Phase I and pharmacodynamic study of taxol in refractory acute leukemias.
Taxol, a novel antimicrotubule agent that enhances tubulin polymerization and microtubule stability, was administered to adults with refractory leukemias as a 24-h i.v. infusion in a Phase I study. The primary objectives were to determine the maximum tolerated dose of taxol administered on this schedule to patients with acute leukemias and describe the nonhematological toxicities which became dose limiting. The starting dose, 200 mg/m2, was based on the maximum tolerated dose in solid tumor trials, in which myelosuppression precluded dose escalation. Seventeen patients received 28 evaluable courses at 200, 250, 315, and 390 mg/m2. Severe mucositis limited further dose escalation. Other nonhematological effects included peripheral neuropathy, alopecia, myalgias, arthralgias, nausea, vomiting, diarrhea, and an acute pulmonary reaction that was presumptively due to taxol's Cremophor vehicle. Mean peak taxol plasma concentrations at all dose levels were in the range of concentrations that were previously demonstrated to induce microtubule bundles, a morphological effect associated with cytotoxicity, in leukemia cells in vitro. Pretreatment blasts from 12 patients were incubated with taxol ex vivo. Taxol-induced microtubule bundles were apparent in the blasts of eight patients who also had cytoreduction of tumor, and sensitivity to bundle formation was related to the magnitude of antitumor activity. In contrast, taxol did not induce microtubule bundles ex vivo in the blasts of the other four total nonresponders. Based on this study, the maximum tolerated doses and recommended Phase II doses for taxol, limited by nonhematological toxicity and administered as a 24-h i.v. infusion to patients with refractory leukemias, are 390 and 315 mg/m2. Phase II trials at these myelosuppressive doses are required to determine taxol's activity in the treatment of leukemias. In addition, further evaluation of microtubule bundle formation ex vivo in Phase II studies is necessary to determine the ultimate utility of this assay in assessing tumor sensitivity to taxol.
Rowinsky
E K
EK
Johns Hopkins Oncology Center, Baltimore, Maryland 21205.
Burke
P J
PJ
Karp
J E
JE
Tucker
R W
RW
Ettinger
D S
DS
Donehower
R C
RC
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000470:Alkaloids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008870:Microtubules / Q000187:drug effects; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects; D017239:Paclitaxel; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D013280:Stomatitis / Q000139:chemically induced
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel