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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00304525
First received: March 17, 2006
Last updated: June 24, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Metastatic Melanoma
Drug: RAF265
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Maximum tolerated dose [ Time Frame: at the end of dose escalation ] [ Designated as safety issue: Yes ]
  • Dose limiting toxicities [ Time Frame: during the PK run-in phase and first cycle (28 day cycle) ] [ Designated as safety issue: Yes ]
  • Safety profile [ Time Frame: throughout the study ] [ Designated as safety issue: Yes ]
  • Evaluate potential pharmacodynamic effects [ Time Frame: throughout the study ] [ Designated as safety issue: No ]
  • Pharmacokinetic profile [ Time Frame: throughout the study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • Determine the response rate for BRAF mutant patients [ Time Frame: Every 2 months ] [ Designated as safety issue: No ]
  • Determine the recommended phase two dose [ Time Frame: at the end of dose escalation ] [ Designated as safety issue: No ]

Enrollment: 104
Study Start Date: April 2006
Study Completion Date: November 2013
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 stengths.
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 maintenence 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 stengths.
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 stengths.
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 stengths.
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 stengths.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 onths
  3. History of melena, hematemesis, or hemoptysis within the last 3 months
  4. Previous therapy with certain molecularly targeted agents
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00304525

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

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00304525     History of Changes
Obsolete Identifiers: NCT00324935
Other Study ID Numbers: CRAF265A2101, 2007-005367-10
Study First Received: March 17, 2006
Last Updated: June 24, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Anti-angiogenesis therapy
Kinase inhibitor therapy
Raf inhibitor
Locally Advanced Melanoma

Additional relevant MeSH terms:
Melanoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas

ClinicalTrials.gov processed this record on October 20, 2014