A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma

NCT ID: NCT01271803

Last Updated: 2019-07-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 131 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-02-17
• Study Completion Date: 2017-12-12

Brief Summary

This open-label, dose-escalation study of vemurafenib in combination with cobimetinib will evaluate the safety, tolerability and pharmacokinetics in participants with BRAFV600 mutation-positive metastatic melanoma. Participants with previously untreated, BRAFV600E mutation-positive, locally advanced/unresectable or metastatic melanoma or those who have progressed on vemurafenib monotherapy immediately prior to enrolling in this trial are eligible. Participants will be assigned to different cohorts with escalating oral doses of vemurafenib and cobimetinib. This study consists of 2 stages, Stage 1 (Dose Escalation Stage [DES] and Cohort Expansion Stage [CES]) and the anticipated time on study treatment is until disease progression, unacceptable toxicity or any other discontinuation criterion is met.

Conditions

Malignant Melanoma

Study Design

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

Study Groups

DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib

Participants will receive oral 60 milligrams (mg) cobimetinib once daily (QD) on Days 1-14, followed by 14 days off on Days 15-28 (14/14 dosing schedule) and oral 720 mg vemurafenib twice daily (BID) on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib

Participants will receive oral 60 mg cobimetinib QD on Days 1-21, followed by 7 days off on Days 22-28 (21/7 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib

Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib

Participants will receive oral 60 mg cobimetinib QD on Days 1-28 (28/0 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib

Participants will receive oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib

Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib

Participants will receive oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib

Participants will receive oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib

Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Cobimetinib Monotherapy (100 mg or 60 mg)

Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule, or oral 100 mg cobimetinib QD on 14/14 dosing schedule of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib

Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib

Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Interventions

Cobimetinib

Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Intervention Type: DRUG

vemurafenib

Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Intervention Type: DRUG

Other Intervention Names

GDC-0973

Eligibility Criteria

Inclusion Criteria

• Participants with histologically confirmed melanoma (unresectable Stage IIIc and Stage IV metastatic melanoma, as defined by American Joint Committee on Cancer [AJCC])
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1
• Eastern Cooperative Oncology Group (ECOG) Performance Status of less than or equal to (</=) 1
• Participants must

1. be previously untreated for locally advanced/unresectable or metastatic melanoma or

2. previously treated but without prior exposure to any BRAF or MEK inhibitor therapy or

3. progressed on vemurafenib while participating in a Phase I (including clinical pharmacology studies), II, or III clinical study or expanded access programs (EAP) immediately prior to enrollment in this study or

4. progressed on vemurafenib administered in a postmarketing setting immediately prior to enrollment in this study.

• Life expectancy >/=12 weeks

Exclusion Criteria

• History of prior significant toxicity from another RAF or MEK pathway inhibitor requiring discontinuation of treatment
• Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment
• Experimental therapy within 4 weeks prior to first dose of study drug treatment except vemurafenib
• Major surgery within 4 weeks of first dose of study drug treatment or planning a major surgery during the study

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

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

UCLA Department of Medicine

Los Angeles, California, United States

University of California at San Francisco

San Francisco, California, United States

The Angeles Clinic and Research Institute, Santa Monica Office

Santa Monica, California, United States

University of Colorado; Anschutz Cancer Pavilion

Aurora, Colorado, United States

University of Chicago

Chicago, Illinois, United States

Indiana University - Department of Medicine, Division of Gastroenterology/Hepatology

Indianapolis, Indiana, United States

Karmanos Cancer Inst. ; Hudson Webber; Cancer Research Building

Detroit, Michigan, United States

New York University Medical Center

New York, New York, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Peter Maccallum Cancer Institute; Medical Oncology

Melbourne, Victoria, Australia

Countries

United States; Australia

References

Ascierto PA, Ribas A, Larkin J, McArthur GA, Lewis KD, Hauschild A, Flaherty KT, McKenna E, Zhu Q, Mun Y, Dreno B. Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib +/- cobimetinib: a pooled analysis of four clinical trials. J Transl Med. 2020 Aug 3;18(1):294. doi: 10.1186/s12967-020-02458-x.

Reference Type: DERIVED

PMID: 32746839 (View on PubMed)

Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, Flaherty L, Logan T, Chmielowski B, Lewis K, Kee D, Boasberg P, Yin M, Chan I, Musib L, Choong N, Puzanov I, McArthur GA. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014 Aug;15(9):954-65. doi: 10.1016/S1470-2045(14)70301-8. Epub 2014 Jul 15.

Reference Type: DERIVED

PMID: 25037139 (View on PubMed)

Baudy AR, Dogan T, Flores-Mercado JE, Hoeflich KP, Su F, van Bruggen N, Williams SP. FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973. EJNMMI Res. 2012 May 31;2(1):22. doi: 10.1186/2191-219X-2-22.

Reference Type: DERIVED

PMID: 22651703 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NO25395

Identifier Type: -

Identifier Source: org_study_id