A Phase 1/2 Study of DCC-3116 in Patients With MAPK Pathway Mutant Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1/2, multicenter, open label, first in human (FIH) study of DCC-3116 as monotherapy, and in combination with trametinib, binimetinib, or sotorasib in patients with advanced or metastatic solid tumors with RAS/MAPK pathway mutation. The study consists of 2 parts, a dose-escalation phase, and an expansion phase.

Official Title
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A Phase 1/2, First-in-Human Study of DCC-3116 as Monotherapy and in Combination With RAS/MAPK Pathway Inhibitors in Patients With Advanced or Metastatic Solid Tumors With RAS/MAPK Pathway Mutations

Conditions
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Pancreatic Ductal Adenocarcinoma, Non-Small Cell Lung Cancer, Colorectal Cancer, Melanoma, Advanced Solid Tumor, Metastatic Solid Tumor

Intervention / Treatment
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* Drug: DCC-3116
* Drug: Trametinib
* Drug: Binimetinib
* Drug: Sotorasib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants ≥18 years of age Dose Escalation Phase (Part 1): Participants must have a pathologically confirmed diagnosis of an advanced or metastatic solid tumor with a documented RAS, NF1, or RAF mutations. A molecular pathology report documenting mutational status of RAS, NF1, or RAF must be available. Progressed despite standard therapies, and received at least 1 prior line of anticancer therapy. Participants with a documented mutation in BRAF V600E or V600K must have received approved treatments known to provide clinical benefit prior to study entry. Participants enrolled in the DCC-3116 and sotorasib cohort (Cohort D) must have a KRAS G12C mutation. Dose Expansion Phase (Part 2): Cohort 1: Patients with Pancreatic Ductal Adenocarcinoma (PDAC). Pathologically confirmed PDAC with a documented mutation in KRAS. Received only 1 prior line of systemic therapy in the advanced or metastatic setting. Cohort 2: Patients with Non-Small Cell Lung Cancer (NSCLC) Pathologically confirmed NSCLC with a documented mutation in KRAS, NRAS, NF1, or BRAF. Received at least 2 prior lines but no more than 4 prior lines of systemic therapy in the advanced or metastatic setting. Cohort 3: Patients with Colorectal Cancer (CRC) Pathologically confirmed CRC with a documented mutation in KRAS, NRAS, NF1, or BRAF. Received at least 2 prior lines of systemic therapy in the advanced or metastatic setting. Cohort 4: Patients with Melanoma Pathologically confirmed melanoma with a documented mutation in NRAS. Received at least 1 but not more than 2 prior lines of systemic therapy in the advanced or metastatic setting that included T-cell checkpoint inhibitor-based therapy. Have not received prior MEK inhibitor therapy. Cohort 5: Patients with KRAS G12C mutant NSCLC Pathologically confirmed NSCLC with a documented mutation in KRAS G12C. Received at least 1 prior line but no more than 3 prior lines of systemic therapy in the advanced or metastatic setting. Have not received prior sotorasib or other KRAS G12C inhibitor therapy. Must provide a fresh tumor biopsy from a primary or metastatic cancer lesion that can be biopsied with acceptable risk as determined by the Investigator, and an archival tumor tissue sample, if available. If a fresh tumor biopsy is not possible, then an archival tumor tissue sample must be provided. Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 (Dose Escalation) or 0 to 1 (Dose Expansion) at Screening Adequate organ function and bone marrow function. If a female of childbearing potential must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements. Male participants must agree to follow contraception requirements. Must provide signed consent to participate in the study and is willing to comply with study-specific procedures. Exclusion Criteria: Must not have received the following within the specified time periods prior to the first dose of study drug: Prior therapies (anticancer or therapies given for other reasons) that are known strong or moderate inhibitors or inducers of CYP3A4 or P-gp including certain herbal medications (eg, St. John's Wort): 14 days or 5× the half-life of the medication (whichever is longer) All other prior anticancer therapies or any therapy that is investigational for the participant's condition 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 toxicities from prior therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Presence or history of central nervous system (CNS) metastases or leptomeningeal disease, with some exceptions New York Heart Association Class III or IV heart disease, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, 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. Prolongation of the QT interval corrected by Fridericia's formula (QTcF) based on repeated demonstration of QTcF >450 ms in males or >470 ms in females at screening, or history of long QT syndrome. Left ventricular ejection fraction (LVEF) <50% at Screening Systemic arterial thrombotic or embolic events Systemic venous thrombotic events Malabsorption syndrome Bone disease that requires ongoing treatment or has required treatment. Major surgery within 4 weeks of the first dose of study drug. All surgical wounds must be healed and free of infection or dehiscence before the first dose of the study drug. Any other clinically significant comorbidities. For participants receiving DCC-3116 and trametinib combination or DCC-3116 and binimetinib combination: previous treatment with trametinib or binimetinib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to trametinib or binimetinib. For participants receiving DCC-3116 and sotorasib combination in Dose Escalation Part 1: previous treatment with sotorasib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to sotorasib. For participants receiving DCC-3116 and sotorasib combination: Use of proton pump inhibitors (PPIs) and H2 receptor antagonists that cannot be discontinued 3 days prior to the start of study drug administration. Known allergy or hypersensitivity to any component of the investigational drug products. Known human immunodeficiency virus unless the following requirements are met: CD4 count >350/µL No AIDS-defining opportunistic infection in the last 12 months Stable anti-retroviral regimen with medications that are not prohibited by the protocol for at least 4 weeks with HIV viral load less than 400 copies/mL prior to enrollment. Known active hepatitis B, active hepatitis C infection or if the participant is taking medications that are prohibited per protocol. If female, the participant is pregnant or lactating. Ongoing participation in an interventional study. For participants receiving DCC-3116 and binimetinib combination: Known Gilbert's syndrome

