A phase I study of systemic sorafenib in combination with isolated limb infusion with melphalan (ILI-M) in patients (pts) with locally advanced in-transit melanoma

Abstract

9065 Background: Sorafenib is a multi-kinase inhibitor that may also enhance the cytotoxicity of concurrently administered chemotherapy. In a preclinical model of regionally advanced melanoma, the combination of systemic Sorafenib and regional melphalan led to augmented tumor responses. Methods: A Phase I multicenter study was performed to evaluate the safety and pharmacokinetics (PK) of systemic Sorafenib in combination with ILI-M in patients with measurable in-transit melanoma of the extremity. Sorafenib dose escalation cohorts consisted of 200mg, 300mg, and 400mg administered systemically twice daily for one week prior and one week after a standard dose ILI-M corrected for ideal body weight. Tumor biopsies pre-therapy and pre-ILI were obtained to assess molecular changes associated with Sorafenib pretreatment. Response was defined at 3 months using RECIST. Results: Nine pts with high disease burden, including 7 previous ILI-M alone failures, have been treated; 3 in the first cohort and 6 in the second cohort. There were no grade 5 toxicities. Four patients had CTCAE Grade 4 toxicities including neutropenia (2), CPK elevation (1), and skin ulceration (1). In the remaining 5 patients, there were no >grade 3 toxicities. The maximally tolerated dose (MTD) has not yet been defined. Initial in field response determination in 6 of the 9 patients out at least 3 months includes 2 partial responses and 4 disease progressions. Conclusions: Systemic Sorafenib administered pre and post ILI-M is a well tolerated, novel targeted therapy approach to regionally advanced melanoma. An additional 10 patients will be enrolled to define the MTD. Correlation of response with drug PK, Sorafenib downregulation of pErk and Mcl1, and a melphalan resistance signature is in progress. No significant financial relationships to disclose.