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 Vemurafenib (RO5185426) or Dacarbazine

• Register: EUCTR
• Last refreshed on: 21 September 2015
• Main ID: EUCTR2009-012293-12-DE
• Date of registration: 11/11/2009
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd.
• Public title: 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 Vemurafenib (RO5185426) or Dacarbazine
• 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 Vemurafenib (RO5185426) or Dacarbazine. - BRIM 3
• Date of first enrolment: 17/02/2010
• 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: yes Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Australia, Canada, France, Germany, Israel, Italy, Netherlands, New Zealand, Sweden, Switzerland, United Kingdom, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd

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 naïve 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 study treatment.
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 study treatment.
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 study-related 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 520
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 160

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

Therapeutic area: Diseases [C] - Cancer [C04]

First-line therapy for adult patients with histologically confirmed metastatic melanoma (unresectable Stage IIIC or Stage IV) harbouring the V600E positive mutation
MedDRA version: 17.0 Level: LLT Classification code 10027481 Term: Metastatic melanoma System Organ Class: 100000004864

Intervention(s)

Trade Name: Zelboraf 240 mg Film-coated Tablets
Product Code: RO5185426/F17
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VEMURAFENIB
CAS Number: 918504-65-1
Current Sponsor code: RO5185426-006
Other descriptive name: RG7204, PLX4032, Zelboraf
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 240-

Trade Name: Dacarbazine Pliva
Product Name: Dacarbazine
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: Dacarbazine
CAS Number: 4342-03-4
Other descriptive name: DTIC
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
INN or Proposed INN: Dacarbazine
CAS Number: 4342-03-4
Other descriptive name: DTIC
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Primary end point(s): The co-primary efficacy endpoints are progression-free survival and overall survival.
PFS, according to the RECIST 1.1 criteria, is defined as the interval (days) between randomization and the date of progression (based on the actual tumour assessment date), or death for any cause, whichever comes first. The death of a patient without a reported progression will be considered as an event on the date of death.
Patients who have neither progressed nor died will be censored on the date of last evaluable tumour assessment (TA). Patients who had no post-baseline assessments and did not have an event will be censored at the time of randomization (i.e., Day 1).
OS is defined as the interval (days) between randomization and death for any cause. For a patient alive at the time of analysis data cutoff, OS time will be censored at the last date the patient was known to be alive.

Secondary Objective: •To further assess efficacy of RO5185426 compared to dacarbazine based on 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 paraffin-embedded tumour (FFPET) samples

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

Timepoint(s) of evaluation of this end point: Overall survival: event-driven, assessed approximately 2 years after first patient is randomized Progression-free survival (PFS): tumour assessments after 6 and 12 weeks, and every 9 weeks thereafter

Secondary Outcome(s)

Secondary end point(s): - Best overall response rate (BORR), time to response, duration of Response, time to treatment failure
- Safety and tolerability: AEs, laboratory parameters
- To further characterize the pharmacokinetics of RO5185426 (arm A only) by measuring maximum plasma concentration (Cmax), and area under the plasma concentration-time curve (AUC)

Timepoint(s) of evaluation of this end point: - best overall response rate (BORR), time to response, duration of assessments after 6 and 12 weeks, and every 9 weeks thereafter ] - Safety and tolerability: AEs, laboratory parameters [ Time Frame:throughout study, laboratory assessments every 3 weeks ] - To further characterize the pharmacokinetics of RO5185426 (arm A only) by measuring maximum plasma concentration (Cmax), and area under the plasma concentration-time curve (AUC) [Time Frame: multiple sampling on day 1, cycles 1,2,3 and every 2 cycles thereafter]

Secondary ID(s)

2009-012293-12-NL

NO25026

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd