This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Xiong, H. Q. Articles by Abbruzzese, J. L. Search for Related Content PubMed PubMed Citation Articles by Xiong, H. Q. Articles by Abbruzzese, J. L.

Phase I and Pharmacological Study of Oral 9-Aminocamptothecin Colloidal Dispersion (NSC 603071) in Patients with Advanced Solid Tumors¹

Departments of Gastrointestinal Medical Oncology [H. Q. X., J. L. A.], Pharmaceutical Research [H. T. T., T. L. M.], and Experimental Therapeutics [R. A. N.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Purpose: 9-Aminocamptothecin colloidal dispersion (9-ACCD; NSC 603071) is a specific inhibitor of topoisomerase I that can be given p.o. This Phase I trial was conducted to determine the toxicity profile, maximal tolerated dose, and pharmacokinetics profile, including bioavailability, of p.o. 9-ACCD in patients with advanced solid tumors.

Experimental Design: After receiving one i.v. dose of 9-ACCD, patients were treated with 9-ACCD p.o., starting with a 2-week schedule, to establish the safety. Once safety was established, patients were treated continuously for 4 weeks followed by a rest period of 2 weeks at dosages of 0.2, 0.3, 0.45, 0.56, 0.7, and 0.63 mg/m²/day. Serial blood samples were collected for the pharmacokinetics study on day 1 after the i.v. dose and day 2 after p.o. administration. Lactone and total 9-aminocamptothecin were analyzed by high-pressure liquid chromatographic assay.

Results: Thirty-two patients were treated on the study. The dose-limiting toxicity was myelosuppression at the dosage of 0.7 mg/m²/day. Other toxic effects included nausea, vomiting, fatigue, and transient elevation of the total bilirubin level. The maximal tolerated dose was 0.63 mg/m²/day. There was no objective response. The mean terminal half-life of p.o. total 9-ACCD was 1.2 ± 1.2 h, and the volume of distribution was 17.7 ± 20.6 l/m². The mean bioavailability of total 9-ACCD was 68.1 ± 36.4%.

Conclusions: Despite good tolerance of p.o. administration, the lack of clinical activity and variable absorption of 9-ACCD suggested that further development might not be warranted.