TY - JOUR
T1 - Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations
AU - Goh, B. C.
AU - Ratain, M. J.
AU - Bertucci, D.
AU - Smith, R.
AU - Mani, S.
AU - Vogelzang, N. J.
AU - Schilsky, R. L.
AU - Hutchison, M.
AU - Smith, M.
AU - Averbuch, S.
AU - Douglass, E.
PY - 2001/3/1
Y1 - 2001/3/1
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.
AB - 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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U2 - 10.1200/JCO.2001.19.5.1476
DO - 10.1200/JCO.2001.19.5.1476
M3 - Article
C2 - 11230494
AN - SCOPUS:0035281914
SN - 0732-183X
VL - 19
SP - 1476
EP - 1484
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 5
ER -