Back to resultsBRIM-P: A Study of Vemurafenib in Pediatric Patients With Stage IIIC or Stage IV Melanoma Harboring BRAFV600 Mutations
Primary Purpose
Malignant Melanoma
Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
vemurafenib
Sponsored by
About this trial
This is an interventional treatment trial for Malignant Melanoma
Eligibility Criteria
Inclusion Criteria:
- Pediatric participants, 12 to 17 years of age inclusive
- Histologically confirmed surgically incurable and unresectable Stage IIIC or Stage IV (AJCC) melanoma
- Positive proto-oncogene B-Raf (BRAF) mutation result (Cobas 4800 BRAF V600 Mutation Test)
- Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria
- Performance status: Karnofsky (for participants >/= 16 years of age) or Lansky (for participants < 16 years of age) score of >/= 60
- Adequate bone marrow, liver and renal function
- Participants must have fully recovered from the acute toxic effects of all prior therapy prior to first administration of study drug
Exclusion Criteria:
- Active or untreated central nervous system (CNS) lesions
- History of or known spinal cord compression or carcinomatous meningitis
- Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study
- Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ, and carcinoma in-situ of the cervix
- Previous treatment with selective/specific BRAF or Methyl Ethyl Ketone (MEK) inhibitor (previous treatment with sorafenib is allowed)
- Any previous treatment with study drug (RO5185426) or participation in a clinical trial that includes RO5185426
- Pregnant or lactating females
- Known human immunodeficiency virus (HIV) positivity or acquired immune deficiency syndrome (AIDS)-related illness, active hepatitis B virus, or active hepatitis C virus
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Vemurafenib
Arm Description
Participants received vemurafenib into two separate cohorts with different starting doses based on greater than or equal to (>=)45 kilogram (kg) and other weighing less than (<)45 kg. The starting dose for participants (>=45 kg) was 720 milligram (mg) of vemurafenib by mouth twice daily (BID) and the next dose level for participants in this cohort was 960 mg by mouth BID. The starting dose level for participants weighing <45 kg was to be 480 mg of vemurafenib by mouth BID, but no participants were enrolled into this cohort.
Outcomes
Primary Outcome Measures
Maximum Tolerated Dose (MTD)/Recommended Dose
The MTD was defined as the dose level at which six evaluable participants had been treated and at most one participant experienced a dose limiting toxicity (DLT) and the next highest dose level was too toxic. Dose escalation occurred if 0 out of 3 or at most 1 out of 6 participant experienced DLT while being treated at a dose level; otherwise the dose was declared unsafe and thus above the MTD.
Secondary Outcome Measures
Area Under the Concentration-Time Curve for Vemurafenib
Number of Participants With an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a patient administered a pharmaceutical product and which did not necessarily have to have a causal relationship with study treatment.
Best Overall Response Rate (BORR)
BORR was assessed by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. BORR was defined as the number of participants who achieved a complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >=30% decrease under baseline of the sum of diameters of all target lesions. BORR was summarized along with the associated exact 95% confidence interval (CI) using the method of Clopper-Pearson.
Clinical Benefit Rate (CBR)
CBR was defined as the number of participants that achieved a CR, PR or stable disease (SD) (SD for at least 6 weeks) as assessed by investigators according to the RECIST v1.1. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as at >=30% decrease under baseline of the sum of diameters of all target lesions. SD was defined as steady state of disease with neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).
Progression-free Survival (PFS)
PFS was defined as the time between the day of first treatment and the first documentation of progressive disease or death. Progression was defined as a 20% increase in the sum of the longest diameter of target lesions, the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. Participants who were withdrawn from the study without documented progression were to be censored at the date of the last known tumor assessment when the participant was known to be progression free. Median PFS was estimated using Kaplan-Meier method and 95% CI for median was computed using the Brookmeyer and Crowley method.
