Reference

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

Phase I and Pharmacological Study of Oral 9-Aminocamptothecin Colloidal Dispersion (NSC 603071) in Patients with Advanced Solid Tumors. Xiong, Henry Q.; Tran, Hai T.; Madden, Timothy L.; Newman, Robert A.; Abbruzzese, James L. (Departments of Gastrointestinal Medical Oncology, The University of Texas M.In this study，91421-43-1 is also used. D. Anderson Cancer Center, Houston, TX 77030, USA). Clinical Cancer Research, 9(6), 2066-2071 (English) 2003 American Association for Cancer Research. CODEN: CCREF4. ISSN: 1078-0432. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) 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 det. the toxicity profile, maximal tolerated dose, and pharmacokinetics profile, including bioavailability, of p.o. 9-ACCD in patients with advanced solid tumors. Exptl. Design: After receiving one i.v. dose of 9-ACCD, patients were treated with 9-ACCD p.o., starting with a 2-wk schedule, to establish the safety. Once safety was established, patients were treated continuously for 4 wk followed by a rest period of 2 wk 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 liq. chromatog. 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 h, and the vol. of distribution was 17.7 L/m2. The mean bioavailability of total 9-ACCD was 68.1%. Conclusions: Despite good tolerance of p.o. administration, the lack of clin. activity and variable absorption of 9-ACCD suggested that further development might not be warranted. .

A phase I and pharmacokinetic study of a new camptothecin derivative, 9-aminocamptothecin

A phase I and pharmacokinetic study of a new camptothecin derivative, 9-aminocamptothecin. Rubin, Eric; Wood, Valerie; Bharti, Ajit; Trites, Dorothy; Lynch, Cathy; Hurwitz, Selwyn; Bartel, Sylvia; Levy, Sheryl; Rosowsky, Andre; Toppmeyer, Deborah; Kufe, Donald (Div. Cancer Pharmacol., Harvard Med. Sch., Boston, MA 02115, USA). Clinical Cancer Research, 1(3), 269-276 (English) 1995 American Association for Cancer Research. CODEN: CCREF4. ISSN: 1078-0432. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Camptothecins are the only available antitumor agents which target the nuclear enzyme topoisomerase I. 9-Amino-camptothecin (9-AC) is a water-insol. deriv. of camptothecin which has demonstrated impressive antitumor activity in preclin. models. While two other water-sol. derivs., CPT-11 and topotecan, have successfully completed Phase I and Phase II testing, biochem. and tissue culture studies suggest that camptothecin analogs differ in characteristics which may be important in detg. antitumor activity. The authors performed a Phase I trial of 9-AC to det. the pharmacokinetics, dose-limiting toxicity, and max. tolerated dose of this agent when administered as a 72-h continuous i.v. infusion. Thirty-one patients with resistant solid cancers received 5-60 mg/M2/h 9-AC for 72 h, repeated at 3-wk intervals. The drug was administered in a vehicle contg. dimethylacetamide, polyethylene glycol, and phosphoric acid. 91421-43-1 and 80449-01-0 are cas registry numbers of chemicals which are used as reagents here. Blood samples were collected and the lactone (closed ring) form a 9-AC was quantitated. The max. tolerated dose of 9-AC was detd. to be 45 mg/M2/h. Dose-limiting toxicity consisted of neutropenia. Thrombocytopenia was also prominent. There were no significant nonhematol. toxicities. Minimal responses were seen in patients with gastric, colon, and non-small cell lung cancer. Although significant interpatient variation in plasma 9-AC lactone levels was obsd., pooled data were fit to a two-compartment model, with a terminal half-life of 36 h. Analyses of topoisomerase protein levels in peripheral blood cells indicated decreases in topoisomerase I accompanied by increases in topoisomerase II in two of three patients. 9-AC is an active antitumor agent and may be administered safely as a 72-h infusion in patients with cancer. Although Phase II trials with a 72-h infusion of 9-AC are warranted, alternate schedules should be evaluated given the dramatic preclin. activity seen with more prolonged administrations. .