A Phase 1b Study of Atezolizumab in Combination With Vemurafenib or Vemurafenib Plus Cobimetinib in Participants With BRAFV600-Mutation Positive Metastatic Melanoma

Malignant Melanoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01656642
• Other study ID #: GP28384
• Secondary ID: 2012-002738-35
• Status: Completed
• Phase: Phase 1
• Start date: August 13, 2012
• Est. completion date: March 25, 2020

Study information

• Verified date: July 2020
• Source: Genentech, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 67
• Est. completion date: March 25, 2020
• Est. primary completion date: March 25, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Malignant Melanoma
• Melanoma

Intervention

Drug:
• Atezolizumab
Atezolizumab will be administered q3w or q2w.
• Cobimetinib
Oral repeating dose
• Vemurafenib
Oral repeating dose, depending on arm/cohort

Locations

Country	Name	City	State
United States	University of Colorado Health Science Center; Biomedical Research Bldg. Room 511	Aurora	Colorado
United States	Dana Farber Can Ins	Boston	Massachusetts
United States	Massachusetts General Hospital.	Boston	Massachusetts
United States	MD Anderson Cancer Center	Houston	Texas
United States	The Angeles Clinic and Research Institute - W LA Office	Los Angeles	California
United States	UCLA	Los Angeles	California
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Florida Cancer Specialists - Sarasota	Sarasota	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Genentech, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Dose Limiting Toxicities		21 days (or 28 days for Cohort 4) following the first administration of atezolizumab
Primary	Percentage of Participants With Adverse Events		Baseline up to approximately 6 years
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Overall Survival Duration		Baseline until death up to 6 years
Secondary	Mean Atezolizumab Dose		Approximately 12 months
Secondary	Total Number of Atezolizumab Cycles		Approximately 12 months
Secondary	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)