A Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies

Study Overview
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Brief Summary
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This 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.

Official Title
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A Master Protocol for the Multi-Cohort, Phase 1/2 Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies

Conditions
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Colorectal Cancer, GIST

Intervention / Treatment
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* Drug: DCC-3116
* Drug: Ripretinib
* Drug: Cetuximab
* Drug: Encorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥18 years of age Module A: Part 1 and Part 2: Pathologically confirmed diagnosis of CRC with BRAF V600E mutation. Must have received at least 1 and not more than 2 lines of prior systemic therapy in the advanced or metastatic setting. Must not have received prior treatment with an epidermal growth factor receptor or BRAF inhibitor Module B: Only for Part 1 (Safety/Dose-finding): Pathologically confirmed diagnosis of GIST with a KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutation. Must have progressed on at least one approved systemic regimen given in the locally advanced or metastatic setting or have documented intolerance to it Must not have received prior ripretinib treatment Module B: Only for Part 2 (Expansion) Pathologically confirmed GIST with documented mutation in KIT exon 11 Must have progressed on imatinib given in the locally advanced or metastatic setting or have been intolerant to imatinib and may not have received additional systemic therapy for GIST. Measurable disease. Must have a life expectancy of more than 3 months and an ECOG performance status of 0-1 Adequate organ function and bone marrow reserve based on laboratory assessments performed at Screening Must provide a fresh tumor biopsy and an archival tumor tissue sample, if available. Must agree to provide an on treatment biopsy Exclusion Criteria: Must not have received the following within the specified time periods prior to the first dose of study drug: Medications, including anticancer therapies, that are known strong or moderate inhibitors or inducers of CYP3A4 or P-glycoprotein (P-gp) including certain herbal medications (eg, St. John's wort): 14 days or 5×the half-life of the medication (whichever is longer) Other anticancer therapies and any investigational therapies with a known safety and PK profile: 14 days or 5×the half-life of the medication (whichever is shorter) Investigational therapies with unknown safety and PK profile: 28 days. If there is enough data on the investigational therapy to assess the risk for drug-drug interactions and late toxicities of prior therapy as low, the Sponsor's Medical Monitor may approve a shorter washout of 14 days Grapefruit or grapefruit juice: 14 days Have not recovered from all clinically relevant toxicities from prior therapy New York Heart Association Class III or IV heart disease, active ischemia, or any other uncontrolled cardiac condition, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, congestive heart failure, or myocardial infarction within 6 months prior to the first dose of study drug Symptomatic central nervous system (CNS) metastases or presence of leptomeningeal disease Malabsorption syndrome Bone disease that requires ongoing treatment or has required treatment Radiation for indications other than bone disease must have been completed 4 weeks prior to first dose of study drug, unless it consisted of limited field palliative radiation, including whole brain radiation, which must have been completed at least 2 weeks prior to first dose of study drug Major surgery within 4 weeks of the first dose of study drug Active HIV, Hepatitis B or Hepatitis C infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation (Part 1, Module A)<br>DCC-3116 tablets in escalating dose cohorts in 28-day cycles will be administered in combination with encorafenib once daily (QD) and cetuximab once every 2 weeks (Q2W). | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Cetuximab<br>* Solution for Injection<br>* Other names: Erbitux;Drug: Encorafenib<br>* Oral capsule formulation<br>* Other names: Braftovi;|
| Experimental: Expansion (Part 2, Module A)<br>DCC-3116 tablets will be administered in combination with encorafenib and cetuximab in 28-day cycles to evaluate preliminary efficacy in participants with 2nd- or 3rd-line BRAF V600E mutated colorectal cancer (CRC). | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Cetuximab<br>* Solution for Injection<br>* Other names: Erbitux;Drug: Encorafenib<br>* Oral capsule formulation<br>* Other names: Braftovi;|
| Experimental: Dose Escalation (Part 1, Module B)<br>DCC-3116 tablets in escalating dose cohorts in 28-day cycles will be administered in combination with ripretinib once daily (QD). | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Ripretinib<br>* Oral Tablet Formulation<br>* Other names: QINLOCK, DCC-2618;|
| Experimental: Expansion (Part 2, Module B)<br>DCC-3116 tablets will be administered in combination with ripretinib in 28-day cycles to evaluate preliminary efficacy in participants with 2nd-line advanced gastrointestinal stromal tumor (GIST). | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Ripretinib<br>* Oral Tablet Formulation<br>* Other names: QINLOCK, DCC-2618;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (Escalation Phase) | Identify the observed adverse events and serious adverse events associated with DCC-3116 in combination with cetuximab and encorafenib or ripretinib. | Approximately 24 months | 
| Recommended Phase 2 Doses (RP2D) (Escalation Phase) | Identify the dose-limiting toxicities for each dose level tested and determine the recommended Phase 2 doses of DCC-3116 in combination with cetuximab and encorafenib or ripretinib. | Approximately 18 months | 
| Objective response rate (ORR) (Expansion Phase) | Proportion of participants who achieve CR or PR per RECIST (or mRECIST, as applicable) v1.1. | Approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DoR) (Escalation Phase) | DoR is defined as the time interval from the time that the measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that the progressive disease is objectively documented or death, whichever occurs first. | Approximately 24 months | 
| Disease Control Rate (DCR) (Escalation Phase) | The DCR is defined as the proportion of participants who achieve CR, PR, or stable disease [SD] at the specified time point per RECIST (or mRECIST, as applicable) v1.1. | Approximately 24 months | 
| Time to response (Escalation Phase) | Time to response is defined as the time from initiation of treatment until the first assessment demonstrating CR or PR per RECIST (or mRECIST, as applicable) v1.1. | Approximately 24 months | 
| Progression-free survival (PFS) (Escalation Phase) | PFS is defined as the time from initiation of treatment until documented disease progression per RECIST (or mRECIST, as applicable) v1.1 or death, whichever occurs first. | Approximately 24 months | 
| Overall Survival (OS) | OS is defined as the time from initiation of treatment until death. | Approximately 48 months | 
| Maximum observed concentration (Cmax) | Measure the maximum observed concentration of DCC-3116 combinations. | Predose and up to 12 hours postdose | 
| Time to maximum observed concentration (Tmax) | Measure the time to maximum plasma concentration of DCC-3116 combinations. | Predose and up to 12 hours postdose | 
| Minimum observed concentration (Cmin) | Measure the minimum observed concentration of DCC-3116 combinations. | Predose and up to 12 hours postdose | 
| Area under the concentration-time curve (AUC) | Measure the AUC of DCC-3116 combinations. | Predose and up to 12 hours postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRC, Advanced colorectal cancer, DCC-3116, encorafenib, cetuximab, Advanced gastrointestinal stromal tumors, gastrointestinal stromal tumors, ripretinib