Updated results of a randomized phase II study comparing two schedules of temozolomide in combination with sorafenib in patients with advanced melanoma

Abstract

8527 Background: The preliminary results for 90 patients (pt) on this 4-arm phase II trial testing sorafenib (SO), an oral Raf kinase/VEGFR2 inhibitor, and temozolomide (TEM) in pt with metastatic melanoma (MM) were presented in 2006. Since then 88% of target accrual is completed and the study is open at a second institution. The primary objective of this study is to estimate the duration of progression- free survival (PFS). Secondary objectives are to determine the optimal dosing of TEM, response, and toxicity rates. Correlative studies include BRAF genotyping and assessment of intratumoral Raf inhibition, and apoptosis. Methods: Pt with MM and ECOG PS<2 are eligible. Prior therapy is allowed. Target accrual is 167 pt in 1 stage. All pt receive SO 400 mg po bid continuously. After 1 week of SO alone, pt without brain metastasis or prior TEM (A+B) are randomized to receive either extended dosing (ED): TEM 75 mg/m2 po qd for 6/8 weeks (Arm A), or standard dosing (STD): TEM 150 mg/m2 po qd for days1–5/28 (Arm B). Pt with prior TEM are treated with ED (Arm C) and pt with brain metastasis without prior TEM are treated with STD (Arm D). Responses are assessed using RECIST. Results: Accrual is complete for arms A and B. Results for 147 pt were evaluated ( Table ). SO + TEM resulted in a 19% overall response rate (ORR) [95% CI 11–30%] for pt on arms A+B. In this group, 3/78 pt (4%) developed CNS metastases while on study. Pt on arm D had a 17 % ORR [95% CI 7–34%]. Common grade 3 toxicities were hand-foot syndrome (14%), rash (9%), nausea (9%), and diarrhea (5%). Grade 3 lymphopenia was more common in arm A v. B (43% v. 16%, p=0.01). No significant difference in PFS was found between pt with WT v. mutant BRAF (n=33). Therapy-induced apoptosis was found in 8/9 serial biopsies. Analysis of MAPK phosphorylation in serial biopsies is planned. Conclusions: Updated results confirm the encouraging antitumor activity and tolerability of SO + TEM in pt with MM without a prior history of TEM. No significant financial relationships to disclose. [Table: see text]