Phase 1
N=131
A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma
Malignant Melanoma
Bottom Line
View on ClinicalTrials.gov: NCT01271803 ↗Enrolled (actual)
131
Serious AEs
43.5%
Results posted
Jun 2016
Primary outcome: Primary: Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts — 0; 0; 1; 0 participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- Cobimetinib (Drug); vemurafenib (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Hoffmann-La Roche
- Primary completion
- Oct 2013
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts |
0; 0; 1; 0; 2; 0 | — |
| PRIMARY Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES |
60; 960 | — |
| PRIMARY Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 |
159; 146; 121; 136; 130; 133 | — |
| PRIMARY Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3 |
51.6 | — |
| PRIMARY Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 |
4.00; 4.0; 4.00; 2.03; 3.99; 4.02 | — |
| PRIMARY Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 |
2280; 1990; 1790; 1300; 1850; 1600 | — |
| PRIMARY AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3 |
727 | — |
| PRIMARY Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 |
342; 307; 232; 239; 414; 195 | — |
| PRIMARY Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 |
2.0; 3.98; 4.02; 4.00; 6.00; 6.0 | — |
| PRIMARY AUC0-24 of Cobimetinib on Day 14, Cycle 1 |
5180; 4800; 3540; 4500; 7020; 3820 | — |
| PRIMARY Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 |
11.6; 12.5; 17.0; 13.3; 8.55; 21.0 | — |
| PRIMARY Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study |
36.4; 34.3; 60.9; 56.0; 36.4; 48.2 | — |
| PRIMARY 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 |
38.8; 48.8 | — |
| PRIMARY Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study |
2.42; 2.50; 3.69; 4.55; 2.03; 1.65 | — |
| PRIMARY Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants |
3.99; 2.31; 4.16; 1.25; 2.55; 2.60 | — |
| PRIMARY Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants |
2.08 | — |
| PRIMARY Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants |
5.2; 4.15; 5.17; 5.33; 2.08; 4.00 | — |
| PRIMARY Cmax of Vemurafenib on Day 14, Cycle 1 |
34.7; 29.4; 43.7; 31.7; 51.3; 43.6 | — |
| PRIMARY Tmax of Vemurafenib on Day 14, Cycle 1 |
1.98; 2.15; 1.95; 1.98; 0.33; 5.6 | — |
| SECONDARY 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 |
15.2; 87.3 | — |
| SECONDARY Percentage of Participants With Disease Progression According to RECIST V 1.1 |
36.4; 3.2 | — |
| SECONDARY Median Duration of Response (DOR) |
6.8; 14.3 | — |
| SECONDARY Overall Survival (OS) |
8.5; 31.8 | — |
| SECONDARY Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2 |
8.75; 8.19; -43.33; -65.74; -33.09; -70.73 | — |
| SECONDARY Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC) |
7; 5 | — |
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 ( /=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
Data sourced from ClinicalTrials.gov (NCT01271803). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.