Trial of Vemurafenib and Cobimetinib in Patients With Advanced BRAFV600 Mutant Melanoma

An Exploratory Study of the Immunological Effects of Vemurafenib and Cobimetinib, Administered Alone and in Combination, in Subjects With Advanced BRAF V600E/K Mutant Melanoma

This trial explores the immunologic effects of vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor), administered alone and in combination, to patients with advanced BRAF V600E/K mutant melanoma.

Study Overview

• Status: Withdrawn
• Conditions: Melanoma
• Intervention / Treatment: Drug: Cobimetinib; Drug: Vemurafenib

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent
• Signed HIV testing consent
• Life expectancy ≥ 12 weeks
• Able to swallow pills
• ECOG performance status 2 or less
• Adequate bone marrow function
• Adequate renal function
• Adequate liver function
• Negative urine pregnancy test within 7 days prior to commencement of dosing in premenopausal women
• Histological diagnosis of unresectable AJCC stage III or stage IV, BRAFV600E/K mutant melanoma
• Measurable disease
• Accessible tumor that can be biopsied
• Naive to targeted therapy (Prior immune-based therapy in the adjuvant setting or for advanced disease will be allowed if >2 weeks from study entry)

Exclusion Criteria:

• Active systemic infection
• Active autoimmune disease or history of known or suspected autoimmune disease
• Active brain metastases or leptomeningeal metastases
• Treatment with any immunomodulatory medication within 4 weeks of initiation of study therapy.
• Positive test for hepatitis B virus
• Positive test for hepatitis C virus
• Positive test for human immunodeficiency virus (HIV)
• Pregnant, lactating or breast feeding women
• Localized radiation therapy within the last 14 days
• History of malabsorption

• No consumption of the following within 7 days prior to start of treatment:

  • St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer)
  • Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor
• History or evidence of cardiovascular risk
• History or evidence of retinal pathology

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cohort 1; Ten patients begin Vemurafenib monotherapy, after 10 days, begin combination therapy by adding Cobimetinib.	Drug: Cobimetinib; A potent and highly selective inhibitor of MEK1 and MEK2, central components of the RAS/RAF pathway.; Other Names: GDC-0973, XL518; Drug: Vemurafenib; A low molecular weight, orally available inhibitor of the activated form of the BRAF serine-threonine kinase enzyme, which is commonly found in melanoma; Other Names: RO5185426, PLX4032, or RG7204
Active Comparator: Cohort 2; Ten patients begin Cobimetinib monotherapy, after 10 days, begin combination therapy by adding Vemurafenib.	Drug: Cobimetinib; A potent and highly selective inhibitor of MEK1 and MEK2, central components of the RAS/RAF pathway.; Other Names: GDC-0973, XL518; Drug: Vemurafenib; A low molecular weight, orally available inhibitor of the activated form of the BRAF serine-threonine kinase enzyme, which is commonly found in melanoma; Other Names: RO5185426, PLX4032, or RG7204

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of cobimetinib monotherapy and combination vemurafenib/cobimetinib in subjects with advanced melanoma.	compare immunologic changes described above with the development of study treatment-related adverse events. For example, severity or extent of rash from cobimetinib (a well-described dermatologic toxicity of MEK inhibitors) may be compared to levels of intratumoral immune activation assessed by one or more of the parameters.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-tumor activity of cobimetinib monotherapy and combination vemurafenib/cobimetinib in subjects with advanced melanoma.	compare immunologic changes described above with therapeutic outcomes, including CR, PR, SD, and PD measured by RECIST 1.1. For example, tumor regression may be correlated with levels of intratumoral immune activation or expression of immune checkpoints assessed by one or more of the parameters	2 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Genentech, Inc.
• Investigators: Principal Investigator: Evan J Lipson, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: March 27, 2015
• First Submitted That Met QC Criteria: April 22, 2015
• First Posted (Estimate): April 28, 2015

Study Record Updates

• Last Update Posted (Estimate): November 15, 2016
• Last Update Submitted That Met QC Criteria: November 14, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: immunotherapy; Cobimetinib; Vemurafenib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Vemurafenib
• Other Study ID Numbers: J1517; IRB00051085 (Other Identifier: JHMIRB)