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

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01519323
• Collaborator: (none)
• Enrollment: 6
• Locations: 26
• Arm: 1
• Duration (Months): 35
• Patients Per Site: 0.2
• Patients Per Site Per Month: 0

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: vemurafenib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Jan 1, 2013
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Vemurafenib 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.

Drug: vemurafenib; Cohort 1 (participants >=45 kg): starting dose level 720mg; next dose level 960 mg Cohort 2 (participants <45 kg): starting dose 480 mg; Other Names: Zelboraf

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD)/Recommended Dose [Up to 28 days of treatment]

   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

1. Area Under the Concentration-Time Curve for Vemurafenib [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)]

2. Number of Participants With an Adverse Event (AE) [Up to approximately 2 years 11 months]

   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.

3. Best Overall Response Rate (BORR) [Up to 2 years]

   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.

4. Clinical Benefit Rate (CBR) [Up to 2 years]

   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).

5. Progression-free Survival (PFS) [Randomization date of first subject until disease progression or death or which ever occur first (2 years)]

   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.

6. Overall Survival (OS) [Randomization date of first subject until death (2 years)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Los Angeles	California	United States	90027
2		Aurora	Colorado	United States	80045
3		St. Petersburgh	Florida	United States	33701
4		Bethesda	Maryland	United States	20892
5		Boston	Massachusetts	United States	02115
6		New York	New York	United States	10065
7		Memphis	Tennessee	United States	38105
8		Houston	Texas	United States	77030
9		Westmead	New South Wales	Australia	2145
10		Brisbane	Queensland	Australia	4029
11		Marseille		France	13385
12		Pierre Benite		France	69495
13		Kiel		Germany	24116
14		Mainz		Germany	55101
15		Tuebingen		Germany	72076
16		Jerusalem		Israel	9112001
17		Petach-Tikva		Israel	49100
18		Roma	Lazio	Italy	00165
19		Genova	Liguria	Italy	16147
20		Milano	Lombardia	Italy	20133
21		Wroclaw		Poland	50-367
22		Bratislava		Slovakia	83340
23		Esplugues De Llobregas	Barcelona	Spain	08950
24		Sevilla		Spain	41013
25		Newcastle upon Tyne		United Kingdom	NE1 4LP
26		Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01519323
• Other Study ID Numbers: NO25390; 2011-000874-67
• First Posted: Jan 26, 2012
• Last Update Posted: Oct 10, 2016
• Last Verified: Aug 1, 2016

• Additional relevant MeSH terms: Melanoma; Vemurafenib

Study Results

Participant Flow

Recruitment Details	First investigational site was activated on 22 December 2011.
Pre-assignment Detail	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
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

Baseline Characteristics

Arm/Group Title	Vemurafenib
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 Participants	6
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.8 (0.8)
Sex: Female, Male (Count of Participants)
Female	2 33.3%
Male	4 66.7%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

A MTD could not be determined in this study because of the low number of participants enrolled.

Arm/Group Title	Vemurafenib
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.
Measure Participants	0

2. Secondary Outcome

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)

Outcome Measure Data

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
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.
Measure Participants	3	3
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)
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

Outcome Measure Data

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
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.
Measure Participants	6
Number [participants]	6 100%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to treat population included all participants enrolled.

Arm/Group Title	Vemurafenib
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.
Measure Participants	6
Number (95% Confidence Interval) [percentage of participants]	0 0%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to treat population included all participants enrolled.

Arm/Group Title	Vemurafenib
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.
Measure Participants	6
Number [percentage of participants]	66.7 1111.7%

6. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Intent to treat population included all participants enrolled.

Arm/Group Title	Vemurafenib
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.
Measure Participants	6
Median (95% Confidence Interval) [days]	134.5

7. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Intent to treat population included all participants enrolled.

