Phase I dose-finding and pharmacokinetic trial of irinotecan hydrochloride(CPT-11) using a once-every-three-week dosing schedule for patients with advanced solid tumor malignancy

A Phase I study was performed to determine the maximum tolerated dose (MTD) , toxicities, and pharmacokinetic profile of irinotecan (CPT-11) and its ac tive metabolites when given on a once-every-3-week schedule, Thirty-four pa tients with advanced refractory solid malignancies were treated with CPT-11 (240-340 mg/m(2)) administered as a 90-min i.v. infusion every 3 weeks. Pa tients were divided into two groups: those with and those without prior abd ominal/pelvic (AP) radiotherapy. Gastrointestinal toxicity (nausea, vomitin g, and diarrhea) and hematological toxicity (leukopenia and neutropenia) we re dose-limiting side effects. Other common toxicities included anorexia;ia , asthenia, and acute cholinergic symptoms (abdominal cramps, diaphoresis, and lacrimation). For patients with no prior AP radiation therapy, the MTD was determined to be 320 md/m(2), whereas those with prior AP radiation the rapy had a MTD of 290 md/m(2). Dose-proportional increases in the mean area under the concentration-time curves for CPT-11, SN-38, and SN-38G were not observed over the narrow dose range studied. Mean values of terminal phase half-life, clearance, terminal phase volume of distribution, and steady-st ate volume of distribution for CPT-II were 12.4 +/- 1.8 h, 13.0 +/- 3.8 lit ers/h/m(2), 234 +/- 83 liters/m(2), and 123 +/- 38 liters/m(2), respectivel y. The pharmacodynamic analyses indicated the strongest correlation to be b etween SN-38 area under the concentration-time curves and neutropenia (rho = 0.60; P = 0.001). A total of five responses (one complete response and fo ur partial responses) were observed in the cohort of 32 patients with previ ously treated metastatic colorectal carcinoma. In conclusion, gastrointesti nal toxicity and hematological toxicity were the dose limiting toxicities o f CPT-11 when administered as a 90-min infusion every 3 weeks. In this tria l, the recommended Phase II starting dose for patients,vith no prior AP rad iation therapy was found to be 320 mg/m(2); for patients with prior AP radi ation, the recommended Phase II starting dose was 290 mg/m(2). This once-ev ery-3-week schedule has been incorporated into a Phase I trial of CPT-11 co mbined with 5-fluorouracil and leucovorin.