Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors

Purpose: We conducted a phase I dose-escalation trial of orally administere d irinotecan (CPT-11) to characterize the maximum-tolerated dose (MTD), dos e-limiting toxicities (DLTs), pharmacokinetic profile, and antitumor effect s in patients with refractory malignancies. Patients and Methods: CPT-II solution for intravenous (IV) use was mixed wi th CranGrape juice (Ocean Spray, Lakeville-Middleboro, MA) and administered orally once per day for 5 days every 3 weeks to 28 patients. Starling dosa ges ranged from 20 to 100 mg/m(2)/d. Results: Grade 4 delayed diarrhea was the DLT at the 80 mg/m(2)/d dosage in patients younger than 65 years of age and at the 66 mg/m(2)/d dosage in pa tients 65 or older. The other most clinically significant toxicity of oral CPT-II was neutropenia. A linear relationship was found between dose, peak plasma concentration, and area under the concentration-time curve (AUC) for both CPT-11 and SN-38 lactone, implying no saturation in the conversion of irinotecan to SN-38. The mean metabolic ratio ([AUC(SN-38) (total) + AUC(S N-38G) (total)]/AUC(CPT-11 total)) was 0.7 to 0.8, which suggests that oral dosing results in presystemic conversion of CPT-11 to SN-38. An average of 72% of SN-38 was maintained in the lactone form during the first 24 hours after drug administration. One patient with previously treated colorectal c ancer and liver metastases who received oral CPT-11 at the 80 mg/m(2)/d dos age achieved a confirmed partial response. Conclusion: The MTD and recommended phase II dosage for oral CPT-II is 66 m g/m(2)/d in patients younger than 65 years of age and 50 mg/m(2)/d in patie nts 65 or older, administered daily for 5 days every 3 weeks. The DLT of di arrhea is similar to that observed with IV administration of CPT-11. The bi ologic activity and favorable pharmacokinetic characteristics make oral adm inistration of CPT-11 an attractive option for further clinical development . (C) 1999 by American Society of Clinical Oncology.