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).
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
101
TAK-931 hard gelatin capsules
Sarah Cannon Research Institute Oncology Research Consortium
Denver, Colorado, United States
Sarah Cannon Research Institute
Sarasota, Florida, United States
Allina Health Virginia Piper Cancer Institute
Minneapolis, Minnesota, United States
Siteman Cancer Center
St Louis, Missouri, United States
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
SCRI - Tennessee Oncology - Nashville - Southern Hills Clinic
Nashville, Tennessee, United States
Virginia Mason Medical Center
Seattle, Washington, United States
National Cancer Center Hospital East
Kashiwa, Chiba, Japan
National Cancer Center Hospital
Chuo-ku, Tokyo, Japan
Percentage of Participants With Dose Limiting Toxicities (DLTs) in Western Safety Cohort
DLT:Any following event related to TAK-931 assessed by Common Terminology Criteria for Adverse Events(CTCAE) version4.03;Non-febrile Grade 4 neutropenia; febrile neutropenia: Grade \>=3 neutropenia; Grade4 thrombocytopenia; Grade \>=3 thrombocytopenia of any duration accompanied by Grade 2 bleeding or requiring transfusion; delay in initiation of Cycle 2 by \>14 days due to 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 considered by investigator to be related to study drug and dose-limiting; Participants receiving \<50% of doses (\<7 doses) of planned TAK-931 dosing in Cycle 1 due to study drug-related adverse events(AEs); Grade \>=3 nonhematologic toxicity with few exceptions: Grade 3 arthralgia/myalgia, fatigue, laboratory abnormalities, nausea and/or emesis or diarrhea.
Time frame: Cycle 1 (each cycle = 21 days)
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
An AE was 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 was defined as an adverse event with an onset that occurred after receiving study drug. An SAE was any untoward medical occurrence or effect that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria.
Time frame: From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
Disease Control Rate (DCR) in Tumor-Specific Cohorts
DCR was defined as percentage of participants documented to have unconfirmed CR, PR, or SD for at least 6 weeks from treatment initiation according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as the best response. CR was defined as disappearance of all lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of lesions, taking as reference the baseline sum LD. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started. PD was 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.
Time frame: From first dose up to end of treatment (Up to approximately 14 months)
Cmax: Maximum Observed Plasma Concentration for TAK-931
Time frame: Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-931
Time frame: Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose for TAK-931
Time frame: Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
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 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
CLr: Renal Clearance of TAK-931
CLr is a measure of apparent clearance of the drug from the plasma, renal clearance is a measure of drug excreted through kidneys/urine per unit time.
Time frame: Cycle 1 (each cycle = 21 days) Day 1 pre-dose and at multiple timepoints (up to 8 hours urine sampling) post-dose
t1/2z: Terminal Disposition Phase Half-life for TAK-931
Time frame: Cycle 1 (each cycle = 21 days) Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
CLss/F: Steady-state Apparent Oral Clearance for TAK-931
CL/F was defined as apparent clearance of the drug from the plasma, calculated as the drug dose divided by AUC.
Time frame: Cycle 1 (each cycle = 21 days) Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
Rac(AUC): Accumulation Ratio Based on AUC Over the Dosing Interval (AUCτ) for TAK-931
Time frame: Cycle 1 (each cycle = 21 days) Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
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Overall Response Rate (CR and PR)
Overall response rate was defined as percentage of participants documented to have unconfirmed CR or PR according to RECIST v1.1 as the best response. CR was defined as disappearance of all lesions, PR was defined as at least a 30% decrease in the sum of the LD of lesions, taking as reference the baseline sum LD.
Time frame: From first dose up to end of treatment (Up to approximately 14 months)
Duration of Response (DOR)
DOR was 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 was defined as disappearance of all lesions, PR was defined as at least a 30% decrease in the sum of the LD of lesions, taking as reference the baseline sum LD. PD was 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.
Time frame: From first documented response until disease progression or end of treatment, whichever occurs first (Up to 14 months)
Progression Free Survival (PFS)
PFS was defined as the time from the date of first dose to the date of first documentation of PD (including clinical progression or clinical deterioration) or death due to any cause, whichever occurs first. Per RECIST V1.1, PD was 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.
Time frame: From date of randomization until disease progression or death, whichever occurs first (Up to approximately 34 months)
Overall Survival (OS) in the Tumor-Specific Cohorts
OS was defined as the time from the date of first dose of study drug to death due to any cause.
Time frame: Up to approximately 43 months
Percentage of Participants With Grade >=3 TEAEs, SAEs, TEAEs Leading to Dose Modifications, and TEAEs Leading to Treatment Discontinuation in Tumor-Specific Cohorts
An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it did not necessarily have to have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurred after receiving study drug. TEAEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, where Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4:Life-threatening consequences, urgent intervention indicated; Grade 5:Death related to AE. An SAE was any untoward medical occurrence or effect that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria.
Time frame: From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
Percentage of Participants With Clinically Significant Changes in Laboratory Values, Reported as Adverse Events in Tumor-Specific Cohorts
Clinical laboratory tests included hematology, clinical chemistry and urinalysis. The investigator determined if the results were clinically significant. Only those categories were reported which are clinically significant at post Baseline.
Time frame: From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
Percentage of Participants With Clinically Significant Changes in Vital Sign Measurements, Reported as Adverse Events in Tumor-Specific Cohorts
Vital signs included assessments of systolic and diastolic blood pressure (BP), heart rate (HR), and body temperature. The investigator determined if the results were clinically significant. Only those categories were reported which are clinically significant at post Baseline.
Time frame: From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)