Abstract
ZD1694 ('Tomudex'), a novel, direct and specific thymidylate synthase (TS) inhibitor, was developed in a collaborative research programme between Zeneca Pharmaceuticals and the Institute of Cancer Research (UK) and entered clinical trials in 1991; phase II studies began in 1992, using 3.0 mg m-2 every 3 weeks as a short 15 min infusion. Forty-six patients entered a phase II study of ZD1694 in advanced breast cancer. A total of 74% of patients had received prior systemic therapy (either as adjuvant cytotoxic or hormonal therapy or hormone therapy for advanced disease); 39% had received prior adjuvant cytotoxic chemotherapy. All patients had measurable disease and 50% had liver metastases. In all 43 patients were evaluable for response. Of these patients 26% achieved complete (CR) or partial response (PR) (95% Cl 14-42%). A response rate of 44% was seen in liver metastases. Two patients achieved CR of 265 and 301 days' duration respectively, one in locoregional disease, and one in liver metastases. The most common grade 3/4 adverse events were nausea and vomiting (11%), diarrhoea (11%) and leucopenia (20%). Grade 3/4, self-limited and reversible increases in transaminases were seen in 22% of patients. ZD1694 has useful single agent activity in patients with hormone-refractory advanced breast cancer, comparable with that reported for other anti-metabolites, with acceptable tolerability.
Highlights
ZD1694 ('Tomudex'*) is a novel quinazoline anti-folate, developed in a collaborative research programme
Patients received ZD1694 at a dose of 3.0 mg m-2 as a short 15 min infusion every 3 weeks; if required, subsequent doses could be delayed for a maximum of 21 days until toxicity had resolved, and dose modification was performed according to the worst WHO grade of haematological toxicity (WBC, granulocyte and platelet counts) and diarrhoea experienced with the previous cycle
ZD1694 is a quinazoline anti-folate developed during a rational drug design and research collaboration between the Institute of Cancer Research and Zeneca Pharmaceuticals (Jackman et al, 1993)
Summary
ZD1694 ('Tomudex'*) is a novel quinazoline anti-folate, developed in a collaborative research programme. The goal of the programme was to identify direct and specific inhibitors of thymidylate synthase (TS), avoiding the non-specific effects (upon protein synthesis and RNA) of agents such as methotrexate (MTX) and 5-fluorouracil (5FU) which are believed to play a role in the toxicity profiles (leucopenia, mucositis) of these drugs. ZD1694 undergoes extensive intracellular polyglutamation (Jackman et al, 1993). This effectively causes it to be retained within the cell and allows a convenient intermittent (3 weekly) schedule. Preclinical data and phase I data indicated activity in breast cancer, and a phase I study defined a recommended dose of 3.0 mg m-2, i.v. 3 weekly, with dose-limiting toxicities of leucopenia, diarrhoea, tiredness/asthenia and self-limited asymptomatic rises in transaminase levels (Clarke et al, 1994). We report here on the results of a phase II evaluation of ZD1694 in patients with advanced, hormonerefractory breast cancer
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