Analysis of the Potential Effect of Ponatinib on the QTc Interval in Patients with Refractory Hematologic Malignancies

Ponatinib, an oral multiple tyrosine kinase inhibitor (TKI), is a potent pan-BCR-ABL inhibitor. Preliminary anti-leukemia activity of ponatinib was observed in patients with refractory chronic myeloid leukemia (CML) and advanced hematologic malignancies in a phase 1 study. Due to the QT prolongation noted with other TKIs, the effect of ponatinib on ECGs was examined in this population.

This ongoing phase 1, open-label, dose-escalation, multicenter trial was designed to evaluate the safety of oral ponatinib administered to patients with advanced hematologic malignancies who failed available therapies. Patients received ponatinib orally once daily (2 mg to 60 mg) over at least 1 cycle (28 days) of study treatment unless an unacceptable toxicity or disease progression occurred. Inclusion criteria required screening QTc < 450 ms and prohibited concomitant use of medications known to prolong QTc. For the last 3 cohorts (30 mg, 45 mg and 60 mg), 12-lead ECGs (supine) were recorded using GE MAC1200 ECG recorders at the following time-points: C1D1 pre-dose (triplicate); C1D15 pre-dose (single); C2D1 pre-dose (triplicate); C2D1 2-hour post-dose (triplicate); C2D1 4-hour post-dose (triplicate); C2D1 6-hour post-dose (triplicate). Matching plasma ponatinib concentration data were also obtained at these time-points. This analysis of the cardiac safety of ponatinib only included patients who had replicate ECGs at baseline and a minimum of 1 additional on-treatment time-point with matching plasma ponatinib concentration data. The primary assessment was Fridericia corrected QT (QTcF).

A total of 81 patients were enrolled in the phase 1 study; 39 patients who received 30 mg or more of ponatinib daily were included in this analysis. There was no significant effect on cardiac repolarization as measured by the lack of a significant change in QTcF at all doses. Mean QTcF change from baseline was −10.9, −3.6, and −5.9 ms for the 30 mg, 45 mg and 60 mg cohorts, respectively. In addition, the pharmacokinetic-pharmacodynamic models show the slope of the relationship for QTcF versus plasma ponatinib concentration was negative, indicating no exposure-effect relationship, with an estimated QTcF mean change of −6.4 (upper confidence interval −0.9) ms at C_max for the 60 mg group. ECG data revealed no significant change in heart rate (+3.5, −3.3, and +1.0 bpm for 30 mg, 45 mg and 60 mg cohorts, respectively). There was no signal of any effect on atrioventricular conduction as measured by the PR interval duration (mean change: −0.4, −3.6, and −0.7 ms, respectively). There was a slight, dose responsive, non-clinically significant increase in QRS duration (mean change: −0.8, +1.3, and +3.6 ms, respectively) that may be due to variability secondary to the limited sample size. There were 2 subjects with new atrial fibrillation and new T wave inversion. These morphological changes likely reflect the patient population being studied rather than any potential drug effect. Adverse event (AE) reports from the trial had 3 patients with ECG QT prolonged (2 mg, 4 mg and 45 mg) documented as a treatment-related AE; 2 were grade 3 (4 mg and 45 mg). On review, all 3 patients were found to have baseline (C1D1) prolongation of QTc or were on concomitant medications associated with QTc prolongation. There were no clinical consequences of the ECG findings in these patients.

This analysis of the QTc intervals of patients who received ponatinib 30 mg or higher in the phase 1 clinical trial revealed there was no significant effect of ponatinib on cardiac repolarization.

Sonnichsen:ARIAD: Consultancy. Dorer:ARIAD: Employment. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Talpaz:ARIAD: Research Funding. Deininger:BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; ARIAD: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Litwin:ARIAD: Consultancy. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership.