PI-040 - THE EFFECT OF DORDAVIPRONE (ONC201) ON CARDIAC REPOLARIZATION IN HEALTHY ADULT PARTICIPANTS

S. Faison¹, J. Batonga¹, M. Anderson², T. Arumugham², A. Bartkus³, M. Morrison², M. Mullin², T. Tippin³, O. Naderer³, R. Kleiman⁴; ¹Certara Strategic Consulting, Radnor, PA, USA, ²Chimerix, Inc, Durham, NC, United States, ³Chimerix, Inc., Durham, NC, USA, ⁴Clario, Philadelphia, PA, USA.

Background: Dordaviprone (ONC201) is a novel, orally administered, anti-cancer imipridone with demonstrated antitumor effects in patients with gliomaa. As dordaviprone is a novel compound, it was evaluated for potential effects on heart rate corrected QT duration (QTc) compared to a positive (moxifloxacin) and negative (placebo) control.

Methods: This was a single-center, randomized, positive- and placebo-controlled, 3-period crossover study. Thirty healthy adult participants received a single-dose of 750 mg dordaviprone, 750 mg matched-placebo, or 400 mg moxifloxacin per treatment period according to their randomized sequence. Time-matched PK blood draws and replicate 12-lead ECGs via holter were collected predose through 48 hours following treatment. ECG extractions occurred prior to PK sampling to avoid changes in autonomic tone. Plasma samples were analyzed for dordaviprone, metabolite ONC207, or moxifloxacin using validated liquid chromatography tandem mass spectrometry methods. ECG extractions were analyzed by a blinded central cardiologist.

A repeated measures mixed model analysis of the change from baseline in QTcF was used to estimate the difference in mean change from baseline between dordaviprone and placebo, moxifloxacin was used for assay sensitivity.

Results: Twenty-nine participants were included in the dordaviprone and ONC207 analyses; 30 participants were included in the moxifloxacin analysis. The placebo-corrected mean change from baseline in QTcF for dordaviprone from 0.75 to 8 hr post dose ranged from 9.2 to 13.8 msec with a peak effect of 13.8 msec occurring at 5 hrs postdose. The upper bounds of the 90% CIs ranged from 11.8 to 16.5 msec for all timepoints. Moxifloxacin demonstrated a 10.4 msec (90% CI: 8.7to 12.2) peak increase in QT interval at 3 hrs postdose, demonstrating assay sensitivity.

Dordaviprone treatment related AEs occurred in 37% of participants. The most common dordaviprone treatment-related AEs were mild dizziness in 5 participants (17%) and mild nausea in 2 participants (7%); no other dordaviprone treatment-related AEs occurred in more than 1 participant.

Conclusion: A mean placebo corrected change from baseline in QTcF less than 10 msec could not be ruled out, therefore, concomitant use of dordaviprone with drugs known to prolong QT interval should be done with caution.