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 inje...
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| Format: | Online |
| Language: | English |
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Nature Publishing Group
1998
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150373/ |
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pubmed-2150373 |
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pubmed-21503732009-09-10 Phase I study of the mitomycin C analogue BMS-181174. Macaulay, V. M. O'Byrne, K. J. Green, J. A. Philip, P. A. McKinley, L. LaCreta, F. P. Winograd, B. Ganesan, T. S. Harris, A. L. Talbot, D. C. Research Article 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. Nature Publishing Group 1998-06 /pmc/articles/PMC2150373/ /pubmed/9667686 Text en |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Macaulay, V. M. O'Byrne, K. J. Green, J. A. Philip, P. A. McKinley, L. LaCreta, F. P. Winograd, B. Ganesan, T. S. Harris, A. L. Talbot, D. C. |
| spellingShingle |
Macaulay, V. M. O'Byrne, K. J. Green, J. A. Philip, P. A. McKinley, L. LaCreta, F. P. Winograd, B. Ganesan, T. S. Harris, A. L. Talbot, D. C. Phase I study of the mitomycin C analogue BMS-181174. |
| author_facet |
Macaulay, V. M. O'Byrne, K. J. Green, J. A. Philip, P. A. McKinley, L. LaCreta, F. P. Winograd, B. Ganesan, T. S. Harris, A. L. Talbot, D. C. |
| author_sort |
Macaulay, V. M. |
| title |
Phase I study of the mitomycin C analogue BMS-181174. |
| title_short |
Phase I study of the mitomycin C analogue BMS-181174. |
| title_full |
Phase I study of the mitomycin C analogue BMS-181174. |
| title_fullStr |
Phase I study of the mitomycin C analogue BMS-181174. |
| title_full_unstemmed |
Phase I study of the mitomycin C analogue BMS-181174. |
| title_sort |
phase i study of the mitomycin c analogue bms-181174. |
| description |
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. |
| publisher |
Nature Publishing Group |
| publishDate |
1998 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150373/ |
| _version_ |
1611423807357059072 |