Vemurafenib + Fotemustine to Treat Advanced Melanoma Patients With V600BRAF Mutation Recurred While on Vemurafenib (BeyPro1)

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.

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.

Study Overview

• Status: Completed
• Conditions: Malignant Melanoma Stage IV
• Intervention / Treatment: Drug: Fotemustine + Vemurafenib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Genova, Italy, 16132
    • Paola Queirolo
  • Napoli, Italy, 80131
    • Istituto Nazionale per lo Studio e la Cura dei Tumori "G.Pascale"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fotemustine + Vemurafenib; 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; 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.; Other Names: Zelboraf; Fotemustine

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Paola Queirolo
• Collaborators: Istituto Nazionale per lo Studio e la Cura dei Tumori
• Investigators: Principal Investigator: Paola Queirolo, MD, IRCCS AOU San martino IST

Publications and helpful links

General Publications

• Queirolo P, Spagnolo F, Picasso V, Spano L, Tanda E, Fontana V, Giorello L, Merlo DF, Simeone E, Grimaldi AM, Curvietto M, Del Vecchio M, Bruzzi P, Ascierto PA. Combined vemurafenib and fotemustine in patients with BRAF V600 melanoma progressing on vemurafenib. Oncotarget. 2016 Jul 13;9(15):12408-12417. doi: 10.18632/oncotarget.10589. eCollection 2018 Feb 23.

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: November 6, 2013
• First Submitted That Met QC Criteria: November 6, 2013
• First Posted (Estimate): November 13, 2013

Study Record Updates

• Last Update Posted (Estimate): January 20, 2016
• Last Update Submitted That Met QC Criteria: January 19, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Advanced Melanoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Vemurafenib; Fotemustine
• Other Study ID Numbers: 2012-004172-18