A Study of Vemurafenib in Metastatic Melanoma Participants With Brain Metastases

• ClinicalTrials.gov Identifier: NCT01378975
• Recruitment Status: Completed
• First Posted: June 23, 2011
• Results First Posted: August 1, 2016
• Last Update Posted: August 1, 2016
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief Summary:

This open-label, single-arm, multicenter study will evaluate the efficacy and safety in participants with metastatic melanoma who developed brain metastases. Participants may or may not have received prior systemic treatment for metastatic melanoma [except treatment with v-raf murine sarcoma viral oncogene homolog B (BRAF) or mitogen-activated protein kinase (MEK) inhibitors]. Participants will receive oral doses of 960 mg vemurafenib twice daily until disease progression, unacceptable toxicity or consent withdrawal.

Condition or disease	Intervention/treatment	Phase
Malignant Melanoma	Drug: Vemurafenib	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 146 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Single-arm, Phase II, Multicenter Study, to Evaluate the Efficacy of Vemurafenib in Metastatic Melanoma Patients With Brain Metastases
• Study Start Date: July 2011
• Actual Primary Completion Date: July 2015
• Actual Study Completion Date: July 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1: Previously Untreated Participants; Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Drug: Vemurafenib; 960 mg oral doses twice daily until disease progression, unacceptable toxicity or consent withdrawal.
Experimental: Cohort 2: Previously treated Participants; Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Drug: Vemurafenib; 960 mg oral doses twice daily until disease progression, unacceptable toxicity or consent withdrawal.

Outcome Measures

Primary Outcome Measures :

1. Best Overall Response Rate (BORR) Within Brain of Previously Untreated Participants (Assessed by Independent Review Committee [IRC] Using Modified Response Evaluation Criteria in Solid Tumors [RECIST]) [ Time Frame: Baseline up to the disease progression or death from any cause (approximately 4 years) ]
   BORR assessed by IRC is defined as percentage of participants who were responders [with best overall response (BOR) documented as confirmed complete response (CR) or partial response (PR)]. The RECIST v1.1 criteria modified for independent review of body and brain lesions was based on current radiology practices. The modifications to RECIST v1.1 included allowing target lesions in the brain to be >=5 mm by contrast-enhanced magnetic resonance imaging scan (in traditional RECIST v1.1 this is >=10 mm), allowing up to 5 target lesions in the brain (in traditional RECIST v1.1 only 2 target lesions), and examining the lesions within the brain and outside the brain separately for analytical purposes. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm), PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures :

1. Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 [ Time Frame: Baseline up to the disease progression or death from any cause (approximately 4 years) ]
   Percentage of participants who were responders with BOR documented as confirmed CR or PR, stable disease (SD), progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
2. Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated Brain Metastases as Assessed by the IRC Using RECIST v1.1 [ Time Frame: Baseline up to the disease progression or death from any cause (approximately 4 years) ]
   BORR within brain assessed by IRC is defined as percentage of participants who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
3. Best Overall Response Rate Outside the Brain (Assessed by IRC) [ Time Frame: Baseline up to the disease progression or death from any cause (approximately 4 years) ]
   BORR outside of brain assessed by IRC is defined as percentage of participants who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
4. Duration of Response (DOR) (Assessed by Investigator and IRC) [ Time Frame: Date of the earliest qualifying response until the earliest date of PD or death from any cause (approximately up to 4 years) ]
   Duration of response was defined as the time interval between the date of the earliest qualifying response and the earliest date of PD or death from any cause. For participants who were alive without progression following the qualifying response, DOR were censored on the date of last available tumor assessment on or before the data cutoff date.
5. Progression-Free Survival (PFS) Based on Overall Tumor Response (Assessed by Investigator) [ Time Frame: Baseline up to the disease progression or death from any cause (approximately 4 years) ]
   Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within or outside the brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first.
6. Progression-Free Survival (PFS) Based on Tumor Assessment Within Brain Only (Assessed by Investigator ) [ Time Frame: Baseline up to the disease progression or death from any cause (approximately 4 years) ]
   Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first.
7. Time to Development of New Brain Metastases in Responders [ Time Frame: Date of first treatment and the earliest date of documentation of new brain lesions (approximately up to 4 years) ]
   Time to development of new lesions within the brain was defined as the interval between the date of first treatment and the earliest date of documentation of new brain lesions. Participants who were known to be free of new lesions were censored on the date of last tumor assessment.
8. Overall Survival [ Time Frame: Baseline up to the disease progression or death from any cause (approximately 4 years) ]
   Overall survival was defined as time between enrollment on Day 1 and date of death, irrespective of the cause of death. Participants for whom no death was captured on the clinical database were censored at the latest date they were known to be alive prior to or on the cutoff date.
9. Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) [ Time Frame: Baseline up to the disease progression or death from any cause (approximately 4 years) ]
   Percentage of participants who were responders with BOR documented as confirmed CR or PR, stable disease (SD), progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
10. Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Not Necessarily Follows the RECIST Criteria - as Assessed by Investigator) [ Time Frame: Baseline up to the disease progression or death from any cause (approximately 4 years) ]
    Percentage of participants who were responders (with best overall response (BOR) documented as confirmed complete response [CR] or partial response [PR]) were reported.
11. Percentage of Participants With Adverse Events (AE) [ Time Frame: From signing of informed consent form up to 28 days after the last dose of study drug (approximately up to 4 years) ]
    An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Adult participants, >/= 18 years of age
• Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) with BRAF V600 mutation (cobas 4800 BRAF V600 Mutation Test)
• Measurable brain metastases, defined as lesions that were accurately measured in at least one dimension (longest diameter to be recorded) as ≥0.5 cm in the brain MRI with contrast, treated or untreated
• Participants may or may not have received prior systemic therapy for metastatic melanoma and either a) have received no prior treatment for brain metastases or b) have received prior treatment for brain metastases and have progressed
• Participants may or may not have symptoms related to their brain metastases
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Participants must have recovered from all side effects of their most recent systemic or local treatment for metastatic melanoma

