Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations

B. C. Goh, M. J. Ratain, D. Bertucci, R. Smith, Sridhar Mani, N. J. Vogelzang, R. L. Schilsky, M. Hutchison, M. Smith, S. Averbuch, E. Douglass

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Abstract

Purpose: To conduct a phase I study of ZD9331, a potent, nonpolyglutamatable thymidylate synthase inhibitor using a short daily infusion for 5 consecutive days every 21 days. Patients and Methods: Patients with refractory cancer or cancer for which no standard therapy was available were treated in escalating doses using an accelerated titration design. Plasma and urine samples were collected at timed intervals in the first cycle for pharmacokinetic analysis. Results: Seventy-four patients were enrolled at 12 dose levels from a starting dose of 0.4 mg/m2/d to 16 mg/m2/d and 25 mg/d fixed dosing, of which 67 were assessable for toxicity. Maximum-tolerated dose was reached at 16 mg/m2/d. Myelosuppression was dose-limiting, consisting of thrombocytopenia associated with neutropenic fever. Body-surface area did not cor-relate with drug clearance; therefore, fixed daily dosing of 25 mg/d was studied and found to be tolerable, with two of 12 dose-limiting events. Dose-limiting nonhematologic toxicity consisted of grade 3 erythematous maculopapular rash observed in one patient at 12 mg/m2/d and one patient at 25 mg/d. Pharmacokinetic analysis showed nonlinearity, with clearance increasing with dose. The mean clearance and terminal half-life of the drug were 6.6 ± 2.0 mL/min and 71.3 ± 27.0 hours, respectively. Area-under-the concentration-time curve was a better predictor of toxicity than dose, using multiple linear regression analyses. Minor response (40% shrinkage of tumor) was observed in one patient with colorectal cancer treated at 12 mg/m2/d. Conclusion: The recommended dose for ZD9331 on this schedule is 25 mg/d. Neutropenia, thrombocytopenia, and rash were dose-limiting, and efficacy studies in colorectal cancer are indicated.

Original languageEnglish (US)
Pages (from-to)1476-1484
Number of pages9
JournalJournal of Clinical Oncology
Volume19
Issue number5
StatePublished - Mar 1 2001
Externally publishedYes

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Intravenous Infusions
Exanthema
Thrombocytopenia
Colorectal Neoplasms
Pharmacokinetics
Thymidylate Synthase
Neoplasms
Maximum Tolerated Dose
Body Surface Area
Neutropenia
Pharmaceutical Preparations
Half-Life
ZD 9331
Linear Models
Appointments and Schedules
Fever
Regression Analysis
Urine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Goh, B. C., Ratain, M. J., Bertucci, D., Smith, R., Mani, S., Vogelzang, N. J., ... Douglass, E. (2001). Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations. Journal of Clinical Oncology, 19(5), 1476-1484.

Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations. / Goh, B. C.; Ratain, M. J.; Bertucci, D.; Smith, R.; Mani, Sridhar; Vogelzang, N. J.; Schilsky, R. L.; Hutchison, M.; Smith, M.; Averbuch, S.; Douglass, E.

In: Journal of Clinical Oncology, Vol. 19, No. 5, 01.03.2001, p. 1476-1484.

Research output: Contribution to journalArticle

Goh, BC, Ratain, MJ, Bertucci, D, Smith, R, Mani, S, Vogelzang, NJ, Schilsky, RL, Hutchison, M, Smith, M, Averbuch, S & Douglass, E 2001, 'Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations', Journal of Clinical Oncology, vol. 19, no. 5, pp. 1476-1484.
Goh, B. C. ; Ratain, M. J. ; Bertucci, D. ; Smith, R. ; Mani, Sridhar ; Vogelzang, N. J. ; Schilsky, R. L. ; Hutchison, M. ; Smith, M. ; Averbuch, S. ; Douglass, E. / Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations. In: Journal of Clinical Oncology. 2001 ; Vol. 19, No. 5. pp. 1476-1484.
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abstract = "Purpose: To conduct a phase I study of ZD9331, a potent, nonpolyglutamatable thymidylate synthase inhibitor using a short daily infusion for 5 consecutive days every 21 days. Patients and Methods: Patients with refractory cancer or cancer for which no standard therapy was available were treated in escalating doses using an accelerated titration design. Plasma and urine samples were collected at timed intervals in the first cycle for pharmacokinetic analysis. Results: Seventy-four patients were enrolled at 12 dose levels from a starting dose of 0.4 mg/m2/d to 16 mg/m2/d and 25 mg/d fixed dosing, of which 67 were assessable for toxicity. Maximum-tolerated dose was reached at 16 mg/m2/d. Myelosuppression was dose-limiting, consisting of thrombocytopenia associated with neutropenic fever. Body-surface area did not cor-relate with drug clearance; therefore, fixed daily dosing of 25 mg/d was studied and found to be tolerable, with two of 12 dose-limiting events. Dose-limiting nonhematologic toxicity consisted of grade 3 erythematous maculopapular rash observed in one patient at 12 mg/m2/d and one patient at 25 mg/d. Pharmacokinetic analysis showed nonlinearity, with clearance increasing with dose. The mean clearance and terminal half-life of the drug were 6.6 ± 2.0 mL/min and 71.3 ± 27.0 hours, respectively. Area-under-the concentration-time curve was a better predictor of toxicity than dose, using multiple linear regression analyses. Minor response (40{\%} shrinkage of tumor) was observed in one patient with colorectal cancer treated at 12 mg/m2/d. Conclusion: The recommended dose for ZD9331 on this schedule is 25 mg/d. Neutropenia, thrombocytopenia, and rash were dose-limiting, and efficacy studies in colorectal cancer are indicated.",
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AU - Bertucci, D.

AU - Smith, R.

AU - Mani, Sridhar

AU - Vogelzang, N. J.

AU - Schilsky, R. L.

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AU - Averbuch, S.

AU - Douglass, E.

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N2 - Purpose: To conduct a phase I study of ZD9331, a potent, nonpolyglutamatable thymidylate synthase inhibitor using a short daily infusion for 5 consecutive days every 21 days. Patients and Methods: Patients with refractory cancer or cancer for which no standard therapy was available were treated in escalating doses using an accelerated titration design. Plasma and urine samples were collected at timed intervals in the first cycle for pharmacokinetic analysis. Results: Seventy-four patients were enrolled at 12 dose levels from a starting dose of 0.4 mg/m2/d to 16 mg/m2/d and 25 mg/d fixed dosing, of which 67 were assessable for toxicity. Maximum-tolerated dose was reached at 16 mg/m2/d. Myelosuppression was dose-limiting, consisting of thrombocytopenia associated with neutropenic fever. Body-surface area did not cor-relate with drug clearance; therefore, fixed daily dosing of 25 mg/d was studied and found to be tolerable, with two of 12 dose-limiting events. Dose-limiting nonhematologic toxicity consisted of grade 3 erythematous maculopapular rash observed in one patient at 12 mg/m2/d and one patient at 25 mg/d. Pharmacokinetic analysis showed nonlinearity, with clearance increasing with dose. The mean clearance and terminal half-life of the drug were 6.6 ± 2.0 mL/min and 71.3 ± 27.0 hours, respectively. Area-under-the concentration-time curve was a better predictor of toxicity than dose, using multiple linear regression analyses. Minor response (40% shrinkage of tumor) was observed in one patient with colorectal cancer treated at 12 mg/m2/d. Conclusion: The recommended dose for ZD9331 on this schedule is 25 mg/d. Neutropenia, thrombocytopenia, and rash were dose-limiting, and efficacy studies in colorectal cancer are indicated.

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