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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT00304525

Collaborator

(none)

104

Enrollment

Locations

Arms

Duration (Months)

9.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma	Drug: RAF265	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

104 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (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.

Study Start Date :

Apr 1, 2006

Actual Primary Completion Date :

Nov 1, 2013

Actual Study Completion Date :

Nov 1, 2013

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Confirmed diagnosis of melanoma, locally advanced AJCC Stage IIIB to metastatic Stage IV
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
ECOG performance status of 0 or 1
No concurrent anticancer or investigational therapy for at least 4 weeks prior to enrollment
No major surgery for at least 4 weeks prior to enrollment

Exclusion Criteria:

Significant cardiac disease or other significant medical/psychiatric disease
History of primary central nervous system tumor or brain metastases
History of melena, hematemesis, or hemoptysis within the last 3 months
Previous therapy with certain molecularly targeted agents

Contacts and Locations

Locations

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