Overall Survival (OS)
Overall survival was defined as the time between the date of first treatment to the date of death, regardless of the cause of death. Participants who were alive at the time of the analysis were censored at the date of their last being known alive. Median overall survival was estimated using Kaplan-Meier method and 95% CI for median was computed using the Brookmeyer and Crowley method.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01519323
Brief Title
BRIM-P: A Study of Vemurafenib in Pediatric Patients With Stage IIIC or Stage IV Melanoma Harboring BRAFV600 Mutations
Official Title
An Open-label, Multicenter, Single-arm, Phase I Dose-escalation With Efficacy Tail Extension Study of Vemurafenib (RO5185426) in Pediatric Patients With Surgically Incurable and Unresectable Stage IIIC or Stage IV Melanoma Harboring BRAFV600 Mutations
Study Type
Interventional
2. Study Status
Record Verification Date
August 2016
Overall Recruitment Status
Terminated
Why Stopped
Study was terminated due to low enrollment.
Study Start Date
January 2013 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
December 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This open-label, multicenter. single arm Phase I dose-escalation study with efficacy tail extension will evaluate the maximum tolerated dose/recommended dose, the safety and efficacy of vemurafenib (RO5185426) in pediatric participants (aged 12 through 17) with newly diagnosed or recurrent surgically incurable and unresectable Stage IIIC or Stage IV melanoma harboring BRAFV600 mutations. Participants will receive vemurafenib orally twice daily until disease progression or unacceptable toxicity occurs.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Melanoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Vemurafenib
Arm Type
Experimental
Arm Description
Participants received vemurafenib into two separate cohorts with different starting doses based on greater than or equal to (>=)45 kilogram (kg) and other weighing less than (<)45 kg. The starting dose for participants (>=45 kg) was 720 milligram (mg) of vemurafenib by mouth twice daily (BID) and the next dose level for participants in this cohort was 960 mg by mouth BID. The starting dose level for participants weighing <45 kg was to be 480 mg of vemurafenib by mouth BID, but no participants were enrolled into this cohort.
Intervention Type
Drug
Intervention Name(s)
vemurafenib
Other Intervention Name(s)
Zelboraf
Intervention Description
Cohort 1 (participants >=45 kg): starting dose level 720mg; next dose level 960 mg Cohort 2 (participants <45 kg): starting dose 480 mg
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD)/Recommended Dose
Description
The MTD was defined as the dose level at which six evaluable participants had been treated and at most one participant experienced a dose limiting toxicity (DLT) and the next highest dose level was too toxic. Dose escalation occurred if 0 out of 3 or at most 1 out of 6 participant experienced DLT while being treated at a dose level; otherwise the dose was declared unsafe and thus above the MTD.
Time Frame
Up to 28 days of treatment
Secondary Outcome Measure Information:
Title
Area Under the Concentration-Time Curve for Vemurafenib
Time Frame
Pre-dose, 2, 4, 8, 12 hours post dose on Cycle 1 Day 1 and Cycle 1 Day 22 (each cycle is of 28 days)
Title
Number of Participants With an Adverse Event (AE)
Description
An AE was defined as any untoward medical occurrence in a patient administered a pharmaceutical product and which did not necessarily have to have a causal relationship with study treatment.
Time Frame
Up to approximately 2 years 11 months
Title
Best Overall Response Rate (BORR)
Description
BORR was assessed by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. BORR was defined as the number of participants who achieved a complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >=30% decrease under baseline of the sum of diameters of all target lesions. BORR was summarized along with the associated exact 95% confidence interval (CI) using the method of Clopper-Pearson.
Time Frame
Up to 2 years
Title
Clinical Benefit Rate (CBR)
Description
CBR was defined as the number of participants that achieved a CR, PR or stable disease (SD) (SD for at least 6 weeks) as assessed by investigators according to the RECIST v1.1. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as at >=30% decrease under baseline of the sum of diameters of all target lesions. SD was defined as steady state of disease with neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).
