A phase-I dose-escalation study of SR271425 administered intravenously in split doses (d1-d2-d3) in patients with refractory solid tumors

Abstract

3133 Background: SR271425, a novel DNA-binding cytotoxic agent has a promising broad spectrum of antitumor activity in preclinical models, independent of the schedule of administration. In addition to the usual cytotoxic related toxicities, QTc prolongation, related to Cmax, has been reported at doses >660mg/m2 in rabbit. In order to circumvent this Cmax related QTc prolongation, 5 phase I studies using different schedules of administration were initiated, testing iv infusion of 1-hour, 24-hour, weekly, and split doses. This phase I study aims to test split doses of the 1-hour regimen given d1 to d3, every 3 weeks, to establish the dose limiting toxicity (DLT), the recommended phase II dose and to characterise the PK/PD. Methods: Standard dose escalation was used. Patient’s selection was based on common phase I criteria and on specific cardiac criteria. SR271425 levels (PK samples) were measured using a turboflow LC-MS/MS method. Careful monitoring of ECGs was done and the ECGs were read centrally. Results: 3 centers have enrolled 18 highly pretreated patients to 6 dose levels from 75 to 450 mg/m2/day (from 225 to 1350mg/m2/cycle); 11 males and 7 females with median age 53, median ECOG 1, and brain, breast, lung and renal main tumor types, have received a median number of 2 cycles (range: 1–6). NCI-CTC Grade 1–2 toxicities included nausea, vomiting, asthenia, rash and yellow skin discoloration. No DLT has been reported yet especially no QTc limiting prolongation. 4 stable diseases were observed. In terms of exposure, both Cend and AUC increased in a dose related manner with no evidence of accumulation between day 1 and day 3, consistent with the mean (± SD) terminal elimination half-life of 5.11 ± 1.21 h. Conclusions: Preliminary data of this ongoing study show that split doses allow high cumulative exposure to SR271425 without significant toxicity, especially without QTc prolongation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis