Celecoxib in combination with irinotecan (CPT-11), 5-fluorouracil and leucovorin in patients with advanced cancer: A phase I, pharmacokinetic study

2092 Background: We demonstrated in preclinical model that CPT-11 induced diarrhea can be prevented by celecoxib. Higher doses of CPT-11 could be administered with celecoxib in vivo resulting in improved therapeutic efficacy. Methods: In this phase I study, we escalated CPT-11 dose in FOLFIRI regimen with a fixed dose of celecoxib. We also investigated potential pharmacokinetic (PK) modulation of CPT-11 by celecoxib. CPT-11 dose escalation was planned in 4 dose levels (DL): 180, 200, 220 and 260 mg/m2 along with standard doses of 5-fluorouracil and leucovorin in FOLFIRI schedule administered 2-weekly. Celecoxib was administered in dose of 400 mg p.o. bid, starting day 2 of cycle 1. PK of CPT-11, SN-38 and SN-38G were obtained on day 1 (pre-celecoxib) and day 14 (with celecoxib) in 3 patients (pts) with complete sampling. Standard 3+3 dose escalation schema was used. Plasma concentrations of CPT-11, SN-38, and SN-38G were analyzed with validated HPLC method with fluorescence detection. PK parameters assessed included Cmax, and AUC for CPT-11, SN-38 and SN-38G. Institutional Review Board approval was obtained for this study. All patients signed informed consent. Results: Fourteen pts with advanced cancers were enrolled. Pt characteristics were: 8 males, 6 females, median age 52 yrs, ECOG 0/1/2: 1/12/1 pts; all had prior chemotherapy (median 1 regimen). Diagnosis: 7 colorectal, 6 esophageal, 1 unknown primary. One pt (1/6) had a DLT at DL2 (febrile neutropenia). Two pts had a DLT at DL3 (G3 emesis and myocardial infarct); trial was halted at DL3. Diarrhea was limited and cause for discontinuation in none. Grade 2 and 3 diarrhea occurred in 2 pts each. Celecoxib had no influence on the PK of CPT-11 and its metabolites. SD was best response noted in 6/8 and PR in 1/8 evaluable pts. Three pts with esophageal cancer received 12 cycles (maximum for protocol) and continue treatment off study. Conclusions: MTD of CPT-11 in FOLFIRI schedule with celecoxib is 200 mg/m2. Diarrhea at this dose is self-limited. No PK interactions between CPT-11 and celecoxib were apparent. The activity of this combination in esophageal cancer appears promising. (Supported by grant from NCCN) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Eli Lilly, Genentech, Roche