A phase I dose-finding study of sunitinib (SU) in combination with gemcitabine (G) in patients (pts) with advanced solid tumors

Abstract

14522 Background: Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor that shows significant antitumor activity in renal cell carcinoma (RCC) and other cancers. This study assessed the maximum tolerated dose (MTD), safety and pharmacokinetic (PK) profile of SU in combination with G in advanced solid tumor pts. Methods: Pts received escalating oral doses of SU (25–50 mg/day) on a 6-week (wk) cycle (4 wks on, 2 wks off treatment; 4/2 schedule) with G (750–1250 mg/m2) IV over 30 min on Days 1, 8, 22, and 29. Subsequently, patients received SU on a 3-wk cycle (2 wks on, 1 wk off; 2/1 schedule) with G on Days 1 and 8. Safety was evaluated using adverse event (AE) reports and laboratory analyses. Objective responses were assessed by RECIST; PK data were analyzed at each dose level. Results: 34 pts (most common tumor types: RCC, n=19; pancreatic, n=11) received SU+G, including 8 pts on Schedule 4/2 and 26 pts on Schedule 2/1. Schedule 4/2 was not pursued beyond the initial dose level. On schedule 2/1, MTD has not yet been reached, and enrollment continues at the highest dose level (SU 50 mg/day + G 1250 mg/m2). On Schedule 2/1, grade (Gr) 4 non-hematologic AEs included myocardial infarction (n=1) and pulmonary embolism (n=1), neither considered related to study treatment. Gr 4 laboratory abnormalities included thrombocytopenia (n=1) and neutropenia (n=6), with no instances of febrile neutropenia. Evidence of antitumor efficacy has been observed on both schedules, in pts with pancreatic or renal cancer. Among 9 pts with poor-risk or sarcomatoid RCC, 5 pts exhibited partial responses and 3 had stable disease, across different dose levels. At all dose levels analyzed to date, the Cmax and AUC of the drugs and their metabolites following combination therapy were similar to those following single-agent SU or G dosing; these data indicate that there are no clinically significant drug-drug interactions during co-administration. Conclusions: Combination therapy with SU and G in pts with advanced solid tumors is well tolerated, does not result in significant drug-drug interactions, and is associated with notable antitumor activity. The efficacy and safety of this combination will be studied further in disease-specific clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Bayer, Genentech, Pfizer, Wyeth Pfizer Pfizer, Wyeth Pfizer