Phase I trial of 1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU) terminated by severe neurologic toxicity

FMAU (1-[2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl]-5-methyluracil) a newly synthesized fluorinated nucleoside, has potent in vitro antiviral and antileukemic activity and is active in murine leukemia lines resistant to cytosine arabinoside. In the initial phase I trial neurotoxicity, c...

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Bibliographic Details
Published in:Investigational new drugs 1989-07, Vol.7 (2-3), p.195-201
Main Authors: ABBRUZZESE, J. L, SCHMIDT, S, RABER, M. N, LEVY, J. K, CASTELLANOS, A. M, LEGHA, S. S, KRAKOFF, I. H
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic agents
Antineoplastic Agents - adverse effects
Antineoplastic Agents - therapeutic use
Arabinofuranosyluracil - adverse effects
Arabinofuranosyluracil - therapeutic use
Biological and medical sciences
Chemotherapy
Colonic Neoplasms - drug therapy
Drug Evaluation
Electroencephalography
Female
Fibrosarcoma - drug therapy
Hematologic Diseases - chemically induced
Humans
Male
Medical sciences
Middle Aged
Neoplasm Metastasis
Neoplasms - drug therapy
Nervous System Diseases - chemically induced
Nervous System Diseases - physiopathology
Nervous System Neoplasms - drug therapy
Pharmacology. Drug treatments
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Summary:FMAU (1-[2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl]-5-methyluracil) a newly synthesized fluorinated nucleoside, has potent in vitro antiviral and antileukemic activity and is active in murine leukemia lines resistant to cytosine arabinoside. In the initial phase I trial neurotoxicity, characterized by extrapyramidal dysfunction, was found to be the dose-limiting toxic effect, and a dosage of 32 mg/m2/day for 5 days was suggested for phase II studies. We report a second phase I study of FMAU using this schedule. Mild, transient neurologic dysfunction was encountered in patients treated at the starting dose of 4 mg/m2/day x 5 days and became severe and irreversible in two patients who received the highest cumulative doses administered at the 8 mg/m2/day x 5 days level. Both severely affected patients died. Severe neurotoxicity developed and progressed in these patients despite serial neurologic examinations, including detailed neuropsychologic tests implemented in an effort to detect early neurotoxicity. Because of these findings, further study of this drug as an antileukemic agent cannot be recommended. If it is to be used as an antiviral agent, further phase I study at lower doses is advised.
ISSN:0167-6997
1573-0646
DOI:10.1007/BF00170857