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Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 332-333 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.7249
Clinically Relevant QTc Prolongation Is Not Associated With Current Dose Schedules of LBH589 (panobinostat)Novartis Pharmaceuticals Corporation, East Hanover, NJ
Novartis Institute for Biomedical Research, Cambridge, MA
Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia To the Editor: In their recent, well-designed phase IIb clinical trial of vorinostat in patients with refractory cutaneous T-cell lymphoma, Olsen et al assess cardiac adverse events and compare them with results from other studies of histone deacetylase (HDAC) inhibitors.1 They concluded that vorinostat results in a "much lower incidence and severity of QTc changes than reported with two other HDAC inhibitors, depsipeptide and LBH589 (panobinostat)." However, this claim is based on a comparison of incidence rates derived from a phase II study that utilizes a marketed dose of vorinostat versus an exploratory panobinostat dose-finding schedule2 that is no longer in development. Such a comparison is thus not meaningful or valid and gives a misleading impression of the cardiac adverse events associated with panobinostat use. Table 1 displays the incidence and severity of QTc prolongation observed in a variety of studies with varying doses and schedules of panobinostat. These data show that the overall incidence of panobinostat-induced QTcF prolongation varies from as high as 33.3% in the initial, intensive dose regimen with daily intravenous (IV) panobinostat2 for 7 days to as low as 6.3% in patients treated with oral panobinostat three times weekly3 or 6.8% in patients treated with IV panobinostat once weekly.4 The initial, intensive 7-consecutive-day dose schedule of panobinostat 14 mg/m2/d IV was chosen for a single phase I study2 based on the hypothesis that the leukemia patient target population might require an extended dosing period for disease control. This dose schedule was later discontinued due to the high incidence of QTcF prolongation associated with its use. Alternative dose schedules have been developed for both IV and oral panobinostat, which minimize cardiac adverse events (Table 1) while still maintaining activity in patients with a variety of solid tumors and nonleukemic hematological malignancies.3,4 Indeed, the overall incidence rates of 6.3% and 6.8% QTcF prolongation observed in the recent dose-escalation studies of oral3 and IV4 panobinostat, respectively, are similar to the incidence of 4% QTc prolongation reported in the Olsen et al phase IIb study of oral vorinostat 400 mg.1
Moreover, it is evident from the data in Table 1 that the incidence and severity of QTcF prolongation associated with panobinostat vary dramatically as a function of the dose and schedule of drug used. Although the current doses and schedules of both oral3 and IV4 panobinostat have a much lower incidence and severity of QTcF prolongation than was observed in the initial report with the intensive IV dose regimen,2 additional panobinostat dose schedules are in development to explore whether adverse events can be minimized still further while maintaining efficacy in a variety of tumor types. Comparisons of the incidence and severity of QTc prolongation between vorinostat and panobinostat are difficult given the currently available data, and several caveats must be considered: One caveat is that all panobinostat studies performed to date have been phase I dose-escalation trials, which enrolled only small numbers of patients across a range of doses. Better approximations of the actual incidence of QTc prolongation in oncology patient populations must therefore await the results of larger studies. As one example, although the results of some early dose-finding studies of vorinostat showed nonspecific asymptomatic ST5,6 and/or QT6 changes, QTc prolongation was not detected until larger phase II studies were performed.1 A further caveat is that the ECG monitoring employed in the phase I panobinostat studies has been intensive, with at least 30 ECGs performed during the first 28-day cycle followed by weekly ECG monitoring thereafter. In comparison, ECG monitoring was conducted less frequently in vorinostat studies.1,6-8 Finally, it is also recognized that differences in baseline patient populations with regard to pre-existing cardiovascular disease as well as both prior and concomitant therapy may confound comparisons between studies. The QT interval is an important variable in oncology drug development, but its significance in early-phase clinical trials is still uncertain. At least four HDAC inhibitors examined to date—including vorinostat,1 panobinostat,2-4 depsipeptide,9,10 and LAQ82411—have shown clinical evidence of QT prolongation in phase I and/or II studies. Although QT prolongation poses a risk of malignant cardiac arrhythmia with torsade de pointes and sudden cardiac death, it is important to note that, with few exceptions,9 the QT abnormalities observed in HDAC inhibitor clinical trials have not translated into symptomatic or clinically meaningful events. Evidence collected to date indicates that these QTc changes may be a class effect of HDAC inhibitors,12 with the actual incidence and severity of QTc prolongation a function of the specific dose and schedule used for each HDAC inhibitor as well as the patient selection criteria. Indeed, longer-term data that emerge as HDAC inhibitors reach later phases of development will be needed to determine the clinical relevance of QT abnormalities observed in these preliminary studies. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Lei Zhang, Novartis Pharmaceuticals Corporation (C); Michael R. Cooper, Novartis Institute for Biomedical Research (C); David Lebwohl, Novartis Pharmaceuticals Corporation (C); Eric Masson, Novartis Pharmaceuticals Corporation (C); Glen Laird, Novartis Pharmaceuticals Corporation (C) Consultant or Advisory Role: None Stock Ownership: Lei Zhang, Novartis Institutes for Biomedical Research; Michael R. Cooper, Novartis Pharmaceuticals Corporation; David Lebwohl, Novartis Pharmaceuticals Corporation; Eric Masson, Novartis Pharmaceuticals Corporation; Glen Laird, Novartis Pharmaceuticals Corporation Honoraria: H Miles Prince, Novartis Pharmaceuticals Corporation Research Funding: None Expert Testimony: None Other Remuneration: None
REFERENCES
1. Olsen EA, Kim YH, Kuzel TM, et al: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25:3109-3115, 2007 2. Giles F, Fischer T, Cortes J, et al: A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 12:4628-4635, 2006 3. Prince HM, George D, Patnaik A, et al: Phase I study of oral panobinostat (LBH589) in advanced solid tumors and non-Hodgkin's lymphoma. ECCO Poster presented Setember 23-27, 2007, Barcelona, Spain (abstr 701) 4. Sharma S, Vogelzang N, Beck J, et al: Phase I pharmacokinetic and pharmacodynamic study of once-weekly i.v. panobinostat (LBH589). ECCO Poster presented September 23-27, 2007, Barcelona, Spain (abstr 702) 5. Kelly WK, Richon VM, O’Connor O, et al: Phase I clinical trial of histone deacetylase inhibitor: Suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 9:3578-3588, 2003 6. Kelly WK, O’Connor OA, Krug LM, et al: Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923-3931, 2005 7. O’Connor OA, Heaney ML, Schwartz L, et al: Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 24:166-173, 2006 8. Duvic M, Talpur R, Ni X, et al: Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109:31-39, 2007 9. Shah MH, Binkley P, Chan K, et al: Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 12:3997-4003, 2006 10. Piekarz RL, Frye AR, Wright JJ, et al: Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res 12:3762-3773, 2006 11. Rowinsky EK, de Bono J, Deangelo DJ, et al: Cardiac monitoring in phase I trials of a novel histone deacetylase (HDAC) inhibitor LAQ824 in patients with advanced solid tumors and hematologic malignancies. J Clin Oncol 23:16S, 2005 (suppl; abstr 3131) 12. Strevel EL, Ing DJ, Siu LL: Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 25:3362-3371, 2007
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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