False Negative ECG Device Results May Increase the Risk of Adverse Events in Clinical Oncology Trials.

BACKGROUND: Sites participating in clinical trials may not have the expertise and infrastructure to accurately measure cardiac intervals on 12-lead ECGs and rely heavily on the automated ECG device generated results for clinical decision-making. METHODS: Using a dataset of over 260,000 ECGs collected in clinical oncology studies, we investigated the mean difference and the rate of false negative results between the digital ECG machine QTc and QRS measurements compared to those obtained by a centralized ECG core lab. RESULTS: The mean differences between the core lab and the automated algorithm QTcF and QRS measurements were + 1.8 ± 16.0 ms and - 1.0 ± 8.8 ms, respectively. Among the ECGs with a centralized QTcF value > 450 or > 470 ms, 39.5% and 47.8% respectively had a device reported QTcF value ≤ 450 ms or ≤ 470 ms. Among the ECGs with a centrally measured QTcF > 500 ms, 55.8% had a device reported value ≤ 500 ms. Automated QTcF measurements failed to detect a QTcF increase > 60 ms for 53.9% of the ECGs identified by the core lab. Automated measurements also failed to detect QRS prolongation, though to a lesser extent than failures to detect QTc prolongation. Among the ECGs with a centrally measured QRS > 110 or 120 ms, 7.9% and 7.3% respectively had a device reported QRS value ≤ 110 ms or ≤ 120 ms. CONCLUSION: Relying on automated measurements from ECG devices for patient inclusion and treatment (dis)continuation decisions poses a potential risk to patients participating in oncology studies.

Evaluation of Cardiac Repolarization in the Randomized Phase 2 Study of Intermediate- or High-Risk Smoldering Multiple Myeloma Patients Treated with Daratumumab Monotherapy.

INTRODUCTION: Daratumumab is a CD38-targeting monoclonal antibody that has demonstrated clinical benefit for multiple myeloma. Daratumumab inhibition of CD38, which is expressed on immune cell populations and cardiomyocytes, could potentially affect cardiac function. This QTc substudy of the phase 2 CENTAURUS study investigated the potential effect of intravenous daratumumab monotherapy on QTc prolongation and other electrocardiogram (ECG) parameters, including concentration-QTc effect modeling. METHODS: Patients had intermediate- or high-risk smoldering multiple myeloma. Patients with QT interval corrected by Fridericia's formula (QTcF) > 470 ms, QRS interval ≥ 110 ms, or PR interval ≥ 200 ms were excluded. Triplicate ECGs were collected at screening, Dose 1, and Dose 8. Analyses of on-treatment ECGs were conducted with a time-matched baseline (primary analysis). By time-point, pharmacokinetic-pharmacodynamic (PK/PD), and outlier analyses were conducted. RESULTS: Of 123 patients in CENTAURUS, 31 were enrolled in the QTc substudy. Daratumumab produced a small increase in heart rate (5-12 beats per minute) of unclear significance. There was a small but clinically insignificant effect on QTc, as measured by both time-matched time-point and PK/PD analyses. The primary analysis demonstrated a maximum mean increase in QTcF of 9.1 ms (90% 2-sided upper confidence interval [CI], 14.1 ms). The primary PK/PD analysis predicted a maximum QTcF increase of 8.5 ms (90% 2-sided upper CI, 13.5 ms). No patient had an abnormal U wave, a new QTcF > 500 ms, or > 60 ms change from baseline for QTcF. CONCLUSION: Analysis of ECG intervals and concentration-QTc relationships showed a small but clinically insignificant effect of daratumumab. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02316106.

Assessment of the effect of erdafitinib on cardiac safety: analysis of ECGs and exposure-QTc in patients with advanced or refractory solid tumors.

