A Study to Evaluate RAF265, an Oral Drug Administered to Subjects With Locally Advanced or Metastatic Melanoma (CHIR-265-MEL01)

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.

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Melanoma
• Intervention / Treatment: Drug: RAF265

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 Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Zürich, Switzerland, 8091
    • Novartis Investigative Site
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Univ.ofColoradoCancerCenter
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Regents University Cancer Clinical Research Unit
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Medical Oncology
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Dept of Cancer for Melanoma
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute DFCI
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center Dept.ofBethIsraelDeaconess(3)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Health System Dept of Hospital of UnivofPenn
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute Dept of Hillman Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center Dept. of Cancer Center
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Onc. Dept,

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:

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• CRAF265A2101 Results at Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: March 17, 2006
• First Submitted That Met QC Criteria: March 17, 2006
• First Posted (Estimate): March 20, 2006

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 11, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Anti-angiogenesis therapy; Kinase inhibitor therapy; Raf inhibitor; Locally 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
• Other Study ID Numbers: CRAF265A2101; 2007-005367-10 (EudraCT Number)