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

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.

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.