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BRIM-P: A Study of Vemurafenib in Pediatric Patients With Stage IIIC or Stage IV Melanoma Harboring BRAFV600 Mutations

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ClinicalTrials.gov Identifier: NCT01519323
Recruitment Status : Terminated (Study was terminated due to low enrollment.)
First Posted : January 26, 2012
Results First Posted : July 28, 2016
Last Update Posted : October 10, 2016
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Malignant Melanoma
Intervention Drug: vemurafenib
Enrollment 6
Recruitment Details First investigational site was activated on 22 December 2011.
Pre-assignment Details Participants were enrolled in two separate cohorts with different starting doses based on greater than or equal to (>=)45 kilogram (kg) and other weighing less than (<)45 kg. Participants >=45 kg were then enrolled in a dose escalation period. No participants were enrolled in the <45 kg cohort.
Arm/Group Title Vemurafenib Dose Escalation Cohort Level 1 Vemurafenib Dose Escalation Cohort Level 2
Hide Arm/Group Description Participants received 720 milligram (mg) of vemurafenib by mouth twice daily (BID). Participants received 960 mg of vemurafenib by mouth BID.
Period Title: Overall Study
Started 3 3
Completed 0 0
Not Completed 3 3
Reason Not Completed
Death             3             2
Study terminated by sponsor             0             1
Arm/Group Title Vemurafenib
Hide Arm/Group 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.
Overall Number of Baseline Participants 6
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants
15.8  (0.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants
Female
2
  33.3%
Male
4
  66.7%
1.Primary Outcome
Title Maximum Tolerated Dose (MTD)/Recommended Dose
Hide 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
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Hide Analysis Population Description
A MTD could not be determined in this study because of the low number of participants enrolled.
Arm/Group Title Vemurafenib
Hide Arm/Group 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.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
2.Secondary Outcome
Title Area Under the Concentration-Time Curve for Vemurafenib
Hide Description [Not Specified]
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)
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Hide Analysis Population Description
Pharmacokinetic (PK) population included all enrolled participants who received at least one dose or a partial dose of study treatment and provided at least one post-dose blood sample for PK analysis.
Arm/Group Title Vemurafenib 720 mg Vemurafenib 960 mg
Hide Arm/Group Description:
Participants enrolled in the first cohort received vemurafenib 720 mg by mouth BID.
Participants enrolled in the second cohort received vemurafenib 960 mg by mouth BID.
Overall Number of Participants Analyzed 3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour*nanogram per millitre (h*ng/mL)
Cycle 1 Day 1
16300
(80.5%)
57000
(95.5%)
Cycle 1 Day 22
486000
(26.7%)
963000
(23.4%)
3.Secondary Outcome
Title Number of Participants With an Adverse Event (AE)
Hide 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
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Hide Analysis Population Description
Safety population included all participants who received at least one dose or a partial dose of study treatment.
Arm/Group Title Vemurafenib
Hide Arm/Group 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.
Overall Number of Participants Analyzed 6
Measure Type: Number
Unit of Measure: participants
6
4.Secondary Outcome
Title Best Overall Response Rate (BORR)
Hide 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
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Hide Analysis Population Description
Intent to treat population included all participants enrolled.
Arm/Group Title Vemurafenib
Hide Arm/Group 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.
Overall Number of Participants Analyzed 6
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
0
(0 to 45.93)
5.Secondary Outcome
Title Clinical Benefit Rate (CBR)
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all participants enrolled.
Arm/Group Title Vemurafenib
Hide Arm/Group 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.
Overall Number of Participants Analyzed 6
Measure Type: Number
Unit of Measure: percentage of participants
66.7
6.Secondary Outcome
Title Progression-free Survival (PFS)
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all participants enrolled.
Arm/Group Title Vemurafenib
Hide Arm/Group 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.
Overall Number of Participants Analyzed 6
Median (95% Confidence Interval)
Unit of Measure: days
134.5
(83.0 to 157.0)
7.Secondary Outcome
Title Overall Survival (OS)
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all participants enrolled.
Arm/Group Title Vemurafenib
Hide Arm/Group 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.
Overall Number of Participants Analyzed 6
Median (95% Confidence Interval)
Unit of Measure: days
246.5
(156.0 to 364.0)
Time Frame All AEs were reported for approximately 2 years 11 months. Related serious adverse events were required to be reported regardless of the time elapsed from the last study drug administration, even if the study had been closed.
Adverse Event Reporting Description An AE was defined as any untoward medical occurrence in a participant administered the investigational product which does not necessarily have a causal relationship with this treatment.
 
Arm/Group Title Vemurafenib
Hide Arm/Group 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.
