Phase 1 and Pharmacokinetic Study of Intravenous Irinotecan in Refractory Solid Tumor Patients with Hepatic Dysfunction

Purpose: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule. Experimental Design: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT): Group 1 ( n = 19): total bilirubin 1.5 to 3.0 × institutional upper limit of normal (IULN) and ALT/AST ≤5.0 × IULN; Group 2 ( n = 7): total bilirubin 3.1 to 5.0 × IULN and ALT/AST ≤5.0 × IULN; Group 3 ( n = 6): total bilirubin ≤1.5 × IULN and ALT/AST 5.1 to 20.0 × IULN; Group 4 ( n = 10): total bilirubin 1.5 to 3.0 × IULN and ALT/AST 5.1 to 20.0 × IULN. Irinotecan was given as a 90-minute i.v. infusion weekly for the first 4 weeks in each 6-week cycle at starting doses which escalated from 40 to as much as 75 mg/m 2 . After the first treatment, doses were adjusted based on individual patient toxicities. Starting doses for patients with hepatic dysfunction were derived from the maximum tolerated doses noted in the four hepatic dysfunction groups. Results: Forty-two patients were treated. Among the most frequent adverse events were neutropenia (41%, grades 3/4), diarrhea (15%, grades 3/4), nausea (10%, grade 3), and vomiting (5%, grades 3/4). Two patients died from drug-induced neutropenic sepsis. Two patients had objective tumor responses (complete response, liver metastases from unknown primary; partial response, colon cancer). Hepatic dysfunction reduced irinotecan clearance while increasing relative exposure to the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). SN-38 exposures in patients receiving doses of 40 to 75 mg/m 2 were comparable to exposures in patients with normal liver function treated with a starting dose of 125 mg/m 2 . Conclusions: Irinotecan starting doses that seem to be safe for hepatically impaired patients treated with the weekly schedule are 60, 50, 60, and 40 mg/m 2 for groups 1 to 4, respectively. At these starting doses, exposure to SN-38 and the adverse event profile are similar to that observed in patients with normal liver function and antitumor activity can be observed.