A phase I/II study of capecitabine (X), irinotecan (I) and oxaliplatin (O) as first-line therapy in patients (pts) with advanced or metastatic colorectal cancer (MCRC)

13540 Background: Triplets of I, O and infusional 5-FU/Leucovorin (LV) are associated with high response rates and long survival in first-line MCRC [Falcone et al. JCO 2002;20:4006–14]. The oral fluoropyrimidine X has proved higher response rates and improved safety vs. 5-FU/LV in MCRC. Methods: This ongoing dose-escalation study aims to establish dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase II doses (RPIID) of I and O in combination with X as first-line therapy for MCRC and to assess the efficacy and safety of this XIO combination. Starting doses were: I (180mg/m2 i.v. on day 1), O (85mg/m2 i.v. on day 1), and X (850mg/m2 bid orally on days 2–15). Dose escalations are based on toxicity observed at the previous dose level (DL), until DLT, MTD and RPIID are documented, at which time a phase II component begins. Results: We enrolled 18 pts (13 men, 5 women), median age 61 (range 44–74) at 4 DLs. ECOG PS was 0 or 1 in 17 pts, and 2 in 1 pt. Pts received a median of 7 cycles (range 1–15) of XIO. All pts are evaluable for toxicity and 14 for response. The most common adverse events were: neutropenia (83% all grades (G) with 4 G3, 4 G4), diarrhea (67%, 4 G3, one of which was a DLT). Nausea (78%) and vomiting (56%) were mild and controlled with anti-emetics. Fatigue occurred in 50% pts, with 1 G3. The DLT was febrile neutropenia (3 pts at DLs 1, 3, & 4 respectively). One pt at DL4 developed severe neutropenia and sepsis during cycle 3, had aspiration pneumonia and died in hospital from respiratory and cardiac complications. MTD has not yet been reached. Responses were observed at all DLs: 11 partial responses with 2 still unconfirmed (79%, 95% CI 54–100), and 2 stable disease (14%). Progression-free survival and overall survival have not been reached. Conclusions: XIO is well tolerated and demonstrated significant efficacy as first-line treatment in MCRC. Severe neutropenia was significant but was of short duration and manageable. It is likely to be the main DLT. MTD has not yet been identified but is expected in the next few pts. A phase II study to confirm the efficacy and safety of the XIO combination will follow. Supported by Roche, Sanofi Aventis, and Pfizer Canada Inc. [Table: see text]

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