Phase I study of PTK787/ZK222584 (PTK/ZK) and RAD001 for patients with advanced solid tumors and dose expansion in renal cell carcinoma patients

5039 Background: PTK/ZK is an orally active tyrosine kinase inhibitor that blocks all known VEGF receptors. RAD001 is an orally active macrolide which selectively inhibits mTOR. Combination therapy with VEGFR and mTOR inhibition may have additive efficacy in several tumor types, particularly renal cell carcinoma (RCC). Materials and Methods: A phase I/II study of PTK/ZK and RAD001 was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety and tolerability. Patients were given escalating daily doses of PTK/ZK in combination with RAD001 (see table ) in 28-day cycles. Patients were assessed for adverse events every 2 weeks and tumor response every 2 cycles. A dose expansion cohort of 20 patients with metastatic RCC is ongoing to further evaluate safety and preliminary efficacy. Results: To date, 27 patients have received a total of 136 cycles. The dose escalation phase included 14 patients and 3 dose levels; dose-limiting toxicities included grade 3 diarrhea and hypertriglyceridemia (14%); asthenia, fatigue and mucositis (7%). Pharmacokinetic studies are pending. A MTD of PTK/ZK 1,000 mg and RAD001 5 mg daily was determined and studied in an expanded cohort of RCC patients. Prior therapy with a VEGF inhibitor was allowed. To date, 13 evaluable RCC patients demonstrate 2 (15%) partial responses and 8 (62%) with stable disease > 3 months; median TTP is 6 months. Conclusions: PTK/ZK and RAD001 combination is well-tolerated and demonstrates clinical activity in patients with RCC despite prior exposure to VEGF inhibition. An MTD of 1,000 mg daily of PTK/ZK and 5 mg daily of RAD001 is the recommended dose for Phase II/III testing. [Table: see text] No significant financial relationships to disclose.