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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II, Open-label, Dose Escalation Trial to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of RAF265 (CHIR-265)Administered Orally to Patients With Locally Advanced or Metastatic Melanoma.

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Drug: RAF265


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of melanoma, locally advanced AJCC Stage IIIB to metastatic Stage IV 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 ECOG performance status of 0 or 1 No concurrent anticancer or investigational therapy for at least 4 weeks prior to enrollment No major surgery for at least 4 weeks prior to enrollment Exclusion Criteria: Significant cardiac disease or other significant medical/psychiatric disease History of primary central nervous system tumor or brain metastases History of melena, hematemesis, or hemoptysis within the last 3 months Previous therapy with certain molecularly targeted agents

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RAF265 - Arm 1<br>Patients received 10mg RAF265 as a once weekly dose until progressive disease was confirmed. | Drug: RAF265<br>* 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.<br>|
| Experimental: RAF265 - Arm 2<br>RAF265 is given as a single PK run-in dose, a single loading dose on day 1 of cycle 1, followed by once daily maintenance doses. | Drug: RAF265<br>* 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.<br>|
| Experimental: RAF265 - Arm 3<br>Patients were treated with once weekly dosing of RAF265 | Drug: RAF265<br>* 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.<br>|
| Experimental: RAF265 - Arm 4<br>Patients with locally advanced or metastatic melanoma will utilize a dose close to or at the MTD/RPTD of the liquid formulation that was determined in Arm 2. | Drug: RAF265<br>* 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.<br>|
| Experimental: RAF265 - Arm 5<br>RAF265 was administered as a continuous dose for 2 weeks followed by a dose holiday of 1 week. | Drug: RAF265<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose |  | at the end of dose escalation | 
| Dose limiting toxicities |  | during the PK run-in phase and first cycle (28 day cycle) | 
| Safety profile |  | throughout the study | 
| Evaluate potential pharmacodynamic effects |  | throughout the study | 
| Pharmacokinetic profile |  | throughout the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate whether somatic mutations in BRAF and N-RAS genes are associated with modulation of pharmacodynamic markers and clinical response |  | throughout the study | 
| Determine the response rate for BRAF mutant patients |  | Every 2 months | 
| Determine the recommended phase two dose |  | at the end of dose escalation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-angiogenesis therapy, Kinase inhibitor therapy, Raf inhibitor, Locally Advanced Melanoma