Temodar and Sutent as Therapy for Melanoma
This study is designed to evaluate the safety and appropriate dose of the combination of Temodar and Sutent as first-line therapy for patients with metastatic malignant melanoma (Phase 1). Once the safety and appropriate dose is determined, additional patients will be studied at that dose to determine if there is clinical benefit as determined by the primary end-point of progression-free survival (PFS) at 6 months and additional secondary endpoints (Phase II).
Metastatic Malignant Melanoma
Drug: Temozolomide and SU11248
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Temodar and Sutent as Therapy for Patients With Malignant Melanoma, a Phase I/II Study|
- Safety and tolerability of this combination [ Time Frame: March 2006 through October 2007 ] [ Designated as safety issue: Yes ]
- Determine the Maximum Tolerated Dose (MTD) of this combination [ Time Frame: March 2006 through October 2007 ] [ Designated as safety issue: No ]
- Progression-free survival (PFS) at 6 months [ Time Frame: March 2006 through October 2007 ] [ Designated as safety issue: No ]
- Progression-free survival (PFS) [ Time Frame: March 2006 through October 2007 ] [ Designated as safety issue: No ]
- Overall survival (OS) [ Time Frame: October 2006 through January 2009 ] [ Designated as safety issue: No ]
- Objective Response Rate (RR)in patients with measurable lesions [ Time Frame: March 2006 through October 2007 ] [ Designated as safety issue: No ]
- Duration of Objective Response in patients with measurable lesions [ Time Frame: March 2006 through October 2007 ] [ Designated as safety issue: No ]
- Correlation of outcome with MGMT promoter methylation [ Time Frame: March 2006 through October 2007 ] [ Designated as safety issue: No ]
|Study Start Date:||March 2006|
|Study Completion Date:||January 2009|
|Primary Completion Date:||October 2007 (Final data collection date for primary outcome measure)|
Experimental: Single arm, Open Label
Single arm, Open Label Temodar and Sutent
Drug: Temozolomide and SU11248
First Cohort: Temozolomide 100 mg/m2 orally week 1 and week 3 of a 28-day cycle; SU11248, 25 mg/day orally on weeks 2, 3, and 4 or a 28 day cycle.
Patients with unresectable metastatic melanoma have a dismal prognosis. The disease responds poorly to currently available chemotherapies and biological agents. The median survival in this patient population is 6 - 10 months and has not improved significantly in decades. The FDA approved DTIC in 1975 and high dose intravenous bolus rIL-2 in 1998 and these are the only agents approved for therapy of patients with metastatic melanoma.
In a Phase III trial reported in 2000, temozolomide (Temodar, Schering-Plough) demonstrated equivalent overall survival to DTIC in patients with metastatic melanoma, and had the advantages of providing improved progression-free survival, ease of administration (oral), and crossing the blood-brain barrier. Temozolomide and DTIC are both precursors of an active metabolite, monomethyl triazenoimidazole carboxamide (MTIC). SU11248 (Sutent, Pfizer) is a multi-targeted receptor tyrosine kinase inhibitor which targets 3 distinct vascular endothelial growth factor receptor (VEGFR-1, -2, and -3), platelet-derived growth factor receptor alpha and beta (PDGFR-α and -β), KIT receptor tyrosine kinases, and fms-related tyrosine kinase 3/Flk2 (FLT3). Although other angiogenic factors have been identified, VEGF is the most potent and specific regulator of angiogenesis and SU11248 targets not just one, but all 3 VEGF signaling pathways. Dacarbazine (DTIC) causes transcriptional up-regulation of VEGF in melanoma cells and this has been postulated as a possible mechanism of escape from chemotherapy efficacy. Temozolomide, which acts through the same metabolite, MTIC, would be expected to have the same activity. PDGFR-α and -β are important new targets in tumor cell proliferation and angiogenesis. PDGF signaling pathways have been implicated in the development and growth of solid tumors. Inhibition of PDGF receptors has been shown to inhibit angiogenesis, tumor vascular maturation and maintenance, and tumor cell proliferation - inducing tumor regression. In a murine model, the combination of chemotherapy with VEGF and PDFG receptor inhibitors resulted in a remarkable survival advantage.
The study is an open-label, single arm trial. The patient sample will be approximately 56-62 individuals, males and females 18 years of age or older with measurable metastatic melanoma. Study participants must meet a number of laboratory criteria in order to be admitted into the study. The study duration is expected to be approximately 2 years. Patients will be offered treatment for up to 1 year and are expected to complete a median of 6 cycles of treatment.
An interim analysis of safety will be conducted after completion of treatment of 6 patients in each cohort and a determination will be made as to whether or not to continue to the next cohort according to the specifications in the protocol. If an acceptable dosing regimen is found, the study will proceed to a Phase II portion. Progression-free survival will be determined for the 6 month time point when all patients have completed the study. The study has ≥90% power to detect an increase in the 6-month progression-free survival rate from ≤15%, the result expected for patients receiving available first-line therapy, to ≥35% for patients receiving the combination of temozolomide and SU11248, based on a one group chi-square test with a 0.05 two-sided significance level.
|United States, California|
|Northern California Melanoma Center|
|San Francisco, California, United States, 94109|
|Principal Investigator:||Lynn E. Spitler, MD||Northern California Melanoma Center|