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, Cohort A Monotherapy)<br>DCC-3116 tablets in escalating dose cohorts given orally twice daily (BID) in 28-day cycles as monotherapy (single agent). If no DLT in 3 participants or 1 DLT/6 participants is observed, dose escalation may continue to the next planned dose cohort. | Drug: DCC-3116<br>* Oral Tablet Formulation<br>|
| Experimental: Dose Escalation (Part 1, Cohort B Combination)<br>Upon determination of the RP2D/MTD single agent, DCC-3116 will be dosed in combination with trametinib. | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Trametinib<br>* Oral Tablet Formulation<br>|
| Experimental: Dose Escalation (Part 1, Cohort C Combination)<br>Upon determination of the RP2D/MTD single agent, DCC-3116 will be dosed in combination with binimetinib. | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Binimetinib<br>* Oral Tablet Formulation<br>|
| Experimental: Dose Escalation (Part 1, Cohort D Combination)<br>Upon determination of the RP2D/MTD single agent, DCC-3116 will be dosed in combination with sotorasib. | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Sotorasib<br>* Oral Tablet Formulation<br>|
| Experimental: Expansion Cohort 1 (Part 2)<br>DCC-3116 tablets given in combination with trametinib in 28-day cycles to evaluate safety and preliminary efficacy of participants with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) (with a documented mutation in KRAS). | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Trametinib<br>* Oral Tablet Formulation<br>|
| Experimental: Expansion Cohort 2 (Part 2)<br>DCC-3116 tablets orally given in combination with trametinib in 28-day cycles to evaluate safety and preliminary efficacy of participants with non-small cell lung cancer (NSCLC) (with a documented mutation in KRAS, NRAS, NF1,or BRAF). | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Trametinib<br>* Oral Tablet Formulation<br>|
| Experimental: Expansion Cohort 3 (Part 2)<br>DCC-3116 tablets orally given in combination with trametinib in 28-day cycles to evaluate safety and preliminary efficacy of participants with colorectal cancer (CRC) (with a documented mutation in KRAS, NRAS, NF1, or BRAF). | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Trametinib<br>* Oral Tablet Formulation<br>|
| Experimental: Expansion Cohort 4 (Part 2)<br>DCC-3116 tablets orally given in combination with binimetinib in 28-day cycles to evaluate safety and preliminary efficacy of participants with melanoma (with a documented mutation in NRAS). | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Binimetinib<br>* Oral Tablet Formulation<br>|
| Experimental: Expansion Cohort 5 (Part 2)<br>DCC-3116 tablets orally given in combination with sotorasib in 28-day cycles to evaluate safety and preliminary efficacy of participants with NSCLC (with a documented mutation in KRAS G12C). | Drug: DCC-3116<br>* Oral Tablet Formulation<br>Drug: Sotorasib<br>* Oral Tablet Formulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | Identify the observed adverse events, serious adverse events associated with DCC-3116 as monotherapy and in combination with trametinib, binimetinib, or sotorasib. | Approximately 24 months | 
| Maximum tolerated dose (MTD) | Identify the dose-limiting toxicities for each dose level tested and determine the maximum tolerated dose/recommended Phase 2 doses of DCC-3116 as monotherapy and in combination with trametinib, binimetinib, or sotorasib. | Approximately 18 months | 
| Objective response rate (ORR) (Expansion Phase) | Proportion of participants who achieve CR or PR per RECIST 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 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 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 v1.1 or death, whichever occurs first. | Approximately 24 months | 
| Maximum observed concentration (Cmax) | Measure the maximum observed concentration of DCC-3116 (single-agent and combinations) | Predose and up to 12 hours postdose. | 
| Time to maximum observed concentration (Tmax) | Measure the time to maximum plasma concentration of DCC-3116 (single-agent and combinations) | Predose and up to 12 hours postdose. | 
| Minimum observed concentration (Cmin) | Measure the minimum observed concentration of DCC-3116 (single-agent and combinations) | Predose and up to 12 hours postdose. | 
| Area under the concentration-time curve( AUC) | Measure the AUC of DCC-3116 (single-agent and 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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RAF, RAS, KRAS, NRAS, BRAF, DCC-3116, NF1