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

Malignant Melanoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01271803
• Other study ID #: NO25395
• Status: Completed
• Phase: Phase 1
• Start date: February 17, 2011
• Est. completion date: December 12, 2017

Study information

• Verified date: July 2019
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 131
• Est. completion date: December 12, 2017
• Est. primary completion date: October 1, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Malignant Melanoma
• Melanoma

Intervention

Drug:
• 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.
• 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.

Locations

Country	Name	City	State
Australia	Peter Maccallum Cancer Institute; Medical Oncology	Melbourne	Victoria
United States	University of Colorado; Anschutz Cancer Pavilion	Aurora	Colorado
United States	University of Chicago	Chicago	Illinois
United States	Karmanos Cancer Inst. ; Hudson Webber; Cancer Research Building	Detroit	Michigan
United States	Indiana University - Department of Medicine, Division of Gastroenterology/Hepatology	Indianapolis	Indiana
United States	UCLA Department of Medicine	Los Angeles	California
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	New York University Medical Center	New York	New York
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

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
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		Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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	Tumor response of CR or PR is considered as objective response. CR: disappearance of all target lesions, reduction in short axis <10 millimeters in pathological lymph nodes (target and non-target lesions); PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Responses were confirmed by repeat assessments =4 weeks after initial documentation.	Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression (up to 82 months)
Secondary	Percentage of Participants With Disease Progression According to RECIST V 1.1	Progressive disease (PD) according to RECIST V 1.1: at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (nadir), including baseline; in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm; appearance of 1 or more lesions is also considered as progression.	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)
Secondary	Median Duration of Response (DOR)	Duration of response, defined as the time from first occurrence of a documented objective response until the time of disease progression, as determined by investigator review of tumor assessments using RECIST v 1.1, or death from any cause during the study (that is within 30 days after the last dose of study treatment).	Time from first occurrence of objective response until the time of disease progression or death from any cause (up to 82 months)
Secondary	Overall Survival (OS)	OS was defined as the time from the date of randomization to the date of death due to any cause. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up. OS analyzed using Kaplan-Meier estimate.	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)
Secondary	Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2	The pharmacodynamic effect of cobimetinib in combination with vemurafenib was assessed by measuring changes in FDG uptake as characterized by the lean body mass corrected (LBM) maximum standardized uptake value (SUV max) measurement using FDG-PET. Post-baseline timepoint Cycle 1 was averaged between Days 10 to 14 and Cycle 2 for Days 14+7.	Cycle 1 (Days 10 to 14), Cycle 2 (Days 14+7)
Secondary	Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC)	Changes in effector molecules of the MAPK pathway that are directly or indirectly affected by BRAF and MEK inhibition (including but not limited to ERK and phosphorylated ERK and MEK) by IHC using biopsies at baseline, between Days 10-14 of Cycle 1, and at disease progression. IHC is a staining process performed on fresh/frozen tumor tissue samples.	At baseline; Cycle 1: Day 14; at disease progression (Up to 32 months)