Melanoma
Conditions
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.
Interventions
DRUGBelvarafenib
Twice daily (BID), continuous dosing
DRUGCobimetinib
Once daily (QD) or three times weekly (TIW) for 21 days, 7 days off
DRUGNivolumab
Once every 4 weeks (Q4W)
Sponsors
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Dose Limiting Toxicity (DLTs) | 28 Days from Cycle 1, Day 1 | — |
| Percentage of Participants With Adverse Events | From Cycle 1, Day 1 Up to 4 Years | Severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) according to RECIST v1.1 | Up to Approximately 4 Years | 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 |
| Progression free survival (PFS) according to RECIST v1.1 | Up to Approximately 4 Years | 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 |
| Duration of response (DOR) according to RECIST v1.1 | Up to Approximately 4 Years | 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 |
| Overall survival (OS) | Up to Approximately 4 Years | Defined as the time from the first study treatment to death from any cause |
| 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 | — |
Countries
Australia, Canada, Germany, South Korea, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed