Phase I dose escalation study of SR271425 administered as 24-hour intravenous continuous infusion in patients with refractory solid tumors

Abstract

3116 Background: SR271425 is a DNA-binding agent from a new class of cytotoxics. This clinical trial aims to determine dose-limiting toxicities (DLTs), maximal tolerable dose (MTD) and PK profile of SR271425 given as 24-hour (h) IV infusion every 3 weeks. Methods: An accelerated dose escalation schema has been used similar to the 2b method (Eisenhauer EA, et al, JCO 2000). SR271425 was administered intravenously over 24 hr every 3 wks. Bloud samples were obtained during the infusion and up to 24 h post-infusion for the determination of SR271425 in plasma using a validated LC-MS/MS Method: Since a predecessor thioxanthone agent has been shown to prolong QTc and caused Torsade de pointes, careful monitoring of QTc was done including central reading of ECGs. Results: 31 patients have been enrolled; 20 men, 11 women, median (med) age 54 range 31–72, med ECOG performance status: 0 range 0–1. Tumor types: 7 colorectal, 5 pancreas, 4 sarcoma, 4 melanoma, 3 renal, 3 prostate, 1 lung, 4 others, eleven dose-levels from 128 mg/m2to 2920 mg/m2, med number of cycles was 2 (1–8). Grade (Gr) 1–2 toxicities included QTc prolongation, nausea/vomiting, venous inflammation at injection site and yellow skin discoloration. Two pts experienced DLT’s (Gr 3 QTc prolongation as defined using CTCv3) with no clinical symptom at 1524 and 2432 mg/m2. Gr 3 neutropenia occurred in 2 pts at the highest dose-levels tested: 2432 and 2920 mg/m2; in 1 pt concomitant Gr 3 anemia and Gr 1 thrombocytopenia were observed. PK data is available in 24 patients; steady state plasma drug concentrations appeared to be reached by the end of infusion, consistent with the drugs elimination half-life of around 8 h. Both Cend and AUC increased in a dose related manner. Mean (± SD) Cl and Vss were 28.0 ± 10.7 L/h and 303 ± 149 L, respectively, and independent of dose. One biological response (PSA decrease in prostatic cancer) and 3 stable disease were observed. Conclusions: Preliminary data show that the 24 h schedule allows increase in the total dose administered by reducing the peak plasma which appears to be correlated with QTc prolongation DLT. At these higher doses tested so far hematological toxicity is observed. The study is ongoing to define the MTD. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis