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
Overview
- Phase
- Phase 1
- Intervention
- TAK-931
- Conditions
- Nonhematologic Neoplasms, Advanced
- Sponsor
- Millennium Pharmaceuticals, Inc.
- Enrollment
- 80
- Primary Endpoint
- Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed diagnosis of an advanced, nonhematologic/solid tumor (with the exception of primary brain tumor).
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .
- •For whom no effective standard therapy is available.
- •Life expectancy of greater than or equal to (\>=3) months.
- •Female participants who:
- •Are postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the screening visit, OR
- •Are surgically sterile, OR
- •If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, OR
- •Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[example, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.)
- •Male participants, even if surgically sterilized (example, status postvasectomy), who:
Exclusion Criteria
- •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.
- •Treatment with clinically significant enzyme inducers within 14 days before the first dose of study drug.
- •Treatment with any investigational products within 30 days before the first dose of study drug.
- •Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before the first dose of study drug.
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- •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.
- •Thromboembolic events (example, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events).
- •Significant, uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).
Arms & Interventions
TAK-931
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.
Intervention: TAK-931
Outcomes
Primary Outcomes
Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03
Time Frame: Baseline up to Cycle 1 (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
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.
Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs)
Time Frame: Baseline up to 30 days after the last dose of study drug or before initiation of new anti-cancer therapy (up to Day 499)
Secondary Outcomes
- Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931(Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]))
- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931(Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]))
- AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931(Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]))
- 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(Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]))
- 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(Cycle 1 Day 1 pre-dose up to any dosing day after 3 consecutive days post-dose (up to Cycle 1 Day 8 [Schedule A and D]; Cycle 1 Day 7 [Schedule B]; Cycle 1 Day 12 [Schedule D]) (Cycle Length of Schedules A and D = 21 days; and Schedule B= 28 days))
- Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931(Cycle 1 Day 1 pre-dose up to any dosing day after 3 consecutive days post-dose (up to Cycle 1 Day 8 [Schedule A and D]; Cycle 1 Day 7 [Schedule B]; Cycle 1 Day 12 [Schedule D]) (Cycle Length of Schedules A and D = 21 days; and Schedule B= 28 days))
- Overall Response Rate (ORR)(From date of first dose to the date of first documentation of progressive disease (PD) or death due to any cause, which ever occurred first (up to Month 45))
- Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931(Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]))
- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931(Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]))
- AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931(Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]))
- AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931(Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8 and 12 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]))
- 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(Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]))
- Progression-free Survival (PFS)(From date of first dose to the date of first documentation of PD or death due to any cause, which ever occurred first (up to Month 45))
- Duration of Response (DOR)(From the date of first documentation of response to the date of first documentation of PD (up to Month 45))