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[Phase I study of raltitrexed (ZD-1694)]

N Horikoshi1, K Aiba, M Fukuoka

  • 1Dept. of Pulmonary Medicine, Osaka City General Hospital.

Gan to Kagaku Ryoho. Cancer & Chemotherapy
|December 5, 1998
PubMed
Summary

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This Phase I study determined the maximum tolerated dose of raltitrexed (ZD-1694), a novel thymidylate synthase inhibitor, for cancer treatment. The recommended dose for Phase II studies is 3.0 mg/m2 every three weeks.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • ZD-1694 (raltitrexed) is a novel folate-based thymidylate synthase inhibitor.
  • Phase I studies are crucial for determining safe and effective dosing of new cancer therapeutics.

Purpose of the Study:

  • To evaluate the safety and tolerability of single and repeated doses of ZD-1694 in patients with various malignant tumors.
  • To determine the maximum tolerated dose (MTD) and recommended dose for Phase II studies.

Main Methods:

  • A multicenter cooperative Phase I study involving 30 patients with various malignant tumors.
  • Single-dose escalation from 1.0 mg/m2 to 3.5 mg/m2, followed by repeated-dose studies at 2.5 mg/m2 and 3.0 mg/m2 every three weeks.
  • Adverse reactions and pharmacokinetic profiles were assessed.

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Main Results:

  • Dose-limiting toxicities (DLT) including neutropenia, nausea/vomiting, and diarrhea were observed at higher doses (3.0-3.5 mg/m2).
  • The maximum tolerated dose (MTD) was determined to be 3.5 mg/m2.
  • The recommended dose for Phase II studies was established as 3.0 mg/m2 every three weeks, with manageable toxicity and reversible transaminase increases.
  • Pharmacokinetic data indicated a long elimination half-life, suggesting intracellular retention, but no plasma accumulation with repeated dosing.

Conclusions:

  • ZD-1694 demonstrates a manageable safety profile with a recommended Phase II dose of 3.0 mg/m2 every three weeks.
  • The drug's pharmacokinetic properties support its potential efficacy in cancer treatment.
  • Further investigation in Phase II studies is warranted to confirm efficacy in specific tumor types.