Phase I clinical and pharmacokinetic study of taxol

P. H. Wiernik, Edward L. Schwartz, J. J. Strauman, J. P. Dutcher, Richard B. Lipton, Elisabeth M. Paietta

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Abstract

Taxol, selected for clinical trial because of its animal antitumor activity and unique structure and mechanism of action, was administered in Cremophor by i.v. infusion over 6 h in a phase I study. Eastern Cooperative Oncology Group toxicity grading was used. Eighty-three taxol courses were administered to 34 patients. Grade 3-4 hypersensitivity reactions occurred in 4 of 13 courses at first 2 dose levels, but premedication with dexamethasone, diphenhydramine, and cimetidine resulted in only 3 additional Grade 2 reactions in the next 70 courses. Neurotoxicity, which resolved or improved after stopping therapy, was Grade 1 with 2 of 10 courses of 230 mg/m2 and Grades 1-3 after 11 of 12 courses of 275 mg/m2. Leukopenia, first seen (Grade 1) after 1 of 8 75 mg/m2 courses, was Grade 3-4 after 10 of 34 courses of 175-230 mg/m2 and 10 of 12 courses of 275 mg/m2. The WBC nadir occurred at a median of 10 days and the median time required for normalization of the WBC was 18 days. Alopecia began 2-3 weeks posttaxol in 2 of 9 patients treated with 75-135 mg/m2 and in all 16 patients (Grade 3) treated with 175-275 mg/m2. Grades 1-2 nausea and vomiting occurred in about one-third of the patients treated at a dose of 105 mg/m2 or more. Taxol disappearance from plasma was biphasic; half-lives of the first and second phases after a 275 mg/m2 dose were 0.32 and 8.6 h, respectively. The apparent volume of distribution was 55 liters/m2, and the peak plasma concentration with a dose of 275 mg/m2, which occurred immediately postinfusion, was approximately 8 μM. Only 5% of parent drug was excreted in the urine within 24 h. Minor objective responses were noted in one patient with gastric cancer and another with ovarian carcinoma. In addition, one patient with massive ascites due to metastatic adenocarcinoma from an unknown primary had only minimal sonographic evidence of ascites for 6 months posttreatment. Neurotoxicity and leukopenia were dose limiting in this schedule. The recommended phase II trial dose is 250 mg/m2, with premedication.

Original languageEnglish (US)
Pages (from-to)2486-2493
Number of pages8
JournalCancer Research
Volume47
Issue number9
StatePublished - 1987

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Paclitaxel
Pharmacokinetics
Premedication
Leukopenia
Ascites
Diphenhydramine
Cimetidine
Alopecia
Nausea
Dexamethasone
Stomach Neoplasms
Vomiting
Clinical Studies
Appointments and Schedules
Hypersensitivity
Adenocarcinoma
Parents
Clinical Trials
Urine
Carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wiernik, P. H., Schwartz, E. L., Strauman, J. J., Dutcher, J. P., Lipton, R. B., & Paietta, E. M. (1987). Phase I clinical and pharmacokinetic study of taxol. Cancer Research, 47(9), 2486-2493.

Phase I clinical and pharmacokinetic study of taxol. / Wiernik, P. H.; Schwartz, Edward L.; Strauman, J. J.; Dutcher, J. P.; Lipton, Richard B.; Paietta, Elisabeth M.

In: Cancer Research, Vol. 47, No. 9, 1987, p. 2486-2493.

Research output: Contribution to journalArticle

Wiernik, PH, Schwartz, EL, Strauman, JJ, Dutcher, JP, Lipton, RB & Paietta, EM 1987, 'Phase I clinical and pharmacokinetic study of taxol', Cancer Research, vol. 47, no. 9, pp. 2486-2493.
Wiernik, P. H. ; Schwartz, Edward L. ; Strauman, J. J. ; Dutcher, J. P. ; Lipton, Richard B. ; Paietta, Elisabeth M. / Phase I clinical and pharmacokinetic study of taxol. In: Cancer Research. 1987 ; Vol. 47, No. 9. pp. 2486-2493.
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AU - Paietta, Elisabeth M.

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N2 - Taxol, selected for clinical trial because of its animal antitumor activity and unique structure and mechanism of action, was administered in Cremophor by i.v. infusion over 6 h in a phase I study. Eastern Cooperative Oncology Group toxicity grading was used. Eighty-three taxol courses were administered to 34 patients. Grade 3-4 hypersensitivity reactions occurred in 4 of 13 courses at first 2 dose levels, but premedication with dexamethasone, diphenhydramine, and cimetidine resulted in only 3 additional Grade 2 reactions in the next 70 courses. Neurotoxicity, which resolved or improved after stopping therapy, was Grade 1 with 2 of 10 courses of 230 mg/m2 and Grades 1-3 after 11 of 12 courses of 275 mg/m2. Leukopenia, first seen (Grade 1) after 1 of 8 75 mg/m2 courses, was Grade 3-4 after 10 of 34 courses of 175-230 mg/m2 and 10 of 12 courses of 275 mg/m2. The WBC nadir occurred at a median of 10 days and the median time required for normalization of the WBC was 18 days. Alopecia began 2-3 weeks posttaxol in 2 of 9 patients treated with 75-135 mg/m2 and in all 16 patients (Grade 3) treated with 175-275 mg/m2. Grades 1-2 nausea and vomiting occurred in about one-third of the patients treated at a dose of 105 mg/m2 or more. Taxol disappearance from plasma was biphasic; half-lives of the first and second phases after a 275 mg/m2 dose were 0.32 and 8.6 h, respectively. The apparent volume of distribution was 55 liters/m2, and the peak plasma concentration with a dose of 275 mg/m2, which occurred immediately postinfusion, was approximately 8 μM. Only 5% of parent drug was excreted in the urine within 24 h. Minor objective responses were noted in one patient with gastric cancer and another with ovarian carcinoma. In addition, one patient with massive ascites due to metastatic adenocarcinoma from an unknown primary had only minimal sonographic evidence of ascites for 6 months posttreatment. Neurotoxicity and leukopenia were dose limiting in this schedule. The recommended phase II trial dose is 250 mg/m2, with premedication.

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