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.

Genentech

Status and phase: Active, not recruiting; Phase 1

Conditions: Melanoma

Treatments: Drug: Nivolumab; Drug: Cobimetinib; Drug: Belvarafenib

Study type: Interventional

Funder types: Industry

Identifiers

NCT04835805

GO42273

2020-003674-41 (EudraCT Number)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 65 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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65 participants in 3 patient groups

Belvarafenib Monotherapy

Experimental group

Description:

Twice daily (BID), continuous dosing.

Treatment:

Drug: Belvarafenib

Belvarafenib Plus Cobimetinib

Experimental group

Description:

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.

Treatment:

Drug: Cobimetinib

Belvarafenib Plus Cobimetinib Plus Nivolumab

Experimental group

Description:

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

Treatment:

Drug: Nivolumab