143: The Effect of Severe Renal Impairment on ONC201 (Dordaviprone) Pharmacokinetics

Statement of Purpose, Innovation or Hypothesis: ONC201 (dordaviprone) is a novel, orally administered, anti-cancer imipridone with demonstrated antitumor effects in patients with glioma. Metabolic clearance via CYP3A4 has been confirmed as a major elimination pathway of ONC201, while renal clearance of ONC201 has been identified as a minor elimination pathway. This study was designed to assess the effect of severe renal impairment (RI) on ONC201 pharmacokinetics (PK).

Description of Methods & Materials: This was a single-center, open-label, parallel-group, single-period, single-dose study. Eight participants with severe RI (eGFR < 30mL/min), and 8 participants matched for age (±10 years), body mass index (±20%), and sex, with normal renal function, received a single 375 mg dose of ONC201. Plasma PK samples were collected at predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72, and 168 hours post dose; urine PK samples were collected predose and during 0-4, 4-8, 8-12, and 12-24 hours post dose. Plasma and urine samples were analyzed for ONC201 and metabolite ONC207 using validated liquid chromatography tandem mass spectrometry methods. PK and safety profiles were evaluated between cohorts. To assess the effect of severe RI on ONC201 exposure, point estimates and 90% confidence intervals (CIs) were calculated for the ratio of geometric means for PK parameters between cohorts.

Data & Results: All 16 participants were included in the analysis population. Geometric mean ratios and 90% CIs of ONC201 exposure for Cmax, AUClast, and AUCinf in the severe RI cohort compared to the healthy‑matched cohort were 1.13 (0.92 to 1.39), 1.48 (0.98 to 2.23), and 1.47 (0.97 to 2.21), respectively. ONC207 results were similar, with greater Cmax and AUCs observed in the severe RI cohort. ONC201 was minimally recovered in urine with a mean percent of ONC201 dose recovered in severe RI and healthy-matched cohorts of 0.233% and 0.188%, respectively. Geometric mean CLr was similar in severe RI (0.043 L/h) and healthy-matched cohorts (0.069 L/h), however, geometric mean CL/F was reduced approximately 30% in the severe RI cohort (27.3 L/h) compared to the healthy-matched cohort (40.0 L/h). Treatment-emergent adverse events (TEAEs) were reported in 75% of severe RI participants and 62.5% of healthy-matched participants; all TEAEs were mild. Treatment-related AEs occurred in 50% of severe RI participants compared to 37.5% of healthy-matched participants. The most common treatment-related AE was headache, occurring in 2 (25%) participants from each cohort; no other treatment-related AEs occurred in more than 1 participant.

Interpretation, Conclusion or Significance: The ratio of ONC201 exposure between severe RI and healthy-matched cohorts was less than 2-fold. ONC201 was minimally recovered in both severe RI and healthy-matched cohorts confirming renal clearance is a minor elimination pathway of ONC201. The observed decrease in severe RI CL/F may be due to changes in CYP3A4 activity due to renal disease. Despite increases in ONC201 exposure, single dose 375 mg ONC201 was well tolerated in both cohorts. The results of this study will be used to inform dosing in patients with RI.

Disclosures: JB, MA, TA, AB, MM, MJM, TT, and OD are employees of and have stock ownership in Chimerix, Inc.

Citations/References: ¹ Arrillaga-Romany I, Kurz S, Tarapore R, et al. LTBK-05. Clinical Efficacy of ONC201 in Recurrent H3 K27M-Mutant Diffuse Midline Glioma Patients. Neuro Oncol. 2021;23(Supplement_6):vi230-vi230. doi:10.1093/neuonc/noab196.925.

Additional Information/Authors: NA