kashiwa, Chiba, Japan, 277-8577

National Cancer Center Hospital

Chuo-ku, Tokyo, Japan, 104-0045

Sponsors and Collaborators

Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor; Takeda

More Information

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03261947
• Other Study ID Numbers: TAK-931-2001; U1111-1192-7975 ( Registry Identifier: World Health Organization ); JapicCTI-163200 ( Registry Identifier: JapicCTI )
• First Posted: August 25, 2017
• Last Update Posted: October 5, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):

Drug therapy

Additional relevant MeSH terms:

Colorectal Neoplasms; Pancreatic Neoplasms; Carcinoma, Non-Small-Cell Lung; Esophageal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Head and Neck Neoplasms; Esophageal Diseases