Arm/Group Title	Vemurafenib
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.
Measure Participants	6
Median (95% Confidence Interval) [days]	246.5

Adverse Events

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
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 (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Vemurafenib
	Affected / at Risk (%)	# Events
Total	3/6 (50%)
Endocrine disorders
Adrenal insufficiency	1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Spinal pain	1/6 (16.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/6 (16.7%)
Intracranial tumour haemorrage	1/6 (16.7%)
Squamous cell carcinoma	1/6 (16.7%)
Renal and urinary disorders
Nephrolithiasis	1/6 (16.7%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/6 (16.7%)
Other (Not Including Serious) Adverse Events
	Vemurafenib
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
Anaemia	2/6 (33.3%)
Lymphopenia	1/6 (16.7%)
Cardiac disorders
Palpitations	1/6 (16.7%)
Sinus bradycardia	1/6 (16.7%)
Endocrine disorders
Hypothyroidism	1/6 (16.7%)
Gastrointestinal disorders
Diarrhoea	4/6 (66.7%)
Nausea	3/6 (50%)
Vomiting	2/6 (33.3%)
Abdominal pain	1/6 (16.7%)
Abdominal pain upper	1/6 (16.7%)
Aphthous ulcer	1/6 (16.7%)
Constipation	1/6 (16.7%)
Gastrooesophageal reflux disease	1/6 (16.7%)
Stomatitis	1/6 (16.7%)
Toothache	1/6 (16.7%)
General disorders
Fatigue	3/6 (50%)
Chest pain	1/6 (16.7%)
Influenza like illness	1/6 (16.7%)
Pain	1/6 (16.7%)
Infections and infestations
Hand-foot-and-mouth disease	1/6 (16.7%)
Nasopharyngitis	1/6 (16.7%)
Oral candidiasis	1/6 (16.7%)
Oral herpes	1/6 (16.7%)
Scrotal abscess	1/6 (16.7%)
Skin infection	1/6 (16.7%)
Upper respiratory tract infection	1/6 (16.7%)
Viral pharyngitis	1/6 (16.7%)
Injury, poisoning and procedural complications
Contusion	1/6 (16.7%)
Overdose	1/6 (16.7%)
Investigations
Alanine aminotransferase increased	2/6 (33.3%)
Platelet count decreased	2/6 (33.3%)
White blood cell count decreased	2/6 (33.3%)
Aspartate aminotransferase increased	1/6 (16.7%)
Blood alkaline phosphatase increased	1/6 (16.7%)
Blood cholesterol increased	1/6 (16.7%)
Blood creatinine increased	1/6 (16.7%)
Blood phosphorus increased	1/6 (16.7%)
Carbon dioxide decreased	1/6 (16.7%)
Electrocardiogram QT prolonged	1/6 (16.7%)
Lymphocyte count decreased	1/6 (16.7%)
Neutrophil count decreased	1/6 (16.7%)
Metabolism and nutrition disorders
Hyperglycaemia	2/6 (33.3%)
Decreased appetite	1/6 (16.7%)
Hyperkalaemia	1/6 (16.7%)
Hypokalaemia	1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Back pain	2/6 (33.3%)
Pain in extremity	2/6 (33.3%)
Bone pain	1/6 (16.7%)
Myalgia	1/6 (16.7%)
Neck pain	1/6 (16.7%)
Osteoporosis	1/6 (16.7%)
Nervous system disorders
Headache	4/6 (66.7%)
Dizziness	1/6 (16.7%)
Paraesthesia	1/6 (16.7%)
Seizure	1/6 (16.7%)
Tremor	1/6 (16.7%)
Renal and urinary disorders
Haematuria	1/6 (16.7%)
Haemoglobinuria	1/6 (16.7%)
Nephrolithiasis	1/6 (16.7%)
Proteinuria	1/6 (16.7%)
Renal colic	1/6 (16.7%)
Reproductive system and breast disorders
Vaginal discharge	1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	2/6 (33.3%)
Cough	1/6 (16.7%)
Laryngeal inflammation	1/6 (16.7%)
Rhinitis allergic	1/6 (16.7%)
Wheezing	1/6 (16.7%)
Skin and subcutaneous tissue disorders
Photosensitivity reaction	3/6 (50%)
Rash	3/6 (50%)
Alopecia	2/6 (33.3%)
Dry skin	2/6 (33.3%)
Dermatitis acneiform	1/6 (16.7%)
Pain of skin	1/6 (16.7%)
Palmar-Plantar erythrodysesthesia syndrome	1/6 (16.7%)
Pruritus	1/6 (16.7%)
Rash maculo-papular	1/6 (16.7%)
Skin mass	1/6 (16.7%)
Vascular disorders
Flushing	2/6 (33.3%)
Hypertension	2/6 (33.3%)
Hot flush	1/6 (16.7%)

Limitations/Caveats

The study was prematurely terminated on 18 December 2015 by the Sponsor due to recruitment challenges and therefore low enrollment.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.