A phase I clinical trial with weekly irinotecan (IRI) and capecitabine (CAP) in patients with advanced gastrointestinal and other solid malignancies

Abstract

2113 Background: In vitro studies demonstrate synergy between fluoropyrimidines and IRI. We conducted a phase I study to evaluate the safety and tolerability of a convenient dosing schedule for the combination of IRI with an oral fluoropyrimidine, CAP. Methods: Thirty-one patients (pt), median age 60 years, performance status 0–1 (97%), prior chemotherapy 30 pt (97%), primary cancer: ovarian (7), breast (5), colorectal (4), others (15) have received 111 cycles (range 1–11) in 6 dose cohorts. IRI 75–115 mg/m2 was administered on days 1 and 8, as a 30-minute intravenous infusion, without prophylactic atropine, every 21 days (1 cycle). CAP 1500–2000 mg/m2/day was administered in 2 divided doses on days 1–14. Results: There was no cycle-1 dose limiting toxicity (DLT) observed at the first 4 dose cohorts. At dose level 5 (IRI 100 mg/m2 / CAP 2000 mg/m2), among the 12 pts entered, one pt developed cycle-1 DLT - grade 3 diarrhea and vomiting. At the next higher dose level (IRI 115 mg/m2 / CAP 2000 mg/m2) 1 of 3 pts developed grade 4 neutropenia associated with fatal gram-negative sepsis in cycle-1. Overall, across all cycles and all dose levels, grade 3 toxicities observed were diarrhea (5 pt), vomiting (2 pt), fatigue (1 pt), neutropenia (3 pt), anemia (3 pt), and hand-foot syndrome (1 pt). Acute toxicities observed within hours of IRI infusion included abdominal cramping (2 pt), diarrhea (1 pt), and salivation (1 pt), that resolved with, and did not recur in subsequent infusions with prophylactic atropine. Anti-tumor responses included partial response in 6 of 22 evaluable (27%) patients (2 breast, 3 ovarian, 1 cervical), a minimal response (1 pt), and a decrease in CA-125 (1 pt). Conclusions: The combination of IRI and CAP is safe, convenient, and well tolerated. This study is ongoing, and expansion at dose level 6 will continue. There is anti-tumor activity in otherwise chemotherapy-refractory patients, and this combination warrants further evaluation in breast and ovarian cancer, among other malignancies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer; Roche