Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors

J Clin Oncol. 1996 May;14(5):1495-503. doi: 10.1200/JCO.1996.14.5.1495.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / adverse effects*
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Antimetabolites, Antineoplastic / therapeutic use
  • Dose-Response Relationship, Drug
  • Female
  • Half-Life
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Quinazolines / adverse effects*
  • Quinazolines / pharmacokinetics
  • Quinazolines / therapeutic use
  • Thiophenes / adverse effects*
  • Thiophenes / pharmacokinetics
  • Thiophenes / therapeutic use
  • Thymidylate Synthase / antagonists & inhibitors*


  • Antimetabolites, Antineoplastic
  • Quinazolines
  • Thiophenes
  • Thymidylate Synthase
  • raltitrexed