Temodar and Sutent as Therapy for Patients With Malignant Melanoma, a Phase I/II Study
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.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety and tolerability of this combination
March 2006 through October 2007
Yes
Lynn E. Spitler, MD
Principal Investigator
Northern California Melanoma Center
United States: Food and Drug Administration
Temodar/Sutent
NCT00304200
March 2006
January 2009
Name | Location |
---|---|
Northern California Melanoma Center | San Francisco, California 94109 |