Phase I study with the DNA sequence-specific agent adozelesin

• Published in: Anti-cancer drugs Vol. 8; no. 6; p. 588
• Main Authors: Burris, H A, Dieras, V C, Tunca, M, Earhart, R H, Eckardt, J R, Rodriguez, G I, Shaffer, D S, Fields, S M, Campbell, E, Schaaf, L, Kasunic, D, Von Hoff, D D
• Format: Journal Article
• Language: English
• Published: England 01.07.1997
• Subjects: Adult; Aged; Antineoplastic Agents, Alkylating - pharmacokinetics; Antineoplastic Agents, Alkylating - therapeutic use; Antineoplastic Agents, Alkylating - toxicity; Blood - drug effects; Cyclohexanecarboxylic Acids - pharmacokinetics; Cyclohexanecarboxylic Acids - therapeutic use; Cyclohexanecarboxylic Acids - toxicity; Cyclohexenes; Dose-Response Relationship, Drug; Female; Humans; Hyperglycemia - chemically induced; Indoles; Infusions, Intravenous; Liver - drug effects; Male; Middle Aged; Neoplasms - drug therapy; Neutropenia - chemically induced; Treatment Outcome
• ISSN: 0959-4973
• DOI: 10.1097/00001813-199707000-00006

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v. infusion, (ii) characterize the toxic effects of the drug using this schedule and (iii) document any antitumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 microg/m2, corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies were entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 microg/m2. The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined as 180 microg/m2. A minor response with a 4 month duration was reported in one previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 microg/m2, repeated every 4 weeks.