Malignant Melanoma
Conditions
Keywords
PD-L1, PD-1, PDL1, antiPD-L1, MPDL3280A, Melanoma, BRAF, MPDL320A
Brief summary
This is an open-label, multicenter, Phase Ib, dose-escalation and cohort-expansion study of atezolizumab (anti-programmed death-ligand 1 \[PD-L1\] antibody) in combination with vemurafenib or vemurafenib plus cobimetinib in participants with BRAFV600-mutation positive metastatic melanoma. Enrolled participants may continue treatment until they are no longer experiencing clinical benefit as assessed by the investigator and in alignment with the protocol.
Interventions
DRUGAtezolizumab
Atezolizumab will be administered q3w or q2w.
DRUGCobimetinib
Oral repeating dose
DRUGVemurafenib
Oral repeating dose, depending on arm/cohort
Sponsors
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic or cytologic documentation of metastatic or Stage IIIc unresectable melanoma, with BRAFV600 mutation as assessed by BRAFV600 Mutation Test. Origin of the primary tumor may be of skin, mucosal, or acral locations but not of uveal origin. Participants having an unknown primary tumor may be eligible if uveal melanoma can be ruled out * Eastern Cooperative Oncology Group performance status of 0 or 1 * Adequate hematologic and end organ function * Measurable disease per RECIST v1.1 * For women of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use two effective forms of contraceptive methods including at least one that results in a failure rate of less than (\<) 1 percent (%) per year during the treatment period and for at least 6 months after the last dose of study drug * For men, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm * Agreement to mandatory archival tissue or fresh biopsy * Agreement to the collection of serial fresh lesion samples (required, if feasible, for entry into Escalation Cohorts 4 and Expansion Cohorts A & B and optional, but encouraged in Escalation Cohorts 2 & 3 and Expansion Cohort C)
Exclusion criteria
* Receipt of prior systemic anti-cancer therapy for unresectable, locally advanced or metastatic melanoma * Receipt of prior immunomodulatory agents, including programmed death-1 or PD-L1 targeted therapy or cytotoxic T-lymphocyte-associated antigen 4 targeted therapy including ipilimumab (this exclusion criterion does not apply to participants enrolled in Expansion Cohort A) * Receipt of prior mitogen-activated protein kinase inhibitor pathway agents including mitogen-activated protein kinase inhibitor and BRAF kinase inhibitor * Major surgical procedure within 28 days prior to Day 1 or anticipation of need for a major surgical procedure during the course of the study * Radiotherapy less than or equal to (\<=) 7 days prior to Day 1 * Adverse events from prior anti-cancer therapy that have not resolved to Grade \<= 1 except for alopecia * Any active malignancy (other than BRAF-mutated melanoma) or a previous malignancy within the past 3 years * For participants to be enrolled into the vemurafenib+cobimetinib+ atezolizumab cohorts: history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy, retinal vein occlusion, or neovascular macular degeneration * Pregnant or breastfeeding women * Intake of St. John's wort or hyperforin (potent cytochrome P450 \[CYP\] 3A4 enzyme inducer) or grapefruit juice (potent CYP3A4 enzyme inhibitor) within 7 days preceding the start of study treatment to the end of treatment * Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation or known hypersensitivity to any component of cobimetinib or vemurafenib * Inability to comply with study and follow-up procedures
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Dose Limiting Toxicities | 21 days (or 28 days for Cohort 4) following the first administration of atezolizumab |
| Percentage of Participants With Adverse Events | Baseline up to approximately 6 years |
Secondary
| Measure | Time frame |
|---|---|
| Cmin of Cobimetinib | Run-in period: predose (0 hour) on D1, 8, and 22; combination treatment period: predose (0 hour) on D1 and 15 of C1 and D15 of C2 (Cycle = 28 days) |
| Area Under the Concentration-Time Curve (AUC) of Atezolizumab | Predose (0 hour), 30 minutes postdose on Day (D) 1 of Cycles (C) 1, 2; predose on D15, D8 of C1; predose on D1 of C3, 4, 5, 7, 8, every 8 cycles thereafter up to 90 days after end of treatment visit (up to approximately 6 years) (Cycle=28 days) |
| Maximum Serum Concentration of Atezolizumab | Predose (0 hour), 30 minutes postdose on Day (D) 1 of Cycles (C) 1, 2; predose on D15, D8 of C1; predose on D1 of C3, 4, 5, 7, 8, every 8 cycles thereafter up to 90 days after end of treatment visit (up to approximately 6 years) (Cycle=28 days) |
| Maximum Plasma Concentration of Vemurafenib | Run-in period: predose (0 hour) on D1, 8, and 22, 3 hours postdose on D22; combination treatment period: predose (0 hour) on D1 of C1 and 2, 3 hours postdose on D1 of C2 (Cycle = 28 days) |
| Percentage of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) | Baseline until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks of combination treatment period for first 24 weeks and then every 9 weeks up to approximately 6 years) |
| Percentage of Participants with Objective Response According to RECIST v1.1 | Baseline until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks of combination treatment period for first 24 weeks and then every 9 weeks up to approximately 6 years) |
| Percentage of Participants with Objective Response According to Immune-Related Response Criteria (irRC) | Baseline until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks of combination treatment period for first 24 weeks and then every 9 weeks up to approximately 6 years) |
| Minimum Observed Plasma Trough Concentration (Cmin) of Vemurafenib | Run-in period: predose (0 hour) on D1, 8, and 22; combination treatment period: predose (0 hour) on D1 of C1 and 2 (Cycle = 28 days) |
| Duration of Objective Response According to irRC | Baseline until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks of combination treatment period for first 24 weeks and then every 9 weeks up to approximately 6 years) |
| Progression Free Survival According to RECIST v1.1 | Baseline until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks of combination treatment period for first 24 weeks and then every 9 weeks up to approximately 6 years) |
| Progression Free Survival According to irRC | Baseline until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks of combination treatment period for first 24 weeks and then every 9 weeks up to approximately 6 years) |
| Overall Survival Duration | Baseline until death up to 6 years |
| Mean Atezolizumab Dose | Approximately 12 months |
| Total Number of Atezolizumab Cycles | Approximately 12 months |
| Percentage of Participants With Anti-Atezolizumab Antibodies | Predose (0 hour) on D1 (run-in period), predose (0 hour) on D1 of C2, 3, 4, 8, every 8 cycles thereafter up to 90 days after end of treatment visit (up to approximately 6 years) (Cycle=28 days) |
| Duration of Objective Response According to RECIST v1.1 | Baseline until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks of combination treatment period for first 24 weeks and then every 9 weeks up to approximately 6 years) |
| Maximum Plasma Concentration of Cobimetinib | Run-in period: predose (0 hour) on D1, 8, and 22; combination treatment period: predose (0 hour) on D1 and 15 of C1 and D15 of C2, 3 hours postdose on D15 of Cycle 1 (Cycle = 28 days) |
Countries
United States
Outcome results
None listed