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A Study of Vemurafenib in Metastatic Melanoma Participants With Brain Metastases

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01378975
First received: June 21, 2011
Last updated: June 20, 2016
Last verified: April 2016
  Purpose
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 Intervention Phase
Malignant Melanoma
Drug: Vemurafenib
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
    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:
  • 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) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.

  • Overall Survival [ Time Frame: Baseline up to the disease progression or death from any cause (approximately 4 years) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    Percentage of participants who were responders (with best overall response (BOR) documented as confirmed complete response [CR] or partial response [PR]) were reported.

  • 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) ] [ Designated as safety issue: No ]
    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.


Enrollment: 146
Study Start Date: July 2011
Study Completion Date: July 2015
Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01378975

  Hide Study 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     History of Changes
Other Study ID Numbers: MO25743 
Study First Received: June 21, 2011
Results First Received: June 20, 2016
Last Updated: June 20, 2016
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on December 09, 2016