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

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State: Public
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Serval ID
serval:BIB_10011
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Ventricular arrhythmia and torsade de pointe: dose limiting toxicities of the MDR-modulator S9788 in a phase I trial.
Journal
Annals of Oncology
Author(s)
Stupp R., Bauer J., Pagani O., Gerard B., Cerny T., Sessa C., Bastian G., Sarkany M., Schläpfer J., Giroux B., Leyvraz S.
ISSN
0923-7534 (Print)
ISSN-L
0923-7534
Publication state
Published
Issued date
1998
Peer-reviewed
Oui
Volume
9
Number
11
Pages
1233-1242
Language
english
Notes
Publication types: Clinical Trial ; Clinical Trial, Phase I ; Journal Article
Publication Status: ppublish
Abstract
BACKGROUND: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (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 with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined.
RESULTS: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) 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 mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute 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 particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase 1 trials of S9788 infused over six hours precluded the further clinical development of S9788.
Keywords
Adult, Aged, Antineoplastic Agents/administration & dosage, Antineoplastic Agents/adverse effects, Arrhythmias, Cardiac/chemically induced, Doxorubicin/administration & dosage, Drug Administration Schedule, Electrocardiography, Female, Humans, Male, Middle Aged, Piperidines/administration & dosage, Piperidines/adverse effects, Torsades de Pointes/chemically induced, Triazines/administration & dosage, Triazines/adverse effects
Pubmed
Web of science
Open Access
Yes
Create date
19/11/2007 11:59
Last modification date
25/09/2019 6:08
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