Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours

Aim of the studyTo define the maximum tolerated dose (MTD) and toxicity of trabectedin (T) and cisplatin (C) given on days 1 and 8 every 3 weeks to adult patients with advanced solid tumours. Plasma pharmacokinetics at cycle 1 and a preliminary anti-tumour activity assessment in ovarian and non-small cell lung cancer (OC, NSCLC) were secondary objectives.MethodsIn the dose finding part (DFP) of the study the dose of T given at each administration was escalated by 100 μg/m2 increments from 300 μg/m2 up to the MTD, with a fixed dose of C of 40 mg/m2. The recommended dose (RD) was assessed in the previously treated and untreated OC and NSCLC patients in the expansion of the RD (ERD) part of the study.T was administered with corticosteroids pre-medication as 3-h infusion and C as 30-min infusion.ResultsThirty-nine patients were treated in the DFP and 10 in the ERD. The MTD of T was 700 μg/m2 due to dose-limiting neutropaenia and the RDs in the previously treated/untreated patients were 500 and 600 μg/m2, respectively. Most common toxicities were nausea/vomiting (67%), asthenia/fatigue (55%) and reversible ASAT/ALAT elevation (51%). Time to recovery from myelosuppression was dose-dependent and treatment could be repeated after ⩾4 weeks in the majority of patients at 600 μg/m2. Confirmed partial responses were observed in 4 of 13 evaluable OC patients and in 1 with uterine leiomyosarcoma. No pharmacokinetic interaction was observed.ConclusionThe administration of T and C on days 1 and 8 resulted in prolonged neutropaenia requiring treatment delay. The evaluation of a single every 3 week schedule is worthwhile because of the hints of anti-tumour activity observed in OC.