A Master Protocol for the Multi-Cohort Phase 1/2 Study of DCC-3116 in Combination with Anticancer Therapies in Participants with Advanced Malignancies
Brief description of study
This master protocol is a Phase 1/2, multicenter, open-label (unless otherwise specified in a combination-specific module) study of DCC-3116 in combination with anticancer therapies. Modules within the master protocol are defined according to different combinations of DCC-3116 with other anticancer agents. Each module will generally be conducted in 2 parts: Part 1 (Safety/Dose-finding) and Part 2 (Expansion). Modules may open and close independently of each other.In Part 1 (Safety/Dose-finding) of each module, dose levels of DCC-3116 in combination with module-specific anticancer therapies will be studied. Escalation and de-escalation will be guided by safety, PK, and pharmacodynamics analyses within the framework of a Bayesian optimal interval (BOIN) design to remain within an expected dose-limiting toxicity (DLT) frequency of no more than 30% for the MTD if any DLTs are observed. Details on sample size can be found in the combination-specific modules. In Part 1, 2-6 participants will initially be enrolled for each new dose level. Toxicity-guided rules according to the BOIN design for escalation and de-escalation will be based on a target DLT toxicity rate for the MTD of 30% and at least 2 participants per dose level having completed the DLT period of 28 days. Dose-limiting toxicities are defined in each combination-specific module. The BOIN design for establishing the MTD uses the following rule, optimized to minimize the probability of incorrect dose assignment, to guide dose escalation/de-escalation: • If the observed DLT rate at the current dose is =0.236, escalate the dose to the next higher dose level • If the observed DLT rate at the current dose is >0.359, de-escalate the dose to the next lower dose level • Otherwise, stay at the current dose For overdose control, the following rule will be applied: if the probability exceeds 0.95 that the DLT rate for a dose level of DCC-3116 is greater than 30% and at least 3 DLT evaluable participants have been treated at that dose level, the respective and any higher dose levels of DCC-3116 will be eliminated from further examination. If the lowest dose of DCC-3116 is eliminated, the module will be stopped for safety. Dose escalation and de-escalation may continue according to the BOIN design until the maximum sample size for the module is reached or if the number of DLT evaluable participants treated at the current dose reaches 15 and the decision is to stay at the current dose level. Additional participants may be enrolled in lower dose levels. To better characterize safety, PK, and pharmacodynamics, up to approximately 15 participants per dose level may be considered for Phase 2 evaluation. After Part 1 (Safety/Dose-finding) for the module is completed, if any DLTs are observed, the MTD for DCC-3116 in combination with module-specific anticancer therapies will be computed using isotonic regression. The recommended dose(s) for Phase 2 evaluation of DCC-3116 in combination with module-specific anticancer therapies to be used in Part 2 (Expansion) will be selected based on not exceeding the MTD and achieving the most targeted overall safety, PK, pharmacodynamics, and preliminary anticancer activity profile. In Part 2 (Expansion) of each module, a two-stage design based on the exact binomial distribution with non-binding futility will be used. Details on sample size and boundaries for futility can be found in the combination-specific modules.
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