Exclusion Criteria:

• Increasing corticosteroid dose during the 7 days prior to first dose of study drug
• Leptomeningeal involvement in participants with no prior treatment for brain metastases
• Previous malignancy requiring active treatment within the past 2 years, except for treated and controlled basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix
• Concurrent administration of any anticancer therapies other than those administered in the study
• Treatment with any cytotoxic, investigational drug or targeted therapy 4 weeks prior to first dose of study drug. Radiation therapy ≤1 week prior to first administration of vemurafenib; and stereotactic radiotherapy ≤1 day prior to prior to first administration of vemurafenib
• Prior treatment with BRAF or MEK inhibitors
• Clinically significant cardiovascular disease or event within the 6 months prior to first dose of study drug

Contacts and Locations

Locations

United States, California

Los Angeles, California, United States, 90025

United States, Colorado

Aurora, Colorado, United States, 80045

United States, Florida

Tampa, Florida, United States, 33612-9497

United States, Massachusetts

Boston, Massachusetts, United States, 02114

Boston, Massachusetts, United States, 02215

United States, Michigan

Detroit, Michigan, United States, 48201

United States, Minnesota

Rochester, Minnesota, United States, 55905

United States, Missouri

Saint Louis, Missouri, United States, 63110

United States, North Carolina

Charlotte, North Carolina, United States, 28204-2839

United States, Texas

Dallas, Texas, United States, 75246

United States, Washington

Seattle, Washington, United States, 98195

Australia, New South Wales

Wentworthville, New South Wales, Australia, 2145

Australia, Victoria

Melbourne, Victoria, Australia, 3002

Canada, Ontario

Toronto, Ontario, Canada, M4N 3M5

France

Bordeaux, France, 33075

Nice, France, 06202

Paris, France, 75006

Paris, France, 75475

Germany

Essen, Germany, 45122

Frankfurt, Germany, 60596

Kiel, Germany, 24105

Mannheim, Germany, 68167

Münster, Germany, 48157

Tübingen, Germany, 72076

Israel

Tel-Hashomer, Israel, 52621

Italy

Milano, Lombardia, Italy, 20133

Siena, Toscana, Italy, 53100

Netherlands

Amsterdam, Netherlands, 1066 CX

Groningen, Netherlands, 9713 GZ

Spain

Pamplona, Navarra, Spain, 31008

Barcelona, Spain, 08036

Madrid, Spain, 28046

United Kingdom

Northwood, United Kingdom, HA6 2RN

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01378975
• Other Study ID Numbers: MO25743
• First Posted: June 23, 2011
• Results First Posted: August 1, 2016
• Last Update Posted: August 1, 2016
• Last Verified: April 2016

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Vemurafenib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action