A Study to Evaluate the Safety and Activity of Belvarafenib as a Single Agent and in Combination With Either Cobimetinib or Cobimetinib Plus Nivolumab in Patients With NRAS-mutant Advanced Melanoma.

Study Overview
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Brief Summary
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This study will evaluate the safety, pharmacokinetics, and activity of belvarafenib as a single agent and in combination with either cobimetinib or cobimetinib plus nivolumab in patients with NRAS-mutant advanced melanoma who have received anti-PD-1/PD-L1 therapy.

Detailed Description
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The study will evaluate three treatment regimens in three arms: a belvarafenib monotherapy arm (Belva arm); a belvarafenib plus cobimetinib arm (Belva + Cobi arm) in an initial dose-finding phase followed by an expansion phase and a belvarafenib plus cobimetinib plus nivolumab arm (Belva + Cobi + Nivo arm) in a run-in phase followed by an expansion phase.

Official Title
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A Phase Ib, Open-Label, Multicenter Study to Evaluate the Safety, Pharmacokinetics, and Activity of Belvarafenib as a Single Agent and in Combination With Either Cobimetinib or Cobimetinib Plus Nivolumab in Patients With NRAS-Mutant Advanced Melanoma Who Have Received Anti-PD-1/PD-L1 Therapy

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Belvarafenib
* Drug: Cobimetinib
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ECOG Performance Status of 0 or 1 Histologically confirmed, metastatic (recurrent or de novo Stage IV) or unresectable locally advanced (Stage III) cutaneous melanoma, that has progressed on or after treatment with anti-PD-1 or anti-PD-L1 therapy. Patients may have received up to two lines of systemic cancer therapy. Treatment with anti-PD-1/PD-L1 in the adjuvant setting is acceptable. Patients must have progressed disease at study entry Documentation of NRAS mutation-positive within 5 years prior to screening Tumor specimen availability Adequate hematologic and end-organ function Measurable disease per RECIST v1.1 Exclusion Criteria: Prior treatment with a pan-RAF inhibitor Treatment with systemic immunotherapy agents (e.g., anti-CTLA4, anti-PD(L)1, cytokine therapy, investigational therapy, etc.) within 28 days prior to C1D1 Symptomatic, untreated, or actively progressing CNS metastases History or signs/symptoms of clinically significant cardiovascular disease Known clinically significant liver disease History of autoimmune disease or immune deficiency Prior treatment with a MEK inhibitor (cobimetinib arm) History of or evidence of retinal pathology on ophthalmologic examination (cobimetinib arm) History of immune-related AE attributed to prior anti-PD(L)1 therapy that resulted in permanent discontinuation of anti-PD(L)1 therapy (nivolumab arm)

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belvarafenib Monotherapy<br>Twice daily (BID), continuous dosing. | Drug: Belvarafenib<br>* Twice daily (BID), continuous dosing<br>|
| Experimental: Belvarafenib Plus Cobimetinib<br>Recommended dose (RD) and schedule of belvarafenib and cobimetinib selected based on the safety data, tolerability, pharmacokinetics, and anti-tumor activity tested in dose-finding phase followed by an expansion phase. | Drug: Cobimetinib<br>* Once daily (QD) or three times weekly (TIW) for 21 days, 7 days off<br>|
| Experimental: Belvarafenib Plus Cobimetinib Plus Nivolumab<br>Recommended dose (RD) and schedule of belvarafenib and cobimetinib plus nivolumab IV infusion every 4 weeks (Q4W) in a run-in phase followed by an expansion phase | Drug: Nivolumab<br>* Once every 4 weeks (Q4W)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Dose Limiting Toxicity (DLTs) |  | 28 Days from Cycle 1, Day 1 | 
| Percentage of Participants With Adverse Events | Severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 | From Cycle 1, Day 1 Up to 4 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) according to RECIST v1.1 | Defined as the percentage of participants with a CR or PR on two consecutive occasions >/= 4 weeks apart, as determined by the investigator according to RECIST v1.1 | Up to Approximately 4 Years | 
| Progression free survival (PFS) according to RECIST v1.1 | Defined as the time from the first study treatment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1 | Up to Approximately 4 Years | 
| Duration of response (DOR) according to RECIST v1.1 | Defined as the time from the first occurrence of a confirmed objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1 | Up to Approximately 4 Years | 
| Overall survival (OS) | Defined as the time from the first study treatment to death from any cause | Up to Approximately 4 Years | 
| Plasma concentration of belvarafenib at specified timepoints |  | Up to 30 Days After the Final Dose of Study Drug | 
| Plasma concentration of cobimetinib at specified timepoints |  | Up to 30 Days After the Final Dose of Study Drug |