Phase I study of the mitomycin C analogue BMS-181174.
BMS-181174 is an aminodisulphide derivative of Mitomycin C (MMC) with activity against a range of tumour cell lines and xenografts, including MMC-resistant tumours. In a phase I study of 82 patients with confirmed malignancy, we administered BMS-181174 at doses of 0.8-75 mg m(-2) by intravenous injection every 28 days. At least three patients were evaluated at each dose level, and 174 courses were administered. The pharmacokinetics were dose linear at BMS-181174 doses of 11.5-75 mg m(-2) and the drug appeared to undergo wide distribution. The maximum-tolerated dose was 65 mg m(-2) in previously treated patients and 75 mg m(-2) in chemotherapy-naive cases. The dose-limiting toxicity was myelosuppression, particularly thrombocytopenia, which was prolonged and cumulative. Three patients treated at 65-75 mg m(-2) died suddenly with evidence of pneumonia/pneumonitis, thought to be drug-related. Other toxicities included thrombophlebitis, possible cardiotoxicity (asymptomatic, reversible decline in left ventricular function) and renal impairment. The partial response rate was 5% (4 out of 82) overall, and 9% (3 out of 32) in patients treated at 65-75 mg m(-2). Responses occurred in treated and previously-untreated patients, including cases of colorectal cancer, non-small-cell lung cancer, ovarian cancer and adenocarcinoma of unknown primary site. BMS-181174 has anti-cancer activity but, because of its toxicity, particularly pneumonitis and thrombophlebitis, no phase II studies are planned.
ICRF Clinical Oncology Unit, Churchill Hospital, Headington, Oxford, UK.
V M
VM
Macaulay
K J
KJ
O'Byrne
J A
JA
Green
P A
PA
Philip
L
L
McKinley
F P
FP
LaCreta
B
B
Winograd
T S
TS
Ganesan
A L
AL
Harris
D C
DC
Talbot
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008937:Mitomycins; D009369:Neoplasms / Q000188:drug therapy*; D013924:Thrombophlebitis / Q000139:chemically induced
D018906:Antineoplastic Agents, Alkylating; D008937:Mitomycins; D016685:Mitomycin; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C