Clinical trial NCT00304525: A Study to Evaluate RAF265, an Oral Drug Administered to Subjects With Locally Advanced or Metastatic Melanoma
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Melanoma
Keywords: Anti-angiogenesis therapy
Kinase inhibitor therapy
Raf inhibitor
Locally Advanced Melanoma
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2006-03-20
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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
3. History of melena, hematemesis, or hemoptysis within the last 3 months
4. Previous therapy with certain molecularly targeted agents

Primary outcomes:
measure: Maximum tolerated dose
timeFrame: at the end of dose escalation
measure: Dose limiting toxicities
timeFrame: during the PK run-in phase and first cycle (28 day cycle)
measure: Safety profile
timeFrame: throughout the study
measure: Evaluate potential pharmacodynamic effects
timeFrame: throughout the study
measure: Pharmacokinetic profile
timeFrame: throughout the study
Secondary outcomes:
measure: Evaluate whether somatic mutations in BRAF and N-RAS genes are associated with modulation of pharmacodynamic markers and clinical response
timeFrame: throughout the study
measure: Determine the response rate for BRAF mutant patients
timeFrame: Every 2 months
measure: Determine the recommended phase two dose
timeFrame: at the end of dose escalation
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Univ.ofColoradoCancerCenter
state: Colorado
city: Augusta
country: United States
facility: Georgia Regents University Cancer Clinical Research Unit
state: Georgia
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Medical Oncology
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Dept of Cancer for Melanoma
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute DFCI
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center Dept.ofBethIsraelDeaconess(3)
state: Massachusetts
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System Dept of Hospital of UnivofPenn
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute Dept of Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center Dept. of Cancer Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center Onc. Dept,
state: Texas
city: Zürich
country: Switzerland
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
affiliation: Novartis Pharmeceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: