168: Population Pharmacokinetic/Pharmacodynamic Analysis of MDM2 Inhibitor Navtemadlin (KRT-232) in Combination with Decitabine in a Phase 1 Dose Escalation Study of Subjects With Acute Myeloid Leukemia

Statement of Purpose: Navtemadlin (or KRT-232), a potent, selective, orally available murine double minute 2 (MDM2) inhibitor, overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis in TP53WT tumors. Navtemadlin is being studied in an ongoing open label, dose escalation phase 1 trial (NCT03041688) in combination with decitabine in patients with AML. The purpose was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of navtemadlin in this setting using a non-linear mixed effects modeling approach.

Description of Methods & Materials: PK/PD data from 22 patients with AML were included in our analysis. In this trial with a 28 day cycle of therapy, patients received intravenous infusion of 20 mg/m2/day decitabine for 10 days per cycle on Day 1 to 10, and oral dose of 60 mg (n=5), 90 mg (n=3), 120 mg (n=3), 180 mg (n=3), 240 mg (n=2), 300 mg (n=3) and 360 mg (n=3) navtemadlin once daily (QD) on Day 4 to 10 and on day 18 to 24. Patients in the highest dose cohort (360 mg) only received the first round of navtemadlin on Day 4 to 10 due to poor tolerability. PK samples were collected over a time course on Day 4 and 18. Serum macrophage inhibitory cytokine-1 (MIC-1) was used as a PD marker and was measured on Day 1, pre-dose and 24 hr post-dose of Day 4 and day 8 doses of the first cycle. Population PK/PD analysis was performed using the first-order conditional estimation with interaction (FOCE-I) using modeling software NONMEM® v7.3, with model evaluation by standard diagnostics and visual predictive checks. Covariate analysis was performed to evaluate the effect of patient factors on navtemadlin PK.

Data & Results: Navtemadlin plasma concentrations (210) and MIC-1 serum concentrations (118) were used to develop the population PK/PD model. Navtemadlin PK was best described by a two-compartment model with first-order absorption and linear elimination. MIC-1 data fit well to an indirect stimulatory response model. Estimated navtemadlin PK model parameters were 12.3 L/hr for apparent oral clearance (CL/F), 69.4 L for apparent central volume (Vc/F), 515 L for apparent peripheral volume (Vp/F), 24.2 L/hr for apparent intercompartmental clearance (Q/F), and 0.435 hr-1 for absorption rate constant. Simulation by the developed model showed generally dose-proportional serum MIC-1, and serum MIC-1 was increased with repeated dosing, then declined and returned to baseline. There was no significant difference in apparent oral clearance over the tested dose range of 60 – 360 mg QD, suggesting dose-proportional PK. No clinically meaningful covariate effects on PK were identified with the available data.

Interpretation, Conclusion or Significance: The PK of navtemadlin in combination with decitabine therapy was comparable to that previously reported with navtemadlin as a single agent in phase 1 study [1]. The PD model was able to describe the delayed modulation of MIC-1 relative to navtemadlin PK [2,3]. The population PK/PD model will be used to explore the exposure-outcome relationship of navtemadlin in combination with decitabine in this patient population.

Disclosures: