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Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors
S J Clarke1, J Hanwell, M de Boer
1Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Purpose:
To perform a phase I clinical and pharmacologic study of ZD1694 (Tomudex, Alderley Park, United Kingdom), a new folate-based thymidylate synthase (TS) inhibitor, in patients with advanced malignancy.
Patients And Methods:
From February 1991 to January 1993, 61 patients with a range of solid tumor received 161 courses of ZD1694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating doses from 0.1 to 3.5 mg/m2. Pharmacokinetic (PK) analysis was performed with the first two courses of treatment. There were 33 men and 28 women with a median age of 53 years (range, 21 to 73). Fifty-five patients (90%) had previously received chemotherapy.
Results:
Reversible liver toxicity and dose-related gastrointestinal (GI) and bone marrow toxicity occurred at > or = 1.6 mg/m2. Liver function usually returned to normal with repeated treatment, but GI and bone marrow toxicities generally became more severe. No renal toxicity was observed. The maximum-tolerated dose (MTD) was 3.5 mg/m2, at which, in addition to antiproliferative toxicities, four of six patients (67%) developed severe malaise that consisted of anorexia, nausea, and asthenia, with rapidly decreasing performance status that limited re-treatment. Abnormal liver function was also seen in four patients (67%). At 3.0 mg/m2, grades III and IV diarrhea were seen in six of 23 patients (26%) and grade IV myelosuppression in two others. Liver toxicity was self-limiting and not associated with severe malaise. Two patients had a partial response to treatment. PK analysis showed that plasma elimination was triexponential, with pronounced variability in the mean terminal half-life (t1/2gamma) for a given dose ranging from 8.2 to 105 hours. There was a linear relationship between dose and both the area under the concentration-time curve (AUC) and maximum concentration (Cmax), but no clear association between these parameters and response or toxicity.
Conclusion:
The dose of ZD1694 recommended for phase II trials is 3.0 mg/m2.
Insights
This phase I study of ZD1694 (Tomudex) found that a dose of 3.0 mg/m2 is recommended for further trials. The folate-based thymidylate synthase inhibitor showed dose-related toxicities, including liver and gastrointestinal issues.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- ZD1694 (Tomudex) is a novel folate-based thymidylate synthase inhibitor.
- Advanced malignancies represent a significant challenge in cancer treatment.
Purpose of the Study:
- To conduct a phase I clinical and pharmacologic evaluation of ZD1694.
- To determine the safety and tolerability of escalating doses of ZD1694 in patients with advanced cancer.
Main Methods:
- A phase I study involving 61 patients with advanced solid tumors.
- Escalating doses of ZD1694 administered intravenously every 3 weeks.
- Pharmacokinetic analysis to assess drug disposition.
Main Results:
- Dose-limiting toxicities including reversible liver toxicity, gastrointestinal, and bone marrow toxicity observed at doses >= 1.6 mg/m2.
- Maximum-tolerated dose (MTD) established at 3.5 mg/m2, associated with severe malaise and abnormal liver function.
- Grade III/IV diarrhea and myelosuppression noted at 3.0 mg/m2; liver toxicity was self-limiting.
Conclusions:
- The recommended dose of ZD1694 for phase II trials is 3.0 mg/m2.
- Further investigation is warranted to optimize ZD1694 dosing and management of toxicities.