Phase I Study of Irinotecan/5-Fluorouracil/Leucovorin (FOLFIRI) with Sunitinib for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.

ABSTRACT

BACKGROUND: Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor. It is synergistic with chemotherapy in preclinical models. We hypothesized that sunitinib in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) would be a tolerable and effective regimen in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. OBJECTIVE: Since the outcomes of advanced gastric and GEJ adenocarcinoma patients are poor, we decided to study a combination of FOLFIRI + S, to establish tolerability and efficacy. PATIENTS AND METHODS: This was a phase I study for patients with advanced chemo-naïve gastric or GEJ adenocarcinoma. Dose escalation used a standard 3 + 3 design. The primary objective was to determine the tolerability and safety of FOLFIRI + S. Secondary objectives were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). RESULTS: A total of 23 patients participated in the study (male 78%, female 22%). The median age was 61 (range 38-77) years. Median follow-up time was 67.5 (95% CI 58.9-76) months. The most frequently reported adverse events were anemia (78%; G3/4 4%), neutropenia (78%; G3/4 43%), nausea (74%; G3/413%), diarrhea (65%; G3/4 4%), vomiting (61%, G3/4 9%) lymphopenia (52%; G3/4 13%), and fatigue (52%; G3/417%). Two dose-limiting toxicities were noted each at dose level (DL) 1 and 1A, one at DL 1B, and three at DL 2. Maximum tolerated dose was determined at DL 1B. At the time of data reporting, 21 patients had died. The median OS and PFS were 12.4 (95% CI 8.9, 16.5) months and 6.2 (95% CI 3.4, 13.5) months, respectively. Of all patients, 35% (eight out of 23) had a partial response. CONCLUSIONS: FOLFIRI + S has signs of clinical activity in patients with advanced gastric and GEJ adenocarcinoma, and the side-effect profile was similar to previously reported studies. Current treatment paradigms in gastric cancer probably negate further study of this regimen. ClinicalTrials.gov identifier NCT00524186.