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

Novartis

Status and phase: Completed; Phase 2; Phase 1

Conditions: Metastatic Melanoma

Treatments: Drug: RAF265

Study type: Interventional

Funder types: Industry

Identifiers

NCT00304525

CRAF265A2101

2007-005367-10 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 104 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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104 participants in 5 patient groups

RAF265 - Arm 1

Experimental group

Description:

Patients received 10mg RAF265 as a once weekly dose until progressive disease was confirmed.

Treatment:

Drug: RAF265

RAF265 - Arm 2

Experimental group

Description:

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.

Treatment:

Drug: RAF265

RAF265 - Arm 3

Experimental group

Description:

Patients were treated with once weekly dosing of RAF265

Treatment:

Drug: RAF265

RAF265 - Arm 4

Experimental group

Description:

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.

Treatment:

Drug: RAF265

RAF265 - Arm 5

Experimental group

Description:

RAF265 was administered as a continuous dose for 2 weeks followed by a dose holiday of 1 week.

Treatment:

Drug: RAF265