Clinical trial NCT01656642: A Phase 1b Study of Atezolizumab in Combination With Vemurafenib or Vemurafenib Plus Cobimetinib in Participants With BRAFV600-Mutation Positive Metastatic Melanoma
Official title: A Phase Ib, Open-Label Study of The Safety and Pharmacology of Atezolizumab (Anti PD-L1 Antibody) Administered in Combination With Vemurafenib or Vemurafenib Plus Cobimetinib in Patients With BRAFV600-Mutation Positive Metastatic Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Melanoma
Keywords: PD-L1
PD-1
PDL1
antiPD-L1
MPDL3280A
Melanoma
BRAF
MPDL320A
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2012-08-03
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Dose Limiting Toxicities
timeFrame: 21 days (or 28 days for Cohort 4) following the first administration of atezolizumab
measure: Percentage of Participants With Adverse Events
timeFrame: Baseline up to approximately 6 years
Secondary outcomes:
measure: Area Under the Concentration-Time Curve (AUC) of Atezolizumab
timeFrame: 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)
measure: Maximum Serum Concentration of Atezolizumab
timeFrame: 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)
measure: Maximum Plasma Concentration of Vemurafenib
timeFrame: 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)
measure: Minimum Observed Plasma Trough Concentration (Cmin) of Vemurafenib
timeFrame: 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)
measure: Maximum Plasma Concentration of Cobimetinib
timeFrame: 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)
measure: Cmin of Cobimetinib
timeFrame: 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)
measure: Percentage of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)
timeFrame: 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)
measure: Percentage of Participants with Objective Response According to RECIST v1.1
timeFrame: 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)
measure: Percentage of Participants with Objective Response According to Immune-Related Response Criteria (irRC)
timeFrame: 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)
measure: Duration of Objective Response According to RECIST v1.1
timeFrame: 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)
measure: Duration of Objective Response According to irRC
timeFrame: 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)
measure: Progression Free Survival According to RECIST v1.1
timeFrame: 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)
measure: Progression Free Survival According to irRC
timeFrame: 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)
measure: Overall Survival Duration
timeFrame: Baseline until death up to 6 years
measure: Mean Atezolizumab Dose
timeFrame: Approximately 12 months
measure: Total Number of Atezolizumab Cycles
timeFrame: Approximately 12 months
measure: Percentage of Participants With Anti-Atezolizumab Antibodies
timeFrame: 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)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute - W LA Office
state: California
city: Aurora
country: United States
facility: University of Colorado Health Science Center; Biomedical Research Bldg. Room 511
state: Colorado
city: Sarasota
country: United States
facility: Florida Cancer Specialists - Sarasota
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital.
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Can Ins
state: Massachusetts
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Genentech, Inc.
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Sullivan RJ, Hamid O, Gonzalez R, Infante JR, Patel MR, Hodi FS, Lewis KD, Tawbi HA, Hernandez G, Wongchenko MJ, Chang Y, Roberts L, Ballinger M, Yan Y, Cha E, Hwu P. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med. 2019 Jun;25(6):929-935. doi: 10.1038/s41591-019-0474-7. Epub 2019 Jun 6.
citation: Ackerman A, Klein O, McDermott DF, Wang W, Ibrahim N, Lawrence DP, Gunturi A, Flaherty KT, Hodi FS, Kefford R, Menzies AM, Atkins MB, Long GV, Sullivan RJ. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014 Jun 1;120(11):1695-701. doi: 10.1002/cncr.28620. Epub 2014 Feb 27.