Phase I study of high-dose interleukin (HD-IL2) and sorafenib in patients with metastatic clear cell renal cell carcinoma (RCC) and melanoma.

Abstract

337 Background: HD-IL2 has demonstrated activity for immune therapy of RCC and melanoma. Sorafenib is a multitargeted kinase inhibitor with antiangiogenic activity and may also modulate antitumor immunity. This ongoing phase I study assesses the safety, tolerability, dose-limiting toxicity (DLT), and maximum tolerated dose of the combination of HD-IL2 and sorafenib in patients with unresectable or metastatic clear cell RCC and melanoma. Methods: Eligible patients with ECOG PS 0-1, adequate organ function, and favorable or intermediate Motzer status (RCC patients) received up to two series of therapy. Each 82-day series consisted of two cycles of bolus HD-IL2 and 8 weeks of sorafenib. HD-IL2 (600,000 IU/kg IV q8h x 8-12 doses) was given on days 1-5 (cycle 1) and 15-20 (cycle 2). Sorafenib was given on days 29-82 and discontinued 48-72 hours prior to the next series. Dosing levels for sorafenib were (1) 200mg daily, (2) 200mg BID, (3) 200mg qAM and 400mg qPM, and (4) 400mg BID. Patients who achieved stable disease (SD), partial response (PR), or complete response (CR) after Series 1 proceeded to Series 2. Results: Fourteen patients (8 RCC, 6 melanoma) have been treated. Nine patients completed Series 1 (5 patients came off study due to poor tolerance of HD-IL2, prior to receiving sorafenib). Six patients had SD or better (3 PR, 3 SD) after Series 1. Of these, five have completed Series 2 and one patient progressed during sorafenib treatment in the second series. No DLTs were observed at the first 3 dose levels. All observed grade 3 and 4 AEs were transient and attributable to the known toxicities of HD-IL2 or sorafenib, and were not considered DLT. Adverse events occurring more frequently in Series 2 (HD-IL2 after sorafenib) included proteinuria and dry skin. One death occurred in a patient with melanoma who received only the first cycle of HD- IL2 (never received sorafenib) and one week later experienced sudden death at home, an event reported as possibly related to the HD-IL2. Conclusions: No DLT was seen in this study of HD-IL2 and sorafenib and the toxicity was predictable and manageable. Both RCC and melanoma patients experienced PR and SD, but not CR. Enrollment to cohort 4 is ongoing. [Table: see text]