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A phase II study in advanced breast cancer: ZD1694 ('Tomudex') a novel direct and specific thymidylate synthase
I Smith1, A Jones, M Spielmann
1Royal Marsden Hospital, London, UK.
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.
Insights
ZD1694 (Tomudex), a thymidylate synthase inhibitor, showed activity in advanced breast cancer. It achieved a 26% response rate, with notable efficacy in liver metastases, and was generally well-tolerated.
Area of Science:
- Oncology
- Pharmacology
Background:
- ZD1694 (Tomudex) is a novel thymidylate synthase inhibitor developed for cancer treatment.
- Clinical trials commenced in 1991, with Phase II studies starting in 1992.
Purpose of the Study:
- To evaluate the efficacy and tolerability of ZD1694 as a single agent in patients with advanced breast cancer.
- To assess response rates, particularly in patients with liver metastases.
Main Methods:
- A Phase II study involving 46 patients with advanced breast cancer.
- Treatment administered at 3.0 mg/m² every 3 weeks via a 15-minute infusion.
- 43 patients were evaluable for response.
Main Results:
- An overall response rate of 26% (complete or partial response) was observed (95% CI 14-42%).
- A 44% response rate was noted in patients with liver metastases.
- Common Grade 3/4 adverse events included nausea/vomiting (11%), diarrhea (11%), and leukopenia (20%).
- Reversible transaminase elevations occurred in 22% of patients.
Conclusions:
- ZD1694 demonstrates useful single-agent activity in hormone-refractory advanced breast cancer.
- Its efficacy is comparable to other anti-metabolites.
- The drug exhibits acceptable tolerability in this patient population.