All-Cause Mortality
Vemurafenib
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Vemurafenib
Affected / at Risk (%)
Total   3/6 (50.00%) 
Endocrine disorders   
Adrenal insufficiency  1  1/6 (16.67%) 
Musculoskeletal and connective tissue disorders   
Spinal pain  1  1/6 (16.67%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Basal cell carcinoma  1  1/6 (16.67%) 
Intracranial tumour haemorrage  1  1/6 (16.67%) 
Squamous cell carcinoma  1  1/6 (16.67%) 
Renal and urinary disorders   
Nephrolithiasis  1  1/6 (16.67%) 
Skin and subcutaneous tissue disorders   
Rash maculo-papular  1  1/6 (16.67%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Vemurafenib
Affected / at Risk (%)
Total   6/6 (100.00%) 
Blood and lymphatic system disorders   
Anaemia  1  2/6 (33.33%) 
Lymphopenia  1  1/6 (16.67%) 
Cardiac disorders   
Palpitations  1  1/6 (16.67%) 
Sinus bradycardia  1  1/6 (16.67%) 
Endocrine disorders   
Hypothyroidism  1  1/6 (16.67%) 
Gastrointestinal disorders   
Diarrhoea  1  4/6 (66.67%) 
Nausea  1  3/6 (50.00%) 
Vomiting  1  2/6 (33.33%) 
Abdominal pain  1  1/6 (16.67%) 
Abdominal pain upper  1  1/6 (16.67%) 
Aphthous ulcer  1  1/6 (16.67%) 
Constipation  1  1/6 (16.67%) 
Gastrooesophageal reflux disease  1  1/6 (16.67%) 
Stomatitis  1  1/6 (16.67%) 
Toothache  1  1/6 (16.67%) 
General disorders   
Fatigue  1  3/6 (50.00%) 
Chest pain  1  1/6 (16.67%) 
Influenza like illness  1  1/6 (16.67%) 
Pain  1  1/6 (16.67%) 
Infections and infestations   
Hand-foot-and-mouth disease  1  1/6 (16.67%) 
Nasopharyngitis  1  1/6 (16.67%) 
Oral candidiasis  1  1/6 (16.67%) 
Oral herpes  1  1/6 (16.67%) 
Scrotal abscess  1  1/6 (16.67%) 
Skin infection  1  1/6 (16.67%) 
Upper respiratory tract infection  1  1/6 (16.67%) 
Viral pharyngitis  1  1/6 (16.67%) 
Injury, poisoning and procedural complications   
Contusion  1  1/6 (16.67%) 
Overdose  1  1/6 (16.67%) 
Investigations   
Alanine aminotransferase increased  1  2/6 (33.33%) 
Platelet count decreased  1  2/6 (33.33%) 
White blood cell count decreased  1  2/6 (33.33%) 
Aspartate aminotransferase increased  1  1/6 (16.67%) 
Blood alkaline phosphatase increased  1  1/6 (16.67%) 
Blood cholesterol increased  1  1/6 (16.67%) 
Blood creatinine increased  1  1/6 (16.67%) 
Blood phosphorus increased  1  1/6 (16.67%) 
Carbon dioxide decreased  1  1/6 (16.67%) 
Electrocardiogram QT prolonged  1  1/6 (16.67%) 
Lymphocyte count decreased  1  1/6 (16.67%) 
Neutrophil count decreased  1  1/6 (16.67%) 
Metabolism and nutrition disorders   
Hyperglycaemia  1  2/6 (33.33%) 
Decreased appetite  1  1/6 (16.67%) 
Hyperkalaemia  1  1/6 (16.67%) 
Hypokalaemia  1  1/6 (16.67%) 
Musculoskeletal and connective tissue disorders   
Back pain  1  2/6 (33.33%) 
Pain in extremity  1  2/6 (33.33%) 
Bone pain  1  1/6 (16.67%) 
Myalgia  1  1/6 (16.67%) 
Neck pain  1  1/6 (16.67%) 
Osteoporosis  1  1/6 (16.67%) 
Nervous system disorders   
Headache  1  4/6 (66.67%) 
Dizziness  1  1/6 (16.67%) 
Paraesthesia  1  1/6 (16.67%) 
Seizure  1  1/6 (16.67%) 
Tremor  1  1/6 (16.67%) 
Renal and urinary disorders   
Haematuria  1  1/6 (16.67%) 
Haemoglobinuria  1  1/6 (16.67%) 
Nephrolithiasis  1  1/6 (16.67%) 
Proteinuria  1  1/6 (16.67%) 
Renal colic  1  1/6 (16.67%) 
Reproductive system and breast disorders   
Vaginal discharge  1  1/6 (16.67%) 
Respiratory, thoracic and mediastinal disorders   
Oropharyngeal pain  1  2/6 (33.33%) 
Cough  1  1/6 (16.67%) 
Laryngeal inflammation  1  1/6 (16.67%) 
Rhinitis allergic  1  1/6 (16.67%) 
Wheezing  1  1/6 (16.67%) 
Skin and subcutaneous tissue disorders   
Photosensitivity reaction  1  3/6 (50.00%) 
Rash  1  3/6 (50.00%) 
Alopecia  1  2/6 (33.33%) 
Dry skin  1  2/6 (33.33%) 
Dermatitis acneiform  1  1/6 (16.67%) 
Pain of skin  1  1/6 (16.67%) 
Palmar-Plantar erythrodysesthesia syndrome  1  1/6 (16.67%) 
Pruritus  1  1/6 (16.67%) 
Rash maculo-papular  1  1/6 (16.67%) 
Skin mass  1  1/6 (16.67%) 
Vascular disorders   
Flushing  1  2/6 (33.33%) 
Hypertension  1  2/6 (33.33%) 
Hot flush  1  1/6 (16.67%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
The study was prematurely terminated on 18 December 2015 by the Sponsor due to recruitment challenges and therefore low enrollment.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
Phone: 800-821-8590
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01519323     History of Changes
Other Study ID Numbers: NO25390
2011-000874-67 ( EudraCT Number )
First Submitted: January 16, 2012
First Posted: January 26, 2012
Results First Submitted: June 17, 2016
Results First Posted: July 28, 2016
Last Update Posted: October 10, 2016