Phase I study of sunitinib with irinotecan/5-fluorouracil/ leucovorin (FOLFIRI) for advanced gastroesophageal cancers.

Abstract

TPS201 Background: The incidence of gastroesophageal junction (GEJ) adenocarcinoma (AC) has dramatically increased in the Western world. Chemotherapy (CT) options have reached a plateau with median survival for advanced GEJ cancer rarely exceeding 12 months. VEGF and PDGF are strong angiogenic promoters in gastric cancer increasing proliferation, invasion and survival of the neoplastic cell. Disrupting this pathway may serve as a new therapeutic strategy in GEJ cancer. Sunitinib (S) is an oral receptor tyrosine kinase inhibitor of VEGFR, PDGRF, KIT, FLT-3, and RET. S is synergistic with CT, including 5FU in preclinical models (Mol Cancer Ther 2:471-478, 2003). We hypothesized that the addition of S to FOLFIRI in advanced GEJ AC would augment therapeutic efficacy. Methods: Primary aim is to determine the MTD of S in combination with FOLFIRI in advanced GEJ cancer. Secondary end-pts include response, overall and progression-free survival, and pharmacokinetics (PKs) of irinotecan (I), SN-38, and S (steady-state) to determine any interactions. Therapy-naïve advanced gastric and GEJ AC patients (pts) with adequate organ function, performance status (ECOG 0-1) are eligible. UGT1A1*28 7/7 homozygous polymorphism is an exclusion. Treatment consists of standard FOLFIRI (I 180 mg/m2, leucovorin 400 mg/m2, 5FU 400 mg/m2 followed by 46-hr infusion 5FU 2,400 mg/m2 q2w) with escalating doses of S given orally daily starting on day 2 (dose range 25 mg–67.5 mg, increments of 12.5 mg per cohort). Per prespecified design, initial intra- and inter-patient dose escalation was permitted, but then changed to a standard 3+3 design after observed toxicities. Initial experience also mandated amendments to an intermittent S dosing schedule of 14 days in a 28-day cycle, with decrease in I dose to 150 mg/m2, 5FU bolus to 320 mg/m2 and 5FU infusion to 2,000 mg/m2 q2w. Dose- limiting toxicities are assessed in the 1st 4 wks of treatment (febrile neutropenia, G4 neutropenia > 7d, G4 thrombocytopenia or anemia, ≥ G3 non- heme toxicity, dose delay > 14d). PKs for I/SN-38 assessed without and with S; PKs for S assessed on days 14 and 15 of cycle 1. Current accrual is at 12 pts. This study is supported by an IISP research grant from Pfizer, Inc. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer