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

Genentech

Status and phase: Completed; Phase 1

Conditions: Malignant Melanoma

Treatments: Drug: Cobimetinib; Drug: Vemurafenib; Drug: Atezolizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT01656642

2012-002738-35 (EudraCT Number)

GP28384

Details and patient eligibility

About

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.

Enrollment: 67 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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67 participants in 7 patient groups

Cohort 1 (C1): Ate+Vem - No Run-in

Experimental group

Description:

Participants will receive atezolizumab (Ate) 1200 milligrams (mg) every 3 weeks (q3w) along with vemurafenib (Vem) 720 mg twice daily (BID) for 21 days in each cycle followed by 7 days off treatment (28-day cycle). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent occurs.

Treatment:

Drug: Atezolizumab

Drug: Vemurafenib

Cohort 2 (C2): Ate+Vem (56 Day Run-in)

Experimental group

Description:

Run-in period (56 days): participants will receive vemurafenib 960 mg orally BID from Day 1 to 49 and vemurafenib 720 mg orally BID from Day 50 to 56. Combination treatment period: Participants will receive fixed dose of atezolizumab 1200 mg intravenous (IV) q3w in combination with vemurafenib 720 mg orally BID in 21 days cycle.

Treatment:

Drug: Atezolizumab

Drug: Vemurafenib

Cohort 3 (C3): Ate+Vem (28 Day Run-in)

Experimental group

Description:

Run-in period (28 days): participants will receive vemurafenib 960 mg orally BID for 21 days, then vemurafenib 720 mg orally BID for 7 days. Combination treatment period: Participants will receive fixed dose of atezolizumab 1200 mg IV q3w in combination with vemurafenib 720 mg orally BID in 21 days cycle.

Treatment:

Drug: Atezolizumab

Drug: Vemurafenib

Cohort 4 (C4): Ate+Vem+Cob (28 Day Run-in)

Experimental group

Description:

Run-in period (28 days): participants will receive vemurafenib 960 mg orally BID for 21 days, then vemurafenib 720 mg orally BID for 7 days in combination with cobimetinib (Cob) 60 mg IV once daily, 21 days on/7 days off schedule (21/7). Combination treatment period: Participants will receive fixed dose of atezolizumab 800 mg IV every 2 weeks (q2w) in combination with vemurafenib 720 mg orally BID and cobimetinib 60 mg orally once daily 21/7 in 28 days cycle.

Treatment:

Drug: Atezolizumab

Drug: Vemurafenib

Drug: Cobimetinib

ECA: Ate+Vem+Cob (Mandatory Biopsy PD)

Experimental group

Description:

Expansion Cohort A (ECA): Approximately 10 participants who experienced disease progression (PD) after receiving prior checkpoint inhibitor therapy will be enrolled and treated with atezolizumab plus (+) vemurafenib + cobimetinib. Serial biopsy tissue sample collections of accessible lesions will be mandatory for all participants enrolled in this cohort. The doses will be decided based on the results of Cohorts 1-4.

Treatment:

Drug: Atezolizumab

Drug: Vemurafenib

Drug: Cobimetinib

ECB: Ate+Vem+Cob (Mandatory Biopsy)

Experimental group

Description:

Expansion Cohort B (ECB): Approximately 20 participants will be enrolled and treated with atezolizumab + vemurafenib + cobimetinib. Serial biopsy tissue sample collections of accessible lesions will be mandatory for all participants. The doses will be decided based on the results of Cohorts 1-4.

Treatment:

Drug: Atezolizumab

Drug: Vemurafenib

Drug: Cobimetinib

ECC: Ate+Vem+Cob (No Mandatory Biopsy)

Experimental group

Description:

Expansion Cohort C (ECC): Approximately 10 participants who experienced disease progression after receiving prior checkpoint inhibitor therapy will be enrolled and treated with atezolizumab + vemurafenib + cobimetinib. Serial biopsy tissue sample collections will be optional for all participants enrolled in this cohort. The doses will be decided based on the results of Cohorts 1-4.

Treatment:

Drug: Atezolizumab

Drug: Vemurafenib

Drug: Cobimetinib