Cardiovascular safety profile of VT-464 in patients (pts) with castrate-resistant prostate cancer (CRPC).
Kurman, MR; Sager, P; Rudoltz, MS; Eisner, J; Goodman, D; Heyman, E; Salvail, D; Bell, C; Moore, WR
Published in: Journal of Clinical Oncology
198 Background: VT-464 is a dual selective inhibitor of CYP17,20 lyase and an androgen receptor antagonist in development for the treatment of CRPC. In early clinical testing, several pts receiving VT-464 in 28-day cycles were noted to have syncopal, pre-syncopal or vaso-vagal episodes with typical prodromes. To further evaluate these events, Holter monitoring (HM) was performed in pts enrolled in two clinical studies. Methods: Continuous HM was performed at Screening, after the first dose of VT-464 C1D8, and C2D1 for study INO-VT-464-CL-001; and at Screening, after the first dose of VT-464, and C2D1 for study INO-VT-464-CL-004. The Screening visit HM data was considered the baseline. Plasma levels of VT-464 (in selected pts) and 12-lead ECGs of 10-seconds duration were extracted in triplicate for each pt from the HM data at Baseline, Day 1 and C2D1 at multiple time points. Results: 57 pt screened for VT-464 treatment, underwent HM. Nonsustained ventricular tachycardia (NSVT) was seen in 6 pts (11%) prior to VT-464, providing a background estimate in this population. 37 pts were treated with VT-464 and had > 1 post-screen HM; 4 pts (11%; all with cardiac disorders) had post-treatment NSVT (all < 5 beats); no episodes of sustained VT were seen. 28 pts had ECG data extracted from HMs that coincided with peak plasma levels of VT-464. There was no QTcF or QRS prolongation; increases in the HR (mean 13.1-19.5 BPM but with a non-significant VT-464 concentration/HR relationship) and small PR increases (mean 32.9 ms; partially driven by several pts) without second degree AV block were observed. Conclusions: VT -464 did not prolong QTcF or QRS intervals and the lack of a significant exposure response HR analysis suggests that the HR increases may not be drug related. The PR prolongation is unlikely to be clinical significance. HM showed a frequency of NSVT consistent with background frequency for this pt population.A detailed examination of study pts experiencing syncope or presyncope revealed these to likely be vasovagal in nature, consistent with the increased vagal tone observed in nonclinical testing. There does not appear to be a pro-arrhythmogenic potential of VT-464 based on data from both nonclinical and clinical assessments. Clinical trial information: NCT02361086.
