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

Phase 1

Completed

• Conditions: Metastatic Melanoma
• Interventions: Drug: RAF265

• Registration Number: NCT00304525
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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

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 Timeline

• Study First Submitted: 2006-03-17
• Study First Submitted QC: 2006-03-17
• Study First Posted: 2006-03-20
• Study Start: 2006-04
• Primary Completion: 2013-11
• Study Completion: 2013-11
• Status Verified: 2020-08
• Disposition First Submitted: 2020-08-20
• Disposition First Submitted QC: 2020-08-28
• Disposition First Posted: 2020-09-02
• Last Update Submitted: 2020-12-11
• Last Update Posted: 2020-12-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 104

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
RAF265 - Arm 1	RAF265	Patients received 10mg RAF265 as a once weekly dose until progressive disease was confirmed.
RAF265 - Arm 2	RAF265	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.
RAF265 - Arm 3	RAF265	Patients were treated with once weekly dosing of RAF265
RAF265 - Arm 4	RAF265	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.
RAF265 - Arm 5	RAF265	RAF265 was administered as a continuous dose for 2 weeks followed by a dose holiday of 1 week.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (11)

Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Medical Oncology; 🇺🇸 Baltimore, Maryland, United States

Georgia Regents University Cancer Clinical Research Unit; 🇺🇸 Augusta, Georgia, United States

University of Pennsylvania Health System Dept of Hospital of UnivofPenn; 🇺🇸 Philadelphia, Pennsylvania, United States

Dana Farber Cancer Institute DFCI; 🇺🇸 Boston, Massachusetts, United States

Novartis Investigative Site; 🇨🇭 Zürich, Switzerland

Vanderbilt University Medical Center Dept. of Cancer Center; 🇺🇸 Nashville, Tennessee, United States

University of Colorado Univ.ofColoradoCancerCenter; 🇺🇸 Aurora, Colorado, United States

Massachusetts General Hospital Dept of Cancer for Melanoma; 🇺🇸 Boston, Massachusetts, United States

University of Texas/MD Anderson Cancer Center Onc. Dept,; 🇺🇸 Houston, Texas, United States

University of Pittsburgh Cancer Institute Dept of Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

Beth Israel Deaconess Medical Center Dept.ofBethIsraelDeaconess(3); 🇺🇸 Boston, Massachusetts, United States