ZD0473 combined with other chemotherapeutic agents for the treatment of solid malignancies

Platinum-based combination chemotherapy regimens are the mainstay of current treatments for advanced solid malignancies. Preclinical in vitro studies have shown synergism with ZD0473 in combination with several agents, including vinorelbine and topotecan. This paper reviews the tolerability and activity observed with ZD0473 in combination with vinorelbine or topotecan, in two Phase I dose-escalating studies in patients with advanced, solid, refractory malignancies. Twenty-four patients were included in the ZD0473 plus vinorelbine trial and were treated with doses of ZD0473 60-150 mg/m2 and vinorelbine 15-25 mg/m2. In this trial, dose-limiting toxicity comprised non-haematological events and the most common grade 3/4 toxicities included neutropenia (54.2%), thrombocytopenia (29.2%) and anaemia (20.8%). Eleven patients were included in the ZD0473 plus topotecan trial and were treated with ZD0473 60-90 mg/m2 and topotecan 0.5 mg/m2/day for 3 or 5 days. In this trial, dose-limiting toxicity comprised haematological events and the most common grade 3/4 toxicities included thrombocytopenia (63.6%), neutropenia (36.4%) and anaemia (18.2%). No objective responses were observed in either trial, but disease stabilisation occurred in 29.2% and 27.3% of patients in the vinorelbine and topotecan trials, respectively.