Vemurafenib + Fotemustine to Treat Advanced Melanoma Patients With V600BRAF Mutation Recurred While on Vemurafenib

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the activity of Vemurafenib in combination with Fotemustine in Patients with unresectable Stage IV melanoma harboring V600 BRAF mutation who recurred while in treatment with Vemurafenib. In addition the feasibility and safety profile of prolonging treatment of this drugs combination will be assessed.

Detailed Description
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Patients are treated with Fotemustine 100 mg/m2 q21 + Vemurafenib. Vemurafenib will be administered continuous oral dosing at 960 mg twice daily or dose administered at time of disease progression with Vemurafenib previous treatment (720 or 480 mg).Treatment will be continued until progression or unacceptable toxicity. The Progression-free survival will be assessed as primary endpoint, other outcomes(i.e., incidence of grade III-IV toxicity, Disease Control Rate, and Overall Survival) will be considered secondary endpoints.

Official Title
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A Phase II Single-arm Study for the Treatment After Recurrence of Advanced Melanoma Patients Harboring the V600BRAF Mutation and Pretreated With Vemurafenib, With the Association of Vemurafenib Plus Fotemustine.

Conditions
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Malignant Melanoma Stage IV

Intervention / Treatment
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* Drug: Fotemustine + Vemurafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed melanoma harboring the V600 mutation Unresectable Stage IV melanoma At least 18 y of age Eastern Cooperative Oncology Group (ECOG) performance status of <2 In progression during treatment with Vemurafenib At least 2 weeks since the last radiotherapy treatment Life expectancy >12 weeks Clinical laboratory values at screening defined as follow: lactate dehydrogenase (LDH) < 2.0 x upper limit of normal (ULN), Hemoglobin >9 g/dL, Absolute neutrophil count 1500/mm3, Platelet count >100,000/mm3, Creatinine <1.5 mg/dL (NOTE: If creatinine is >1.5 mg/dL, subject is eligible if creatinine clearance > 60 mL/min using the Cockgroft-Gault equation), Total bilirubin <1.5 x ULN, Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) <2.5 x ULN Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year Fertile men and women must use an effective method of contraception Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Female subjects who are pregnant or nursing Female subjects of childbearing potential or males not using or not willing to use two forms of effective contraception Any of the following within the 6 months prior to randomization: myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, hypertension not adequately controlled by current medications Concurrent administration of any anti-cancer therapies (e.g. chemotherapy, other targeted therapy, experimental drug, etc) other than those administered in this study Known hypersensitivity to Vemurafenib or another BRAF inhibitor History of congenital long QT syndrome, history or presence of clinically significant ventricular or atrial dysrhythmias ≥ Grade 2 (NCI Common Toxicity Criteria for Adverse Effects (CTCAE) Version 4.0 Corrected QT (QTc) interval ≥ 500 msec at baseline Uncontrolled medical illness (such as infection requiring treatment with intravenous (IV) antibiotics) Has had surgery within 2 weeks (1 week for minor surgery, eg, procedures requiring only local anesthetics) prior to the first dose of study medication

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fotemustine + Vemurafenib<br>Fotemustine 100 mg/m2 q21 + Vemurafenib gelatin capsules supplied as 240-mg strengths. Vemurafenib will be administered continuous oral dosing at 960 mg twice daily or dose administered at time of disease progression with Vemurafenib previous treatment. | Drug: Fotemustine + Vemurafenib<br>* Fotemustine 100mg/m2 IV on day 1 of each 21 day cycle. Number of cycles: until progression or unacceptable toxicity. Vemurafenib administered continuous oral dosing 960 mg twice daily or dose administered at time of progression since progression or unacceptable toxicity.<br>* Other names: Zelboraf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | To assess activity of vemurafenib in combination with fotemustine, in patients harboring the V600BRAF mutation and recurred while on treatment with Vemurafenib. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Grade 3-4 toxicities (any type) |  | 6 months | 
| Rate, duration of response and proportion of patients with duration of response lasting > 24 weeks |  | 6 months | 
| Disease control rate; |  | 6 months | 
| Time to progression of brain metastases (BM), Including incidence of BM in pts free from BM at the time of enrolment |  | 6 months | 
| Overall survival (OS). |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Melanoma