PURPOSE: To characterize the effect of erdafitinib on electrocardiogram (ECG) parameters and the relationship between erdafitinib plasma concentrations and QTc interval changes in patients with advanced or refractory solid tumors. METHODS: Triplicate ECGs and continuous 12-lead Holter data were collected in the dose escalation part (Part 1) of the first-in-human study, with doses ranging from 0.5 to 12 mg. Triplicate ECG monitoring continued in Parts 2-4 where 2 dose regimens selected from Part 1 were expanded in prespecified tumor types. Analyses of ECG data included central tendency analyses, identification of categorical outliers and morphological assessment. A concentration-QTc analysis was conducted using a linear mixed-effect model based on extracted time matching Holter data. RESULTS: Central tendency, categorical outlier, and ECG morphologic analyses from 187 patients revealed no clinically significant effect of erdafitinib on heart rate, atrioventricular conduction or cardiac depolarization (PR and QRS), and no effect on cardiac repolarization (QTc). Concentration-QTc analysis from 62 patients indicated that the slopes of relationship between total and free erdafitinib plasma concentrations and QTcI (mean exponent of 0.395) were estimated as - 0.00269 ms/(ng/mL) and - 1.138 ms/(ng/mL), respectively. The predicted change in QTcI at the observed geometric mean of total and free concentration at the highest therapeutic erdafitinib dose (9 mg daily) was < 10 ms at the upper bound of the two-sided 90% confidence interval. CONCLUSIONS: ECG data and the concentration-QTc relationships demonstrate that erdafitinib does not prolong QTc interval and has no effects on cardiac repolarization or other ECG parameters. Clinical trial registration numbers NCT01703481, EudraCT: 2012-000697-34.

Benefits of Centralized ECG Reading in Clinical Oncology Studies.

BACKGROUND: Many clinical trials of investigational oncologic agents utilize electrocardiogram (ECG) machine measurements of QTc, for inclusion/exclusion and dosing decisions, though their reliability in this setting has not been established. METHODS: We compared the digital ECG machine QTc measurements with those obtained by a centralized ECG core lab on more than 270,000 consecutive ECGs collected from 299 clinical oncology trials. RESULTS: The mean difference between the ECG machine measurements and the central measured QTcF was 1.8 ± 15.7 milliseconds. In addition, 29.7% of ECGs with an ECG machine-measured QTcF >450 milliseconds had a centrally measured QTcF <450 milliseconds, 44.6% of ECGs with an ECG machine-measured QTcF >470 milliseconds had a centrally measured QTcF <470 milliseconds, and 77.2% of ECGs with an ECG machine-measured QTcF >500 milliseconds had a centrally measured QTcF <500 milliseconds. The likelihood of a large discrepancy between the ECG machine- and centrally measured value for QTcF increased at both the high and low ends of the range of ECG machine QTcF measurements. CONCLUSIONS: While on average ECG machine-measured QTcF values were very similar to the central core lab measurements; there were very significant discrepancies which will have important implications for patient recruitment for clinical oncology trials as well as for patient safety during dosing with new oncologic agents. Reliance on ECG machine QTc measurements during clinical oncology trials may lead to unnecessary exclusion of patients as well as unneeded treatment interruptions.

A thorough QT study to assess the effects of tbo-filgrastim on cardiac repolarization in healthy subjects.

Tbo-filgrastim is a recombinant human granulocyte colony-stimulating factor approved by the US Food and Drug Administration to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. We assessed the effect of tbo-filgrastim on cardiac conduction and repolarization in healthy subjects. A three-arm, parallel-group, active- and placebo-controlled, double-blind study randomized healthy adults to a single 5 µg/kg intravenous tbo-filgrastim infusion, a single intravenous placebo infusion, or a single 400 mg moxifloxacin oral dose. The primary end point was placebo-corrected time-matched change from baseline in QT interval corrected using a QT individual correction (QTcI) method. Secondary end points included heart rate, PR interval, QRS duration, change in electrocardiogram patterns, correlation between QTcI change from baseline (milliseconds) and tbo-filgrastim serum concentrations, and safety variables. A total of 145 subjects were enrolled (50 tbo-filgrastim, 50 placebo, 45 moxifloxacin). Peak placebo-corrected change from baseline for QTcI with tbo-filgrastim was 3.5 milliseconds, with a two-sided 95% upper confidence interval of 7.2 milliseconds, demonstrating no signal for any tbo-filgrastim effect on QTc. Concentration-effect modeling showed no evidence of an effect of tbo-filgrastim on cardiac repolarization. Tbo-filgrastim produced no clinically significant changes in other electrocardiogram parameters. Tbo-filgrastim was well tolerated.