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

NCT ID: NCT01656642

Last Updated: 2020-07-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 67 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-08-13
• Study Completion Date: 2020-03-25

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.

Conditions

Malignant Melanoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered q3w or q2w.

Vemurafenib

Intervention Type: DRUG

Oral repeating dose, depending on arm/cohort

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

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered q3w or q2w.

Vemurafenib

Intervention Type: DRUG

Oral repeating dose, depending on arm/cohort

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

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered q3w or q2w.

Vemurafenib

Intervention Type: DRUG

Oral repeating dose, depending on arm/cohort

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

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered q3w or q2w.

Cobimetinib

Intervention Type: DRUG

Oral repeating dose

Vemurafenib

Intervention Type: DRUG

Oral repeating dose, depending on arm/cohort

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

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered q3w or q2w.

Cobimetinib

Intervention Type: DRUG

Oral repeating dose

Vemurafenib

Intervention Type: DRUG

Oral repeating dose, depending on arm/cohort

ECB: Ate+Vem+Cob (Mandatory Biopsy)

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered q3w or q2w.

Cobimetinib

Intervention Type: DRUG

Oral repeating dose

Vemurafenib

Intervention Type: DRUG

Oral repeating dose, depending on arm/cohort

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

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered q3w or q2w.

Cobimetinib

Intervention Type: DRUG

Oral repeating dose

Vemurafenib

Intervention Type: DRUG

Oral repeating dose, depending on arm/cohort

Interventions

Atezolizumab

Atezolizumab will be administered q3w or q2w.

Intervention Type: DRUG

Cobimetinib

Oral repeating dose

Intervention Type: DRUG

Vemurafenib

Oral repeating dose, depending on arm/cohort

Intervention Type: DRUG

Other Intervention Names

MPDL3280A, an engineered anti-PD-L1 antibody; TECENTRIQ; RO5541267; GDC-0973; XL518; Cotellic; RO5514041; Zelboraf; RO5185426

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Genentech, Inc.

Locations

UCLA

Los Angeles, California, United States

The Angeles Clinic and Research Institute - W LA Office

Los Angeles, California, United States

University of Colorado Health Science Center; Biomedical Research Bldg. Room 511

Aurora, Colorado, United States

Florida Cancer Specialists - Sarasota

Sarasota, Florida, United States

Massachusetts General Hospital.

Boston, Massachusetts, United States

Dana Farber Can Ins

Boston, Massachusetts, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

MD Anderson Cancer Center

Houston, Texas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 31171876 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24577748 (View on PubMed)

Other Identifiers

2012-002738-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GP28384

Identifier Type: -

Identifier Source: org_study_id