Modulation of irinotecan (Ir) efficacy with capecitabine (Cp): Albert Einstein and Montefiore Cancer Center experience

Abstract

2072 Background: We have previously demonstrated that Cp may be administered safely as a daily “flat” total dose with Ir given every 3 weeks [Am J Clin Oncol 2002 25: 528–34]. Since the usual North American schedule of Ir is a weekly dosing scheme, we designed a study using a weekly combined drug regimen. Methods: This is an open label standard phase I dose escalation trial. Ir was given as a 30-minute infusion on days 1 and 8, without prophylactic atropine, and Cp on days 1–14 of a 21day cycle. Results: Forty seven patients (pt) -median age 60 (range 32–83) years; performance status 0–1 (96%); diagnoses- ovarian (10), breast (5), cervical (5), colorectal (10) and others (17) have received 202 (1–18) cycles in 6 dose cohorts-Ir (mg/m2)/Cp (mg/m2/day in 2 divided doses) 75/1500, 85/1500, 85/1750, 100/1750, 100/2000, 115/2000. There was no cycle 1 dose limiting toxicity (DLT) in the first four dose cohorts tested. At the highest dose level (Ir/Cp 115/2000), 1 of 3 pt developed grade 4 neutropenia with fatal gram-negative sepsis. At dose level 5 (Ir/Cp 100/2000), 2 of 21 evaluable patients developed cycle 1 DLT - grade 3 diarrhea/vomiting and grade 3 diarrhea. Overall, across all doses and patients, the grade 3–4 toxicities observed were diarrhea (12 pt), vomiting (2 pt), fatigue (5 pt), hand-foot syndrome (1 pt), neutropenia (6 pt), anemia (4 pt), thrombocytopenia (2 pt) and elevation of AST and ALT (1 pt). Acute toxicities observed within hours of Ir included the cholinergic syndrome in 4 patients that resolved with, and did not recur in subsequent infusions with prophylactic atropine. Anti-tumor responses include partial response in 8 of 35 evaluable (23%) pts (2 breast, 4 ovarian, 1 prostate, 1 cervical), a minimal response (1 pt- breast), stable disease in 16 pt (44%) and a decrease in CA-125 (1 pt-ACUP). Conclusions: The combination of Ir and Cp is safe and well tolerated at a dose of 100 mg/m2and 2000 mg/m2/d, respectively. There is moderate anti-tumor activity in heavily treated and chemotherapy refractory patients. This combination warrants further evaluation in breast, cervical, and ovarian cancer and other solid tumors. We are currently evaluating the pharmacokinetic effects of Cp on the disposition of Ir. No significant financial relationships to disclose.