Time Frame
Up to 2 years
Title
Progression-free Survival (PFS)
Description
PFS was defined as the time between the day of first treatment and the first documentation of progressive disease or death. Progression was defined as a 20% increase in the sum of the longest diameter of target lesions, the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. Participants who were withdrawn from the study without documented progression were to be censored at the date of the last known tumor assessment when the participant was known to be progression free. Median PFS was estimated using Kaplan-Meier method and 95% CI for median was computed using the Brookmeyer and Crowley method.
Time Frame
Randomization date of first subject until disease progression or death or which ever occur first (2 years)
Title
Overall Survival (OS)
Description
Overall survival was defined as the time between the date of first treatment to the date of death, regardless of the cause of death. Participants who were alive at the time of the analysis were censored at the date of their last being known alive. Median overall survival was estimated using Kaplan-Meier method and 95% CI for median was computed using the Brookmeyer and Crowley method.
Time Frame
Randomization date of first subject until death (2 years)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Pediatric participants, 12 to 17 years of age inclusive
Histologically confirmed surgically incurable and unresectable Stage IIIC or Stage IV (AJCC) melanoma
Positive proto-oncogene B-Raf (BRAF) mutation result (Cobas 4800 BRAF V600 Mutation Test)
Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria
Performance status: Karnofsky (for participants >/= 16 years of age) or Lansky (for participants < 16 years of age) score of >/= 60
Adequate bone marrow, liver and renal function
Participants must have fully recovered from the acute toxic effects of all prior therapy prior to first administration of study drug
Exclusion Criteria:
Active or untreated central nervous system (CNS) lesions
History of or known spinal cord compression or carcinomatous meningitis
Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study
Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ, and carcinoma in-situ of the cervix
Previous treatment with selective/specific BRAF or Methyl Ethyl Ketone (MEK) inhibitor (previous treatment with sorafenib is allowed)
Any previous treatment with study drug (RO5185426) or participation in a clinical trial that includes RO5185426
Pregnant or lactating females
Known human immunodeficiency virus (HIV) positivity or acquired immune deficiency syndrome (AIDS)-related illness, active hepatitis B virus, or active hepatitis C virus
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
City
St. Petersburgh
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4029
Country
Australia
City
Marseille
ZIP/Postal Code
13385
Country
France
City
Pierre Benite
ZIP/Postal Code
69495
Country
France
City
Kiel
ZIP/Postal Code
24116
Country
Germany
City
Mainz
ZIP/Postal Code
55101
Country
Germany
City
Tuebingen
ZIP/Postal Code
72076
Country
Germany
City
Jerusalem
ZIP/Postal Code
9112001
Country
Israel
City
Petach-Tikva
ZIP/Postal Code
49100
Country
Israel
City
Roma
State/Province
Lazio
ZIP/Postal Code
00165
Country
Italy
City
Genova
State/Province
Liguria
ZIP/Postal Code
16147
Country
Italy
City
Milano
State/Province
Lombardia
ZIP/Postal Code
20133
Country
Italy
City
Wroclaw
ZIP/Postal Code
50-367
Country
Poland
City
Bratislava
ZIP/Postal Code
83340
Country
Slovakia
City
Esplugues De Llobregas
State/Province
Barcelona
ZIP/Postal Code
08950
Country
Spain
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
City
Newcastle upon Tyne
ZIP/Postal Code
NE1 4LP
Country
United Kingdom
City
Sutton
ZIP/Postal Code
SM2 5PT
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
29350463
Citation
Chisholm JC, Suvada J, Dunkel IJ, Casanova M, Zhang W, Ritchie N, Choi Y, Park J, Das Thakur M, Simko S, Wan Rachel Tam N, Ferrari A. BRIM-P: A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma. Pediatr Blood Cancer. 2018 May;65(5):e26947. doi: 10.1002/pbc.26947. Epub 2018 Jan 19.
Results Reference
derived
Learn more about this trial
BRIM-P: A Study of Vemurafenib in Pediatric Patients With Stage IIIC or Stage IV Melanoma Harboring BRAFV600 Mutations
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