QTc monitoring during a phase I study: experience with SR271425.

OBJECTIVE

SR271425 is a thioxanthone cytotoxic drug that induces dose-related cardiac electrophysiologic changes in preclinical models. A phase I trial was conducted to determine the maximally tolerated dose and safety profile, notably cardiac events.

METHODS

SR271425 was administered weekly as a 2-hour single intravenous infusion with a fixed 30 mg/m2 increment at each dose level (DL). A sustained cardiac evaluation was performed. ECG parameters were evaluated at bedside by an investigator or a cardiologist, as well as by central reading for dose limiting toxicity (DLT) determination.

RESULTS

Sixteen patients were treated. Five DLs were explored, from 75 mg/m2/wk to 195 mg/m2/wk. Fourteen patients (87.5%) experienced noncardiac adverse events related to treatment; only 2 patients presented grade 3 toxicity (nausea/vomiting and GGT increase) and no grade 4 toxicities were reported. Asymptomatic grade 1 or 2 QTcF prolongations were observed in 5 patients during central readings, and in 4 cases at bedside. One QTc-DLT, registered at bedside (grade 2), was unconfirmed at central reading, while another QTc-DLT, not noted at bedside, was highlighted by central reading. No arrhythmias or QRS prolongations were observed.

CONCLUSIONS

The maximum tolerated dose of SR271425 was not reached in this trial due to early termination of the trial, not related to cardiac toxicity, following the termination of the development program by the sponsor. Sustained ECG monitoring is quite feasible in oncology phase I trials, but discrepancies between bedside and central evaluation could lead to conflicting decisions for management of patient care.