TAK-931 30 mg, capsules, orally, QD or BID on Days 1-14 of each 21-day treatment cycle in dosing schedule A followed by dosing schedule B, C, D, E and F. In dosing schedules B through F, starting doses and dosing escalations will vary depending on the dosing data obtained from dosing in the previous schedule.

Dose escalation of TAK-931 will be based on evaluation of clinical safety and tolerability and guided by accumulating PK data. 3-4 dose cohorts are expected for each dosing schedule.

If the PK from the early cohorts support BID dosing, then study drug administration in subsequent cohorts may transition to a BID dosing schedule.

TAK-931

Study Director

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and maximum tolerated dose (MTD) of TAK-931 in participants with advanced nonhematologic tumors.

The drug being under investigation in this study is called TAK-931. The effect of TAK-931 is being evaluated in up to 100 participants who have nonhematologic (solid) neoplasms. This study will look at the safety, tolerability, and PK to determine the maximum tolerated dose (MTD) of TAK-931.

This multi-center trial will be conducted in Japan. The overall study duration is approximately 42 months for total of dose escalation cohorts and the safety expansion cohort. Participants will make multiple visits to the clinic with final visit approximately 30-40 days after last dose of study drug for a follow-up assessment.

A Study to Evaluate TAK-931 in Participants With Advanced Nonhematologic Tumors

An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-931, a Cell Division Cycle 7 (CDC7) Inhibitor, in Adult Patients With Advanced Nonhematologic Tumors

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Toxicity was evaluated by NCI CTCAE v4.03. DLT:any of following occurred events during Cycle 1 considered by investigator to be possibly related to therapy:1)Grade4 neutropenia,2)Febrile neutropenia lasting greater(\>)1 hour,3)Grade greater than or equal to (\>=)3 neutropenia with infection,4)Grade \>=3 thrombocytopenia with bleeding,4)Grade 4 thrombocytopenia,5)delay in initiation of Cycle 2 by \>14 days,6)Grade 2:\<Grade 2 ejection fraction,7)other Grade 2 nonhematologic toxicities considered by investigator related to study drug and DLTs,8)who received \<50 percent of doses of planned TAK-931 dosing in Cycle 1 for related AEs:\<7 QD/\<14 BID doses (Schedules A,B);\<11 QD/\<21 BID doses(Schedule D),\<3 QD/\<6 BID doses for(Schedule E),9)Grade \>=3 nonhematologic toxicity except arthralgia/myalgia and fatigue, isolated \>=Grade 3 laboratory abnormalities if it is asymptomatic and resolves to \<=Grade 1 or baseline levels in \<=7 days;inadequately treated Grade 3 nausea and/or vomiting and diarrhea.

H-score were a composite score that comprised of intensity and percentage of staining and were used for assessing amount of protein (in this case pMCM2 \[Ser40\]) present in a tissue sample. The composite score obtained by H-score is derived by adding of the percentages of cell staining at each intensity level multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\], 3+ \[strong staining\]). The H-score has a range of 0 to 300. Lower H-scores represent lower expression of pMCM2 (Ser40) in the tissue sample, while higher scores represent stronger expression of pMCM2 (Ser40) in the tissue samples.

Positive index was calculated by taking the number of cells staining positive for the marker over the total number of cells.

ORR was defined as percentage of participants who had achieved complete response (CR) and partial response (PR), as measured by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V 1.1). CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (\<) 10 millimeter (mm). PR: was at least a 30 percent (%) decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.

PFS was defined as the time from the date of first dose to the date of first documentation of PD or death due to any cause, whichever occurs first, as measured by RECIST V1.1. PD: 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PFS was analyzed using the Kaplan-Meier method.

The DOR was defined as the time from the date of first documentation of a response (CR or PR) to the date of first documentation of PD, as measured by RECIST V 1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to \<10 mm. PR: was at least a 30% decrease in SOD of target lesions, taking as reference the baseline SOD. PD: 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. DOR was analyzed using the Kaplan-Meier method.

Millennium Pharmaceuticals, Inc.

