Phase I/II study of the association of sorafenib and temozolomide (extended schedule) in patients with metastatic melanoma: A new clinical response profile with massive tumor necroses

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9062 Background: Recent progress in melanoma research identified a wide variety of different melanomas in term of biology, clinical behavior and chemosensitivity profiles. This phase I/II study of association of sorafenib (SOR) and temozolomide (TMZ) evaluates the safety and efficacy of this association in patients with metastatic melanoma and tries to correlate clinical responses to early biological and imaging parameters. We report the ph I results and preliminary results of the ph II (still recruiting pts). Methods: Safety was the primary objective of the phase I and three escalating dose levels were tested. Primary objective of the phase II is PFS at 12 weeks and 32 patients were recruited at the recommended (45 planned). Secondary objectives evaluate tumour vascularization by dynamic contrast enhanced ultrasonography (DCE-US), PK profile of TMZ, number and function of circulating lymphocytes, melanoma RNA expression profiles and mutational status (BRAF, NRAS, c-KIT, PTEN, PI3K, βcat), circulating endothelial and progenitor cells. Results: 13 evaluable pts were included in the phase I. The recommended doses are SOR: 400 mg bid and TMZ: 150 mg/m2 /d every other week. Toxicity was manageable. SOR did not influence TMZ PK. RECIST evaluation showed 1 CR (+ 12 months), 1 PR (+ 13 months), 3 SD, 8 PD. Among the 23 evaluable pts included in the phase II, 1 PR, 11 SD and 11 PD were observed. Five pts presented rapid and massive metastases necrosis with obvious tumour cavitation on CT which is very unusual during the course of melanoma treatment. Devascularization seen on DCE-US after 1 month was predictive of tumour response. Integrated correlative biological parameters are being analyzed and will be presented. Conclusions: SOR+TMZ association is well tolerated and gives promising results in some patients with metastatic melanoma. Unexpected major tumour necrosis has been observed in 5 patients. Early tumour devascularization observed by DCE-US seems predictive for tumour response. Extensive biological studies are being performed and might give useful clues allowing the identification of melanoma subtypes that are sensitive to this treatment regimen. No significant financial relationships to disclose.