ZD1694 - A NOVEL THYMIDYLATE SYNTHASE INHIBITOR WITH SUBSTANTIAL ACTIVITY IN THE TREATMENT OF PATIENTS WITH ADVANCED COLORECTAL-CANCER

Purpose: Tomudex (ZD1694; Zeneca Ltd, Macclesfield, United Kingdom) ap pears to have a favorable toxicity profile (defined in phase I studies ) and antitumor activity in a broad range of epithelial rumors. We rep ort here the results of a large phase II study of Tomudex in advanced colorectal cancer (CRC), Patients and Methods: One hundred seventy-sev en patients were entered Onto the study between October 1992 and Septe mber 1993, Patients were required to have advanced CRC without prior c hemotherapy (adjuvant chemotherapy was permissible) and at least one m easurable lesion. Tomudex (ZD1694) was administered at a dose of 3 mg/ m(2) intravenously once every 3 weeks in the absence of toxicity or di sease progression, Patients were assessed for objective response, prog ression, and survival. Results: Of 177 patients entered onto the study , 5% had received prior adjuvant chemotherapy and 83% had liver metast ases. Objective responses were seen in 26% of patients (95% confidence interval, 19% to 33%; four complete responses [CRs] and 41 partial re sponses [PRs]) while median time to progression was 4.2 months and med ian survival 9.6 months. All sites were audited, and responses were re viewed by an independent panel, Common toxicities included mild revers ible transaminitis, nausea and vomiting, and asthenia or flu-like symp toms, and World Health Organization (WHO) grade 3 and 4 leukopenia and diarrhea were seen in 6% and 9.8% of patients, respectively. Stomatit is and alopecia were uncommon, Conclusion: In this large multicenter p hase II study of patients with advanced CRC, interesting activity was seen (objective response rate, 26%). In addition, Tomudex has on accep table toxicity profile and a convenient dosing schedule (single intrav enous injection every 3 weeks) and thus appears to offer real potentia l as a novel agent for the treatment of patients with advanced CRC. (C ) 1996 by American Society of Clinical Oncology.