Encouraging results from a phase I study of capecitabine (X), irinotecan (I) and oxaliplatin (O) as first-line therapy in patients (pts) with metastatic colorectal cancer (MCRC)

Abstract

4086 Background: First-line treatment with I, O and infusional 5-FU/Leucovorin (LV) triplets is associated with high response rates and long survival in MCRC. The oral fluoropyrimidine X is better tolerated and shows improved response rates vs. 5- FU/LV in MCRC. This dose-escalation study aims to establish dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase II doses (RPIID) of I, O and X and to evaluate efficacy and safety in first-line. Methods: Starting doses were: I (180mg/m2 i.v. d1), O (85mg/m2 i.v. d1), × (850mg/m2 bid orally d2–15). Dose escalations are based on toxicity observed at previous dose level (DL), until DLT, MTD and RPIID are reached. Results: We have enrolled 27 pts (21 men, 6 women), median age 59 years (range 25–74), at 6 DLs. ECOG PS was 0 or 1 in 25 pts, and 2 in 2 pts. Pts received a median of 10 cycles (range 1–23). All pts are evaluable for toxicity (24 for efficacy). Most common grade 3/4 hematological adverse events (AEs) during dose escalation: granulocytopenia (41%), anemia (7%), and thrombocytopenia (15%). Most common grade 3 non-hematological AEs: late-onset diarrhea (11%), fever (14%), and fatigue (4%). DLTs at each dose level: DL1 (1 febrile neutropenia with bowel perforation); DL2 (1 grade 3 diarrhea); DL3 (1 febrile neutropenia with grade 2 edema); DL4 (1 severe febrile neutropenia in cycles 2&3, pt deceased due to sepsis); no DLTs were reported at DL5 & 6. MTD has not yet been reached. Overall response rate is 79% (95% CI, 62–97%), including 2 CRs and 17 PRs (3 still unconfirmed). Disease control rate is 92%. Two pts had subsequent curative liver resection and 4 pts are under consideration for curative procedures. Median progression-free survival is 15 months (95% CI, 8–22). Conclusions: XIO is well tolerated and highly effective as first-line treatment for MCRC. Severe neutropenia was significant but of short duration and manageable; it is likely to be the main DLT. MTD has not yet been identified but is expected shortly. A phase II study to confirm the efficacy and safety of XIO, possibly in combination with targeted agents, will follow. Supported by Roche, Sanofi-Aventis, and Pfizer Canada. No significant financial relationships to disclose.