Phase I and pharmacokinetic study of a novel mitomycin C analog KW-2149.
KW-2149 is a new, semisynthetic, C-7-N-substituted, mitomycin C (MMC) analog showing equal or superior antitumor activity in both in vitro and in vivo assays. The preclinical activity profile combined with the hematological toxicity data in rodents and the water solubility of the compound compare favorably with MMC. The aim of this phase I study was to determine the toxicity profile and the optimal dosage of KW-2149. In this phase I study 37 patients received 97 courses of KW-2149 administered as an i.v. bolus injection every 21 days at sequential dose levels: 5, 10, 17, 25, 35, 47, 60, 75, 90 and 100 mg/m2. Hematological toxicity was moderate even at the 100 mg/m2 dose level. Grade IV leucopenia and thrombocytopenia were observed in one of three patients at the 100 mg/m2 dose level. There was some evidence of a delayed-type bone marrow toxicity. Pulmonary toxicity was dose limiting, with grade III toxicity occurring in all three patients treated at a dose of 100 mg/m2. The type of lung toxicity was similar to the one observed with other antitumor antibiotics. No renal or cardiac toxicity was observed. Other toxicities were generally mild. Antitumor activity was observed in four patients. Data of drug monitoring demonstrated rapid metabolism and/or distribution of KW-2149 with a short half-life and the emergence of the cytotoxic metabolites M-16 and M-18. The dose-limiting toxicity of KW-2149 is pulmonary toxicity.
Dirix
L
L
Department of Medical Oncology, Antwerp University Hospital, Belgium.
Catimel
G
G
Koier
I
I
Provè
A
A
Schrijvers
D
D
Joossens
E
E
De Bruijn
E
E
Ardiet
C
C
Evene
E
E
Dumortier
A
A
D000230:Adenocarcinoma / Q000188:drug therapy; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001711:Biotransformation; D001855:Bone Marrow Diseases / Q000139:chemically induced; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006207:Half-Life; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008171:Lung Diseases / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008937:Mitomycins; D009369:Neoplasms / Q000188:drug therapy*; D009382:Neoplasms, Unknown Primary / Q000188:drug therapy; D016879:Salvage Therapy
D000970:Antineoplastic Agents; D008937:Mitomycins; C057625:KW 2149; D016685:Mitomycin