Phase I and pharmacologic study of BMS-181174 given as a 6 h infusion every 4 weeks to patients with advanced solid tumors.
BMS-181174, a new mitomycin C (MMC) analog, showed more activity than the parent compound in tumor xenografts. In a phase I study with a 5-30 min slow bolus administration, hematologic and vascular toxicity were observed as major side effects. A prolonged infusion was suggested to circumvent the vascular toxicity. In this phase I study BMS-181174 was administered as a 6 h infusion every 4 weeks; the doses studied were 3.2, 6.4, 11.5, 19.0, 32.0, 50.0, 75.0 and 100 mg/m2. Twenty-eight patients were enrolled in the study, the majority with colorectal cancer. Hematologic side effects consisted of thrombocytopenia, and mild leuko- and granulocytopenia. The most distressing non-hematologic side effect was vascular toxicity consisting of phlebosclerosis and phlebitis, becoming dose limiting at 100 mg/m2. One patient developed a hemolytic uremic syndrome at a cumulative dose of 350 mg/m2. Pharmacokinetic data are available for 24 patients. The AUC ranged from 3.35 to 41.49 (microg x h/ml) and was highly correlated with the dose administered (r = 0.83). The kinetics appeared to be linear. One patient with metastatic colon cancer had a partial response of liver metastases. BMS-181174 is a MMC analog with a toxicity profile comparable to that of the parent compound. As doses above 50 mg/m2 are complicated by vascular toxicity precluding multiple administrations, further exploration of BMS-181174 will not be performed.
Planting
A S
AS
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, The Netherlands. planting@onch.azr.nl
Schellens
J H
JH
van der Burg
M E
ME
de Boer-Dennert
M
M
Winograd
B
B
Stoter
G
G
Verweij
J
J
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D008937:Mitomycins / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D014652:Vascular Diseases / Q000139:chemically induced*
D018906:Antineoplastic Agents, Alkylating; D008937:Mitomycins; D016685:Mitomycin; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C