A phase I and pharmacokinetic study of indisulam in combination with carboplatin

Abstract

Indisulam (E7070) is an anticancer agent that is currently being evaluated in phase II clinical studies. A significant reduction in glutathione synthetase and glutathione reductase transcripts by indisulam provided a molecular basis for its combination with platinum agents. Indisulam demonstrated high anti-tumour activity in various preclinical cancer models. The objectives of this study were (1) to determine the recommended dose of indisulam in combination with carboplatin in patients with solid tumours and (2) to evaluate the pharmacokinetics of the combination. Patients with solid tumours were treated with indisulam in combination with carboplatin. Indisulam (350, 500, or 600 mg m⁻²) was given as a 1-hour intravenous infusion on day 1 and carboplatin (5 or 6 mg min ml⁻¹) as an intravenous infusion over 30 min on day 2 of a three-weekly cycle. Sixteen patients received study treatment and were eligible. Thrombocytopenia was the major dose limiting toxicity followed by neutropenia. Both drugs contributed to the myelosuppressive effect of the combination. Indisulam 500 mg m⁻² in combination with carboplatin 6 mg min ml⁻¹ was identified not to cause dose limiting toxicity, but a delay of re-treatment by 1 week was required regularly to allow recovery from myelosuppression. The recommended dose and schedule for an envisaged phase II study in patients with non-small cell lung cancer is indisulam 500 mg m⁻² in combination with carboplatin 6 mg min ml⁻¹ repeated four-weekly. Patients who do not experience severe thrombocytopenia at cycle 1 will be permitted to receive an escalated dose of indisulam of 600 mg m⁻² from cycle 2 onwards.