Phase I trial of FK973 : description of a delayed vascular leak syndrome

FK973 is a novel, substituted dihydrobenzoxazine structurally similar to mitomycin. FK973 lacks cross-resistance with mitomycin, doxorubicin, and vincristine in murine tumor models. A phase I study of FK973 was initiated using a 30-minute infusion repeated every 4 weeks. Of 17 patients enrolled on t...

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Veröffentlicht in:Investigational new drugs 1991-11, Vol.9 (4), p.377-382
Hauptverfasser: PAZDUR, R, DAH HSI HO, DAUGHERTY, K, BRADNER, W. T, KRAKOFF, I. H, RABER, M. N
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container_end_page 382
container_issue 4
container_start_page 377
container_title Investigational new drugs
container_volume 9
creator PAZDUR, R
DAH HSI HO
DAUGHERTY, K
BRADNER, W. T
KRAKOFF, I. H
RABER, M. N
description FK973 is a novel, substituted dihydrobenzoxazine structurally similar to mitomycin. FK973 lacks cross-resistance with mitomycin, doxorubicin, and vincristine in murine tumor models. A phase I study of FK973 was initiated using a 30-minute infusion repeated every 4 weeks. Of 17 patients enrolled on the study, a minimum of three patients were entered at each dose level: 7, 14, 21, 30, and 45 mg/m2. The dose-limiting toxicity was a vascular leak syndrome (VLS) characterized by pericardial and pleural effusions, ascites, and subcutaneous edema. These conditions were observed in two patients treated with a dose of 30 mg/m2 and in four who received 45 mg/m2. VLS was observed 2 weeks after the third dose of 30 mg/m2 and one week after the second dose of 45 mg/m2. Of nine patients treated with a cumulative dose greater than 60 mg/m2, five experienced this toxic reaction. Reversible drug-related pneumonitis was noted in one patient after the third course of 30 mg/m2. Moderate nausea and vomiting were initially observed at a dose of 14 mg/m2 and alopecia at 30 mg/m2. Grade 3-4 granulocytopenia was observed in two patients treated with 45 mg/m2. Extensive myocardial degeneration was observed at autopsy in a patient who had received three courses of 30 mg/m2. One patient with metastatic colon carcinoma and another with metastatic pancreatic carcinoma experienced partial clinical responses. Although the drug's clinical activity appears promising, additional investigation is needed into the mechanism of toxicity prior to further clinical development.
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subjects Antineoplastic agents
Antineoplastic Agents - adverse effects
Biological and medical sciences
Chemotherapy
Drug Evaluation
Humans
Medical sciences
Oxazines - adverse effects
Pharmacology. Drug treatments
Syndrome
Time Factors
Vascular Diseases - chemically induced
title Phase I trial of FK973 : description of a delayed vascular leak syndrome
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