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

TAK-931 30 mg, capsule, orally, once daily for 14 days in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule A: TAK-931 30 mg

TAK-931 40 mg, capsule, orally, once daily for 14 days in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule A: TAK-931 40 mg

TAK-931 50 mg, capsule, orally, once daily for 14 days in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule A: TAK-931 50 mg

TAK-931 60 mg, capsule, orally, once daily for 14 days in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule A: TAK-931 60 mg

TAK-931 60 mg, capsule, orally, once daily or twice daily for 7 days, followed by 7 days of rest and repeated (7 days on and 7 days off treatment) in each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule B: TAK-931 60 mg

TAK-931 80 mg, capsule, orally, once daily or twice daily for 7 days, followed by 7 days of rest and repeated (7 days on and 7 days off treatment) in each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule B: TAK-931 80 mg

TAK-931 100 mg, capsule, orally, once daily or twice daily for 7 days, followed by 7 days of rest and repeated (7 days on and 7 days off treatment) in each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule B: TAK-931 100 mg

TAK-931 120 mg, capsule, orally, once daily or twice daily for 7 days, followed by 7 days of rest and repeated (7 days on and 7 days off treatment) in each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule B: TAK-931 120 mg

TAK-931 20 mg, capsule, orally, once daily in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule D: TAK-931 20 mg

TAK-931 30 mg, capsule, orally, once daily in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule D: TAK-931 30 mg

TAK-931 40 mg, capsule, orally, once daily in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule D: TAK-931 40 mg

TAK-931 100 mg, capsule, orally, once daily on Days 1 and 2 followed by 5 days of rest and repeated weekly (2 days on and 5 days off treatment) in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule E: TAK-931 100 mg

TAK-931 120 mg, capsule, orally, once daily on Days 1 and 2 followed by 5 days of rest and repeated weekly (2 days on and 5 days off treatment) in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule E: TAK-931 120 mg

TAK-931 150 mg, capsule, orally, once daily on Days 1 and 2 followed by 5 days of rest and repeated weekly (2 days on and 5 days off treatment) in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Schedule E: TAK-931 150 mg

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Japan

Region of Enrollment

Height

Weight

Body Surface Area (BSA)

The safety population was defined as all participants who received any amount of study drug.

Medical Director

The DLT-evaluable population was defined as all participants who received at least 75% of their planned TAK-931 doses for their first cycle of treatment (unless interrupted by study drug-related AEs) and who had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.

Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03

Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs)

The pharmacokinetic (PK) population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here "overall number of participants analyzed" are participants who were available for this outcome measure assessment at given time period.

Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931

The PK population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here "overall number of participants analyzed" are participants who were available for this outcome measure assessment at given time period.

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931

AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931

AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931

AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931

Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931

AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931

AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931

Baseline

Schedule B: Change at Cycle 1 Day 7

Schedule A and D: Change at Cycle 1 Day 8

Schedule D: Change at Cycle 1 Day 12

Pharmacodynamics population: all participants who received at least the first dose of TAK-931, had a baseline skin punch biopsy sample, and had at least 1 additional postbaseline skin punch biopsy sample. Overall number analyzed "N": participants who were evaluable for the outcome measure. Number analyzed "n": participants who were evaluable for this outcome measure for given categories. Data for this outcome measure was not collected and analyzed for Schedule E Cohorts due to business reasons.

Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931

Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931

The response-evaluable population is defined as participants who receive at least 1 dose of study drug, have measurable disease at baseline, and at least 1 post-baseline response assessment. Here "overall number of participants analyzed" are participants who were available for this outcome measure assessment at given time period.

Overall Response Rate (ORR)

Progression-free Survival (PFS)

The response-evaluable population is defined as participants who receive at least 1 dose of study drug, have measurable disease at baseline, and at least 1 post-baseline response assessment. Responders without documentation of PD were censored at the date of last response assessment that is stable disease or better.

Duration of Response (DOR)

TAK-931 30 milligram (mg), capsule, orally, once daily (QD) for 14 days in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

TAK-931 60 mg, capsule, orally, once daily or twice daily (BID) for 7 days, followed by 7 days of rest and repeated (7 days on and 7 days off treatment) in each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor.

Spots Global Cancer Trial Database for A Study to Evaluate TAK-931 in Participants With Advanced Nonhematologic Tumors

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Study Description

Keywords

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