Clinical trial NCT04835805: 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.
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Melanoma
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2021-04-08
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Percentage of Participants With Dose Limiting Toxicity (DLTs)
timeFrame: 28 Days from Cycle 1, Day 1
measure: Percentage of Participants With Adverse Events
timeFrame: From Cycle 1, Day 1 Up to 4 Years
Secondary outcomes:
measure: Objective response rate (ORR) according to RECIST v1.1
timeFrame: Up to Approximately 4 Years
measure: Progression free survival (PFS) according to RECIST v1.1
timeFrame: Up to Approximately 4 Years
measure: Duration of response (DOR) according to RECIST v1.1
timeFrame: Up to Approximately 4 Years
measure: Overall survival (OS)
timeFrame: Up to Approximately 4 Years
measure: Plasma concentration of belvarafenib at specified timepoints
timeFrame: Up to 30 Days After the Final Dose of Study Drug
measure: Plasma concentration of cobimetinib at specified timepoints
timeFrame: Up to 30 Days After the Final Dose of Study Drug
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: California Pacific Medical Center Research Institute
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family CCC
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre-East Melbourne
state: Victoria
city: Nedlands
country: Australia
facility: Linear Clinical Research Ltd
state: Western Australia
city: Ottawa
country: Canada
facility: Ottawa Hospital Regional Cancer Centre
state: Ontario
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Tuebingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center - PPDS
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Moschos SJ. War against NRAS-Mutant Melanoma Using Targeted Therapies Remains Challenging. Clin Cancer Res. 2022 Jul 15;28(14):2977-2979. doi: 10.1158/1078-0432.CCR-22-1256.