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

NCT01656642 | Completed Phase 1

• 2 other identifiers: GP283842012-002738-35
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 8

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

Keywords

PD-L1; PD-1; PDL1; antiPD-L1; MPDL3280A; Melanoma; BRAF; MPDL320A

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (17)

• 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)

• 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)

• 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)

Study Arms (7)

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

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Vemurafenib

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

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Vemurafenib

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

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Vemurafenib

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

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Cobimetinib; Drug: Vemurafenib

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

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Cobimetinib; Drug: Vemurafenib

ECB: Ate+Vem+Cob (Mandatory Biopsy)

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Cobimetinib; Drug: Vemurafenib

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

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Cobimetinib; Drug: Vemurafenib

Interventions

Atezolizumab DRUG

Atezolizumab will be administered q3w or q2w.

Also known as: MPDL3280A, an engineered anti-PD-L1 antibody, TECENTRIQ, RO5541267

Cohort 1 (C1): Ate+Vem - No Run-in; Cohort 2 (C2): Ate+Vem (56 Day Run-in); Cohort 3 (C3): Ate+Vem (28 Day Run-in); Cohort 4 (C4): Ate+Vem+Cob (28 Day Run-in); ECA: Ate+Vem+Cob (Mandatory Biopsy PD); ECB: Ate+Vem+Cob (Mandatory Biopsy); ECC: Ate+Vem+Cob (No Mandatory Biopsy)

Cobimetinib DRUG

Oral repeating dose

Also known as: GDC-0973, XL518, Cotellic, RO5514041

Cohort 4 (C4): Ate+Vem+Cob (28 Day Run-in); ECA: Ate+Vem+Cob (Mandatory Biopsy PD); ECB: Ate+Vem+Cob (Mandatory Biopsy); ECC: Ate+Vem+Cob (No Mandatory Biopsy)

Vemurafenib DRUG

Oral repeating dose, depending on arm/cohort

Also known as: Zelboraf, RO5185426

Cohort 1 (C1): Ate+Vem - No Run-in; Cohort 2 (C2): Ate+Vem (56 Day Run-in); Cohort 3 (C3): Ate+Vem (28 Day Run-in); Cohort 4 (C4): Ate+Vem+Cob (28 Day Run-in); ECA: Ate+Vem+Cob (Mandatory Biopsy PD); ECB: Ate+Vem+Cob (Mandatory Biopsy); ECC: Ate+Vem+Cob (No Mandatory Biopsy)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• Receipt of prior systemic anti-cancer therapy for unresectable, locally advanced or metastatic melanoma
• 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (8)

UCLA

Los Angeles, California, 90024, United States

Location

The Angeles Clinic and Research Institute - W LA Office

Los Angeles, California, 90025, United States

Location

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

Aurora, Colorado, 80045, United States

Location

Florida Cancer Specialists - Sarasota

Sarasota, Florida, 34232, United States

Location

Massachusetts General Hospital.

Boston, Massachusetts, 02114, United States

Location

Dana Farber Can Ins

Boston, Massachusetts, 02215, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (2)

• 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.

  PMID: 31171876 DERIVED

• 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.

  PMID: 24577748 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

atezolizumab; cobimetinib; Vemurafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Clinical Trials

  Genentech, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 1, 2012
• First Posted: August 3, 2012
• Study Start: August 13, 2012
• Primary Completion: March 25, 2020
• Study Completion: March 25, 2020
• Last Updated: July 21, 2020

Record last verified: 2020-07

Locations

US (8)