A Study to Evaluate RAF265, an Oral Drug Administered to Subjects With Locally Advanced or Metastatic Melanoma

Novartis Pharmaceuticals104 enrolled

Overview

The purpose of this study is to determine the safety profile, pharmacokinetics, pharmacodynamics and maximum tolerated dose of RAF265 in patients with locally advanced and metastatic melanoma. Phase II portion of study (dose expansion) has been cancelled with Amendment 7 as of Dec 2011.

The Ras/Raf/MEK/ERK pathway plays a prominent role in controlling several key cellular functions including growth, proliferation and survival. B-Raf is a member of the Ras/Raf/MEK/ERK pathway and is frequently mutated in melanoma resulting in activation of the MAPK pathway. RAF265 is a novel, orally active, small molecule with potent inhibitory activity against B-Raf kinase and additional antiangiogenic activity through inhibition of vascular endothelial growth factor receptor type 2 (VEGFR-2) in non-clinical studies. The primary objectives of this study are to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and the safety profile of RAF265 when administered orally to subjects with locally advanced or metastatic melanoma; to determine the plasma pharmacokinetics (PKs) of orally administered RAF265; and to evaluate potential pharmacodynamic effects of RAF265 using tumor biopsies, peripheral blood samples, and tumor imaging.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

104

Conditions

Metastatic Melanoma

Interventions

RAF265DRUG

A liquid nonaqueous oral formulation. Switched to a tablet formulations with was 60% bioavailable, relative to the liquid at 50mg dose. The liquid dose will be multiplied by a factor of 1.67 to achieve a comparable tablet dose. Tablets are available in 10mg and 50mg strengths.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Confirmed diagnosis of melanoma, locally advanced AJCC Stage IIIB to metastatic Stage IV 2. Measurable disease - at least one lesion measured in at least one dimension as ≥ 20 mm with conventional techniques or ≥ 10 mm with spiral computed tomography (CT) scan 3. ECOG performance status of 0 or 1 4. No concurrent anticancer or investigational therapy for at least 4 weeks prior to enrollment 5. No major surgery for at least 4 weeks prior to enrollment Exclusion Criteria: 1. Significant cardiac disease or other significant medical/psychiatric disease 2. History of primary central nervous system tumor or brain metastases 3. History of melena, hematemesis, or hemoptysis within the last 3 months 4. Previous therapy with certain molecularly targeted agents

Locations (11)

University of Colorado Univ.ofColoradoCancerCenter

Aurora, Colorado, United States

Georgia Regents University Cancer Clinical Research Unit

Augusta, Georgia, United States

Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Medical Oncology

Outcomes

Primary Outcomes

Maximum tolerated dose

Time frame: at the end of dose escalation

Dose limiting toxicities

Time frame: during the PK run-in phase and first cycle (28 day cycle)

Safety profile

Time frame: throughout the study

Evaluate potential pharmacodynamic effects

Time frame: throughout the study

Pharmacokinetic profile

Time frame: throughout the study

Secondary Outcomes

Evaluate whether somatic mutations in BRAF and N-RAS genes are associated with modulation of pharmacodynamic markers and clinical response

Time frame: throughout the study

Determine the response rate for BRAF mutant patients

Time frame: Every 2 months

Determine the recommended phase two dose

Time frame: at the end of dose escalation

Data from ClinicalTrials.gov

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