Clinical trial NCT01271803: A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma
Official title: A Phase IB, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of Vemurafenib in Combination With GDC-0973 (Cobimetinib) When Administered in BRAFV600E Mutation-Positive Patients Previously Treated (But Without Prior Exposure to BRAF or MEK Inhibitor Therapy) or Previously Untreated for Locally Advanced/Unresectable or Metastatic Melanoma or Those Who Have Progressed After Treatment With Vemurafenib
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Melanoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2011-01-07
Enrollment: 131
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts
timeFrame: 28 Days
measure: Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES
timeFrame: 28 Days
measure: Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1
timeFrame: Cycle 1: predose (0 hours [hr]) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
measure: Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3
timeFrame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
measure: Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1
timeFrame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
measure: Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1
timeFrame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
measure: AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3
timeFrame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
measure: Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1
timeFrame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
measure: Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1
timeFrame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
measure: AUC0-24 of Cobimetinib on Day 14, Cycle 1
timeFrame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
measure: Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1
timeFrame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
measure: Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
timeFrame: Predose (0 hr) on Days -1, 1; 2, 4, 6, 8 hr postdose on Day -1
measure: 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
timeFrame: Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
measure: Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
timeFrame: Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
measure: Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
timeFrame: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
measure: Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants
timeFrame: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
measure: Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
timeFrame: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
measure: Cmax of Vemurafenib on Day 14, Cycle 1
timeFrame: Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14
measure: Tmax of Vemurafenib on Day 14, Cycle 1
timeFrame: Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14
Secondary outcomes:
measure: 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
timeFrame: Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression (up to 82 months)
measure: Percentage of Participants With Disease Progression According to RECIST V 1.1
timeFrame: 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)
measure: Median Duration of Response (DOR)
timeFrame: Time from first occurrence of objective response until the time of disease progression or death from any cause (up to 82 months)
measure: Overall Survival (OS)
timeFrame: 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)
measure: Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2
timeFrame: Cycle 1 (Days 10 to 14), Cycle 2 (Days 14+7)
measure: Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC)
timeFrame: At baseline; Cycle 1: Day 14; at disease progression (Up to 32 months)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Department of Medicine
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Santa Monica
country: United States
facility: The Angeles Clinic and Research Institute, Santa Monica Office
state: California
city: Aurora
country: United States
facility: University of Colorado; Anschutz Cancer Pavilion
state: Colorado
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University - Department of Medicine, Division of Gastroenterology/Hepatology
state: Indiana
city: Detroit
country: United States
facility: Karmanos Cancer Inst. ; Hudson Webber; Cancer Research Building
state: Michigan
city: New York
country: United States
facility: New York University Medical Center
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Institute; Medical Oncology
state: Victoria
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.