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

NCT01271803 | Completed Phase 1 Results

• 1 other identifier: NO25395
• Study Type: interventional
• Target: 131
• Locations: 2 countries
• Sites: 10

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

Outcome Measures

Primary Outcomes (19)

• Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts

  DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade less than or equal to (≤) 1 within 7 days, b) Grade 3 rash or photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cutaneous squamous cell carcinoma (cuSCC) that was subsequently resected, d) Grade greater than or equal to (≥) 3 fatigue or hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum creatine phosphokinase (CPK) levels, which is asymptomatic, deemed by the investigator to be clinically insignificant and that returned to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (absolute neutrophil count \[ANC\] less than \<500/microliter \[μL\]), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase.

  28 Days

• Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES

  The highest dose level(s) at which fewer than one-third of participants experienced a DLT was declared the MTD. DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade ≤1 within 7 days, b) Grade 3 rash/photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cuSCC that was subsequently resected, d) Grade ≥3 fatigue/hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum CPK levels, which is asymptomatic, deemed to be clinically insignificant and returns to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (ANC \<500/ μL), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase.

  28 Days

• Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1

  Cycle 1: predose (0 hours [hr]) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1

• Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3

  Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1

• Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1

  Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1

• Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1

  Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1

• AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3

  Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1

• Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1

  Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14

• Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1

  Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14

• AUC0-24 of Cobimetinib on Day 14, Cycle 1

  Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14

• Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1

  Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

  Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14

• Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study

  Predose (0 hr) on Days -1, 1; 2, 4, 6, 8 hr postdose on Day -1

• Cmax of Vemurafenib on Day -1, Cycle 1 of Cohorts 1C and 2A in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study

  Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1

• Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study

  Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1

• Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants

  Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1

• Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants

  Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1

• Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants

  Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1

• Cmax of Vemurafenib on Day 14, Cycle 1

  Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14

• Tmax of Vemurafenib on Day 14, Cycle 1

  Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14

Secondary Outcomes (6)

• Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1

  Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression (up to 82 months)

• Percentage of Participants With Disease Progression According to RECIST V 1.1

  Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months)

• Median Duration of Response (DOR)

  Time from first occurrence of objective response until the time of disease progression or death from any cause (up to 82 months)

• Overall Survival (OS)

  Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months)

• Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2

  Cycle 1 (Days 10 to 14), Cycle 2 (Days 14+7)

Study Arms (12)

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

Cobimetinib Monotherapy (100 mg or 60 mg)

EXPERIMENTAL

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.

Drug: Cobimetinib

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

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

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: vemurafenib

Interventions

Cobimetinib 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.

Also known as: GDC-0973

CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib; CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib; Cobimetinib Monotherapy (100 mg or 60 mg); DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib; DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib; DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib; DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib; DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib; DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib; DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib; DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib; DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib

vemurafenib 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 1A): 60 mg Cobimetinib + 720 mg Vemurafenib; CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib; DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib; DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib; DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib; DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib; DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib; DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib; DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib; DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib; DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib

Eligibility Criteria

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

You may qualify if:

• 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
• be previously untreated for locally advanced/unresectable or metastatic melanoma or
• previously treated but without prior exposure to any BRAF or MEK inhibitor therapy or
• 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
• progressed on vemurafenib administered in a postmarketing setting immediately prior to enrollment in this study.
• Life expectancy \>/=12 weeks

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (10)

UCLA Department of Medicine

Los Angeles, California, 90024, United States

Location

University of California at San Francisco

San Francisco, California, 94115, United States

Location

The Angeles Clinic and Research Institute, Santa Monica Office

Santa Monica, California, 90025, United States

Location

University of Colorado; Anschutz Cancer Pavilion

Aurora, Colorado, 80045, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

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

Indianapolis, Indiana, 46202, United States

Location

Karmanos Cancer Inst. ; Hudson Webber; Cancer Research Building

Detroit, Michigan, 48201, United States

Location

New York University Medical Center

New York, New York, 10036, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Peter Maccallum Cancer Institute; Medical Oncology

Melbourne, Victoria, 3000, Australia

Location

Related Publications (3)

• 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.

  PMID: 32746839 DERIVED

• 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.

  PMID: 25037139 DERIVED

• 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.

  PMID: 22651703 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

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

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-LaRoche

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: January 5, 2011
• First Posted: January 7, 2011
• Study Start: February 17, 2011
• Primary Completion: October 1, 2013
• Study Completion: December 12, 2017
• Last Updated: July 29, 2019
• Results First Posted: June 17, 2016

Record last verified: 2019-07

Locations

US (9); AU (1)