Phase I and pharmacological study of oral 9-aminocamptothecin colloidal dispersion (NSC 603071) in patients with advanced solid tumors.
OBJECTIVE
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.


METHODS
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/m(2)/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/m(2)/day. Other toxic effects included nausea, vomiting, fatigue, and transient elevation of the total bilirubin level. The maximal tolerated dose was 0.63 mg/m(2)/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/m(2). 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.
Xiong
Henry Q
HQ
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. qxiong@mdanderson.org
Tran
Hai T
HT
Madden
Timothy L
TL
Newman
Robert A
RA
Abbruzzese
James L
JL
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D002166:Camptothecin