BRIM 3: A Randomized, Open-label, Controlled, Multicenter, Phase III Study in Previously Untreated Patients With Unresectable Stage IIIC or Stage IV Melanoma with V600E BRAF Mutation Receiving RO5185426 or Dacarbazine. - BRIM 3

• Register: EUCTR
• Last refreshed on: 11 April 2016
• Main ID: EUCTR2009-012293-12-IT
• Date of registration: 15/12/2009
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd. - Pharmaceuticals Division, PDR
• Public title: BRIM 3: A Randomized, Open-label, Controlled, Multicenter, Phase III Study in Previously Untreated Patients With Unresectable Stage IIIC or Stage IV Melanoma with V600E BRAF Mutation Receiving RO5185426 or Dacarbazine. - BRIM 3
• Scientific title: BRIM 3: A Randomized, Open-label, Controlled, Multicenter, Phase III Study in Previously Untreated Patients With Unresectable Stage IIIC or Stage IV Melanoma with V600E BRAF Mutation Receiving RO5185426 or Dacarbazine. - BRIM 3
• Date of first enrolment: 28/03/2010
• Target sample size: 680
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-012293-12
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

France, Germany, Italy, Netherlands, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female patients ≥ 18 years of age 2. Patients with histologically confirmed metastatic melanoma (surgically incurable and unresectable stage IIIC or stage IV, AJCC). Unresectable stage IIIC disease must have confirmation from a surgical oncologist 3. Treatment na?ve patients (i.e., NO prior systemic anticancer therapy for advanced disease; Stage IIIC and IV). Only prior adjuvant immunotherapy is allowed 4. Patients must have a positive BRAF V600E mutation result determined by a designated laboratory using a Roche CoDx BRAF mutation test prior to administration of RO5185426 5. ECOG performance status of 0 or 1 6. Life expectancy > 3 months 7. Measurable disease (by RECIST criteria version 1.1) prior to the administration of RO5185426 8. Patients must have recovered from effects of any major surgery or significant traumatic injury at least 14 days before the first dose of study treatment 9. Cutaneous SCC lesions identified at baseline, must be excised. Adequate wound healing is required prior to study entry. Baseline skin exam is required for all patients 10. Adequate hematologic, renal, and liver function as defined by laboratory values performed within 28 days prior to initiation of dosing Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Hemoglobin ≥ 9 g/dL Serum creatinine ≤ 1.5 X ULN AST and ALT ≤ 2.5 X ULN Bilirubin ≤ 1.5 X ULN (for patients with Gilbert s Syndrome, bilirubin ≤ 3 X ULN) Alkaline phosphatase ≤ 2.5 X ULN (< 5 times ULN for patients with concurrent liver metastases) 11. Negative serum pregnancy test within 10 days prior to commencement of dosing in pre-menopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year 12. Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician (in accordance with local requirements) 13. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry 14. Before study entry, written informed consent must be obtained from patient prior to performing any studyrelated procedures.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Patients with active CNS lesions are excluded (i.e., those with radiographically unstable, symptomatic lesions). However, patients treated with stereotactic therapy or surgery are eligible if patient remains without evidence of disease progression in brain ≥ 3 months. They must also be off corticosteroid therapy for ≥ 3 weeks. Whole brain radiotherapy is not allowed with the exception of patients who have had definitive resection or stereotactic therapy of all radiologically detectable parenchymal lesions 2. History of carcinomatous meningitis 3. Regional limb infusion or perfusion therapy 4. Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study 5. Pregnant or lactating women 6. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate RO5185426 absorption. Patients must be able to swallow pills 7. Mean QTc interval ≥ 450 msec at screening 8. NCI CTCAE Version 4.0 grade 3 hemorrhage within 4 weeks of starting the study treatment 9. Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/ unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled hypertension, cerebrovascular accident or transient ischemic attack, or symptomatic pulmonary embolism 10. Known clinically significant active infection 11. History of allogenic bone marrow transplantation or organ transplantation 12. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, which in the judgment of the investigator would make the patient inappropriate for entry into this study 13. Patients with a previous malignancy within the past 5 years are excluded except for patients with basal or squamous cell carcinoma (SCC) of the skin, melanoma in-situ, and carcinoma in-situ of the cervix. Isolated elevation in PSA in the absence of radiographic evidence of metastatic prostate cancer is allowed 14. Patients who have been previously treated with a BRAF inhibitor 15. Known HIV positivity or AIDS-related illness, or active HBV, and active HCV 16. Patients who have been previously randomized to this trial at another participating site.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

First-line therapy for adult patients with histologically confirmed metastatic melanoma (unresectable Stage IIIC or Stage IV) harbouring the V600E positive mutation.
MedDRA version: 12.1 Level: LLT Classification code 10027481 Term: Metastatic melanoma

Intervention(s)

Product Code: RO5185426/F17
Pharmaceutical Form: Film-coated tablet
Current Sponsor code: RO5185426/F17
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 240-

Trade Name: Dacarbazine Pliva
Pharmaceutical Form: Powder for infusion*
INN or Proposed INN: Dacarbazine
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Dacarbazine Pliva
Pharmaceutical Form: Powder for infusion*
INN or Proposed INN: Dacarbazine
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Secondary Objective: - To further assess efficacy of RO5185426 compared to dacarbazine based on progression-free survival (PFS), best overall response rate (BORR), time to response, duration of response, and time to treatment failure. - To evaluate the tolerability and safety profile of RO5185426 using the NCI CTCAE (version 4.0) - To further characterize the pharmacokinetic (PK) profile of RO5185426 - To contribute to the validation of the Roche Companion Diagnostic (CoDx) cobas 4800 BRAF V600E test for the detection of BRAF mutations in DNA extracted from formalin-fixed paraffinembedded tumour (FFPET) samples.

Main Objective: To evaluate efficacy of RO5185426 as a monotherapy compared to dacarbazine in terms of overall survival (OS) in previously untreated patients with advanced melanoma harbouring the BRAF V600E mutation.

Primary end point(s): The primary efficacy endpoint is overall survival, which is defined as the interval (days) between randomization and death for any cause.

Secondary ID(s)

2009-012293-12-NL

NO25026