Phase I combination study of plitidepsin and carboplatin in advanced solid tumours

Abstract

2558 Background: Plitidepsin is a cyclic depsipeptyde isolated from the marine tunicate Aplidium albicans, nowadays manufactured by synthesis. It is a rapid and potent inductor of apoptosis. In phase I trials, muscle (myalgia and CPK increase) and liver toxicities were dose-limiting and preliminary activity was observed in malignant melanoma, renal, head and neck, lung, neuroendocrine, colorectal and hematological malignancies. Preclinical synergism with carboplatin (CBCDA) against solid tumors and acute leukaemia suggest plitidepsin can reverse platinum chemoresistance in vivo through reduction of glutathione levels. This phase I trial was initiated in order to evaluate the safety, pharmacokinetics (PK) and antitumour activity of the combination of CBCDA and weekly administration of plitidepsin (Recommended dose (RD) in monotherapy: 3.2 mg/m2). Methods: Patients (pts) with advanced solid tumours and good performance status (WHO PS = 2) were enrolled. Plitidepsin was given over 1 hr infusion on days 1 , 8 and 15 every 4 weeks followed by CBDCA (AUC 5) as a 1 hr infusion on day 1. Dose levels planned for plitidepsin were 1.8, 2.4 and 3.0 mg/m2 in cohorts of 3 pts. PK sampling was performed during the first cycle (cy) of treatment. Results: 18 pts have been treated to date (8M/10F). Median age (range): 59 (39–73) yrs. WHO PS>0: 3pts. Tumour types included colorectal (5), malignant melanoma (4), ovary (2), other gastrointestinal tumors (7). No DLT was observed at plitidepsin 1.8 and 2.4 mg/m2 (3 pts treated in each cohort). Two out of 5 pts exhibited DLT at pltidepsin 3.0 mg/m2, consisting of delay of second cy >2 weeks (grade 3 transaminitis and grade 3 thrombocytopenia) and omission of second infusion in first cy (grade 3 ALT increase). Plitidepsin at 2.4 mg/m2 was expanded to 8 pts. There were 4 pts with stable disease (cholangio, liver, colorectal, gatro-esophageal junction and esophagus carcinomas). Conclusions: The RD for the combination is plitidepsin 2.4 mg/m2 (0.8 mg/m2 lower than in monotherapy) days 1, 8 and 15 every 4 weeks followed by CBDCA (AUC 5). DLTs of the combination at the highest dose were different vs single plitidepsin (liver and haematological vs muscular). PK analyses from the three cohorts to detect interactions and updated safety data for the RD cohort are in progress. [Table: see text]