Sunitinib (Su) In Combination With Pemetrexed (P) In Patients (Pts) With Advanced Solid Malignancies: A Phase I Dose Escalation Study

3566 Background: SU is an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R, and RET, approved multinationally for the treatment of advanced RCC and imatinib-resistant/intolerant GIST. NSCLC xenograft data indicate SU enhanced the antitumor activity of P and support studies with SU+P. This ongoing, open-label, phase I study investigated the maximum tolerated doses (MTDs), safety, pharmacokinetic (PK) profile and efficacy of SU+P in pts with advanced solid malignancies. Methods: Successive pt cohorts received escalating daily doses of oral SU at 25, 37.5, or 50 mg on continuous 3-wk cycles (continuous daily dose [CDD] schedule) or for 2 wks of a 3-wk cycle (2/1 schedule) with escalating doses of P at 300–500 mg/m2 IV q21d. MTD was defined as the highest dose at which 0/3 or 1/6 pts had dose-limiting toxicities (DLTs) during cycle 1. Safety was evaluated and PK profiles were analyzed for SU, P and SU+P. In pts with measurable disease, objective response was determined by RECIST. Results: As of Dec 2007, 20 pts received SU (CDD) + P in 4 dose-escalation cohorts (NSCLC n=3). DLTs included febrile neutropenia (n=1; SU 37.5 mg + P 500 mg/m2), grade (G) 3 anorexia ≥7 days and G5 cerebral hemorrhage (each n=1; SU 50 mg + P 500 mg/m2). MTD was established as SU 37.5 mg (CDD) + P 500 mg/m2. Non-hematologic, all causality ≥G3 AEs (≥2 pts) included: fatigue (n=5), anorexia (n=3), febrile neutropenia, syncope, and hypoxia (each n=2). G4 lab abnormalities included lymphopenia (n=2), neutropenia, thrombocytopenia and leucopenia (each n=1). Two G5 AEs were reported: cerebral hemorrhage (considered possibly related to SU) and sudden death (considered related to underlying disease). PK data revealed no clinically significant drug-drug interactions with co-administration (all dose levels). To date 1 pt (cholangiocarcinoma, SU 37.5 mg + P 300 mg/m2) had a documented PR maintained >12 cycles and 8 pts have SD (5 pts with SD >3 months, [NSCLC n=1] range 3.0–6.5+ months). Data will also be presented on the ongoing 2/1 schedule cohort. Conclusions: SU 37.5 mg/day (CDD schedule) + P 500 mg/m2 q21d has a manageable safety profile and shows preliminary evidence of efficacy. Further studies of SU+P are planned in additional pt populations including NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer