A Novel Approach to QTc Studies: Assessing Cardiac Safety of the mTOR Kinase Inhibitor CC-223 within the Dose-Escalation/Expansion Study
Authors: Kleiman Robert B , Chopra Rajesh , Hans de Haan , Hege Kristen , James Angela J , Wang Xiaomin , Wu Xiaoling , O'Mara Edward 
Published: October 2019

Abstract
Introduction: A variety of chemically diverse drugs are known to alter cardiac repolarization and to produce sudden cardiac death. Current regulatory guidelines therefore require the characterization of a new drug's effect on cardiac repolarization, and in particular, the effects on the QTc interval in a thorough QT/QTc study (ICH E14 Guidance, 2005). QTc studies are usually performed with healthy volunteers but may be performed in the targeted patient (pt) population if the toxicity profile of a drug precludes its use in healthy individuals. Early-phase oncology dose-escalation studies generally include pharmacokinetic/pharmacodynamic (PK/PD) evaluations from relatively large pt populations, which could provide a robust data set for concurrent cardiac safety evaluation. We have combined these approaches and present the results from a first-in-human phase 1 study of CC-223, a potent and selective dual inhibitor of mechanistic target of rapamycin (mTOR) kinases.
Patients and Methods: Adult (aged > 18 years) pts with histologically confirmed advanced non-Hodgkin lymphoma, multiple myeloma, or advanced, unresectable solid tumors who had progressed on (or were unable to tolerate) standard therapy or for whom standard therapy does not exist were eligible. The dose of CC-223, administered orally, ranged from 7.5 to 60.0 mg/day in 28-day continuous cycles. PK blood samples and corresponding triplicate electrocardiograms (ECG) were collected at 2 time points: predose and 1.5-3 hours after the dose in cycle 2. ECG analysis was performed on all pts who received ≥ 1 dose of CC-223 with baseline and on-treatment ECG results available. The primary cardiac assessment was the by time point change from baseline for cardiac interval duration measurements, including heart rate (HR), PR interval, QRS duration, and QTcF interval (QT interval corrected for HR using the Fridericia formula). Secondary analyses included a time-averaged central tendency analysis, analysis of morphology and measurement outliers, and PK/PD analysis of the relationship between the plasma concentration of CC-223 and its M1 metabolite vs QTcF change from baseline.
Results: As of April 1, 2013, 158 pts met the requirements for inclusion in the ECG analysis, and of those, 149 were also included in the PK/PD analysis. The data revealed no effect of CC-223 on cardiac interval duration measurements. The by time point analyses of HR, PR, QRS, and QTcF demonstrated no clinically significant ECG effects of CC-223 during cycle 1 or subsequent cycles. The time-averaged central tendency analyses also demonstrated only small changes in cardiac interval duration. For QTcF, the time-averaged mean change from baseline was −18.5 to −1.0 ms in cycle 1 and −8.7 to 7.3 ms in subsequent cycles. There were few nonspecific ECG morphological findings and few measurement outliers. The PK/PD analysis showed no evidence of any significant exposure-effect relationship between CC-223 or the M1 metabolite and QTcF (Figure). The estimated QTcF change at the maximum concentration (Cmax) of 354 ng/mL for CC-223 was −0.2 ms, with an upper 1-sided 95% CI of 1.2 ms, and the estimated QTcF change at Cmaxof 1532 ng/mL for the M1 metabolite was 0.4 ms, with an upper 1-sided 95% CI of 1.8 ms. Adverse events (AEs) related to cardiac function included 2 reports of ventricular arrhythmias; neither event was serious, both resolved while the pts were on study, and neither were considered study drug related.
Conclusions: The QTcF intervals and PK/PD relationships for CC-223 and its active metabolite revealed no significant effect on cardiac repolarization or other ECG parameters. This study used a robust data set in pts, avoided potential AE exposure in healthy volunteers, and had the additional benefit of fulfilling the QTc study requirement for new drugs by the Food and Drug Administration. As such, combining a phase 1 study with the required QTc analysis can be an improved, cost-effective approach for assessing cardiac safety during early drug development.

Disclosures
Kleiman: Celgene Corporation: Consultancy. Chopra:Celgene: Employment, Equity Ownership. Hans:Celgene Corporation: Consultancy. Hege:Celgene Corporation: Employment, Equity Ownership. James:Celgene Corporation: Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. O'Mara:Celgene Corporation: Employment, Equity Ownership.