Electrocardiographic Characterization of Ramucirumab on the Corrected QT Interval in a Phase II Study of Patients With Advanced Solid Tumors.

LESSONS LEARNED: Cardiotoxicity can be a serious complication of anticancer therapies. To enable earlier identification of drug-related cardiac effects, the International Conference on Harmonization (ICH) adopted the ICH E14 Guidelines for evaluating the potential for QT/corrected QT (QTc) interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs.The results of the evaluation of ramucirumab on the QT/QTc interval show a lack of effect on QTc prolongation in patients with advanced cancer.
BACKGROUND: Ramucirumab is a human immunoglobulin G1 monoclonal antibody that specifically blocks vascular endothelial growth factor receptor-2 and is approved for the treatment of advanced gastric, non-small cell lung, and colorectal cancers. This phase II study was conducted to determine if treatment with ramucirumab causes prolongation of the corrected QT interval using Fridericia's formula (QTcF) in patients with advanced cancer.
METHODS: Patients received intravenous ramucirumab (10 mg/kg) every 21 days for 3 cycles. The first 16 patients received moxifloxacin (400 mg orally), an antibiotic associated with mild QT prolongation as a positive control. During cycle 3, determination of QTcF prolongation was made with triplicate electrocardiograms at multiple time points to compare with baseline.
RESULTS: Sixty-six patients received therapy; 51 patients completed 9 or more weeks of therapy for the complete QTcF evaluation period. The upper limit of the 90% two-sided confidence intervals for the least square means of change in QTcF from baseline at each time point was less than 10 milliseconds. Concentration-QTcF analysis showed a visible, but not significant, negative association between ramucirumab concentration and QTcF change from baseline.
CONCLUSION: Ramucirumab at a dose of 10 mg/kg administered every 21 days for 3 cycles did not produce a statistically or clinically significant prolongation of QTcF. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Author Summary

Discussion

QTcF correction change from baseline was the primary endpoint for this study. Fifty-one patients received at least 9 weeks of ramucirumab (10 mg/kg) plus diphenhydramine treatment (the complete corrected QT [QTc] evaluation period). Using the time-matched QTcF values from day −1 as the baseline, repeated-measures analysis of covariance showed that the upper limit of the two-sided 90% confidence intervals of the least square means of change from baseline for QTcF values was less than 10 milliseconds at all study time points in cycle 3 (Fig. 1). The first 16 patients received treatment with moxifloxacin (400 mg orally), an antibiotic associated with mild QTc prolongation, which demonstrated assay sensitivity.

Figure 1.

Graph showing 90% confidence interval of change from baseline at cycle 3 for QTcF after ramucirumab plus diphenhydramine treatment. Red dotted line and blue dotted line indicate 10- and 5-millisecond time points, respectively. The scale of the x-axis (time) is non-uniform.

Abbreviation: QTcF, QT corrected by Fridericia’s formula.

The relationship between ramucirumab concentrations and change in QTcF was assessed using data from time points at which both the electrocardiogram data and the concentration data were available; the time-matched mean change from baseline QTcF was analyzed for correlation with the serum concentration of ramucirumab, using linear mixed models (Fig. 2). The slope of the model in this analysis was not statistically significantly different from zero. The estimated value of the slope was −0.00207, showing a small negative association between concentration of ramucirumab and the change from baseline in QTcF. Mean ramucirumab concentration-time profiles at cycles 1 and 3 were very similar, with slightly higher mean concentrations for cycle 3, reflecting a small amount of accumulation following 3 doses of ramucirumab.

Figure 2.

QTcF changes from baseline versus total drug concentrations at cycle 3 for the evaluable population. Mean Cmax = 571 µg/mL. Mean change in QTcF at mean Cmax = 2.8 milliseconds (90% CI: −3.8 to 9.5).

Abbreviations: CI, confidence interval; QTcF, QT corrected by Fridericia’s formula.

Safety analyses included all treated patients (n = 66). Most treatment-emergent adverse events (TEAEs) in patients receiving ramucirumab were consistent with the known adverse event (AE) profile. Sixty-five patients experienced at least one TEAE, regardless of causality. Forty-two patients (63.6%) experienced at least one TEAE considered related to ramucirumab; the most common were headache (16.7%; 1.5% grade 3), nausea (15.2%), hypertension (10.6%; 4.5% grade 3), and vomiting (10.6%).

This phase II study demonstrated that ramucirumab did not produce a prolongation of QTcF. The 90% two-sided (95% one-sided) upper confidence limit did not exceed 10 milliseconds. This conclusion is also supported by concentration-QTcF modeling, which showed a visible but not significant negative association between concentration of ramucirumab and change from baseline in QTcF.