Phase I dose-finding study of trabectedin (T) in combination with cisplatin (C) in patients (pts) with advanced solid tumors.

Abstract

2517 Background: T is a synthetic compound originally derived from the marine organism Ecteinascidia turbinata with a mechanism of action based on DNA binding and involving the transcription-dependent nucleotide excision repair system. In vitro and in vivo preclinical data have shown a synergistic effect of the combination -T+C-. Methods: Primary Objectives: to identify the recommended dose (RD) of T given as 3-hour infusion in combination with standard dose of C every 3 weeks. Secondary: safety, antitumor activity and pharmacokinetics (PK). Pts with advanced solid tumors for whom treatment with T or platinum compounds was indicated were recruited. A maximum of 1 prior chemotherapy line and platinum sensitivity was required. T was given at escalating doses in subsequent cohorts of pts from 0.75 mg/m2 with a fixed dose of 75 mg/m2 C. The maximum tolerated dose was the dose level (DL) at which 1/3 or 2/6 pts had dose limiting toxicities (DLTs); the RD was set at 1 DL immediately below that. Results: At a T dose of 0.75 mg/m2 (DL1), 2 of 4 pts had DLTs: grade (G) 4 neutropenia >7 days and uncontrolled G 3 vomiting. T dose was reduced to 0.60 mg/m2 (DL-1) and 6 pts were recruited: 2 with ovarian carcinoma (OC) and 4 with soft tissue sarcoma (STS). No DLTs were reported. The most common adverse events were fatigue nausea, vomiting; the most common lab abnormalities were ALT elevations, G 3-4 neutropenia and G 3-4 thrombocytopenia. Out of 10 evaluable pts, 1 partial response (OC) and 5 stable disease (1 OC, 1 breast and 3 STS; 4 of them lasting ≥4 cycles) were reported. PK studies in 6 pts at 0.6 mg/m2 shown that the plasma exposure (AUC) to T and to C was about double and 60% higher, respectively, in the combination as compared to single agents in separate series. Conclusions: The RD of T given as 3-hour infusion in combination with 75mg/m2 of C is 0.6 mg/m2, 50 % lower than the RD as single agent. At these dose level and schedule the safety profile of both drugs is comparable to that of either single agent and is associated with antitumor activity. PK interaction leading to increased plasma exposure to both drugs may explain the clinical findings. Additional pts with platinum sensitive OC will be accrued at the RD to better define the PK profile.