Ventricular arrhythmia and torsade de pointe: Dose limiting toxicities of the MDR-modulator S9788 in a phase I trial

Background: S9788 is a triazineaminopiperidine derivative capable of revers ing multidrug resistance (MDR) in vitro. In preclinical models S9788 was se veral fold more potent MDR inhibitor than verapamil or cyclosporine. At P-g lycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. Patients and methods. In a two step phase I trial we treated 39 patients wi th refractory cancer with S9788 and bolus doxorubicin. The steps differed m ainly in the S9788 infusion duration: in the first part 23 patients receive d the MDR-reversing drug S9788 over 30 minutes, in the second step of the s tudy 16 patients were administered S9788 over 150 minutes. The doses of S97 88 were escalated in cohorts of three patients up to a dose level (DL) of 9 6 mg/m(2) on the 30 minutes infusion, and to 144 mg/m(2) on the 150 minutes infusion. The pharmacokinetics of S9788 were determined. Results. With the 30-minute infusion schedule symptomatic cardiac arrhythmi a were found to be dose limiting. In all patients at the highest DL transie nt cardiac repolarization prolongation with a long QT-interval on ECG was d emonstrated. With the 150-minute administration schedule, S9788 could be es calated up to 144 mg/m(2) without subjective toxicity. However, transient Q T prolongation was present in all patients. A third degree AV-block and a Q T increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m(2)) was demonstrated on Holter recording in one patient . Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a m ean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-min ute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. Conclusions. With the tested infusion schedules, cardiac toxicity, in parti cular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experienc e together with the observation of asymptomatic torsade de pointe in two ot her phase I trials of S9788 infused over six hours precluded the further cl inical development of S9788.