Metastatic Melanoma
Conditions
Keywords
Anti-angiogenesis therapy, Kinase inhibitor therapy, Raf inhibitor, Locally Advanced Melanoma
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.
Interventions
DRUGRAF265
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.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Pharmacokinetic profile | throughout the study |
| 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 |
| Maximum tolerated dose | at the end of dose escalation |
Secondary
| Measure | Time frame |
|---|---|
| Determine the response rate for BRAF mutant patients | Every 2 months |
| Determine the recommended phase two dose | at the end of dose escalation |
| Evaluate whether somatic mutations in BRAF and N-RAS genes are associated with modulation of pharmacodynamic markers and clinical response | throughout the study |
Countries
Switzerland, United States
Outcome results
None listed