A phase I study of ZD0473 combined with paclitaxel for the treatment of solid malignancies.

ZD0473 is a cytotoxic platinum agent, which in preclinical studies has exhibited synergistic activity when combined with paclitaxel. The aim of this open-label phase I study was to determine the maximum tolerated dose (MTD), safety, and antitumour activity of ZD0473 followed by paclitaxel in patients with refractory solid malignancies. Patients received paclitaxel and ZD0473 on day 1 every 3 weeks. Seven dose levels were planned (ZD0473 60-180 mg/m2, paclitaxel 135-175 mg/m2), with dose escalation dependent on the incidence of dose-limiting toxicity. Included in the study were 23 patients who received 76 treatment cycles at dose levels 1 (60 mg/m2 ZD0473, 135 mg/m2 paclitaxel) to 6 (150 mg/m2 ZD0473, 175 mg/m2 paclitaxel). Dose-limiting thrombocytopenia (platelet count <25x10(9)/l) occurred in two of six patients at dose level 6, which defined the MTD. Grade 3/4 haematological toxicities included: anaemia (21.7%), neutropenia (39.1%), thrombocytopenia (34.8%), and leucopenia (34.8%). The most common grade 3/4 non-haematological toxicities included: alopecia (13.0%), pleural effusion (13.0%), somnolence (8.7%), and vomiting (8.7%). Of the 23 patients, 11 (47.8%) had disease stabilization, including 4 with non-small-cell lung cancer (NSCLC) who had a > or =25% reduction in tumour dimensions. ZD0473 combined with paclitaxel has a manageable tolerability profile and shows some evidence of antitumour activity in patients with NSCLC.

Citation

Chris Twelves, Martin Reck, Alan Anthoney, Ulrich Gatzemeier, Stan Kaye. A phase I study of ZD0473 combined with paclitaxel for the treatment of solid malignancies. Cancer chemotherapy and pharmacology. 2003 Oct;52(4):277-81

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PMID: 12827291

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