PII-053 - CONCENTRATION-QT MODELING ANALYSIS OF GEMTUZUMAB OZOGAMICIN FOLLOWING FRACTIONATED DOSING REGIMEN IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA.

J. Rashid¹, J. Hibma¹, R. Benner², P. Bousset³, E. Vandendries⁴, Y. Chen¹; ¹Pfizer, La Jolla, CA, USA, ²Pfizer, Groton, CT, USA, ³Pfizer, Paris, France, ⁴Pfizer, Cambridge, MA, USA.

Background: Gemtuzumab ozogamicin (GO) is a CD33-directed antibody-drug conjugate approved in patients with acute myeloid leukemia (AML). QTc prolongation of GO was not previously evaluated. The objectives of this analysis are to characterize the relationship between QTc and concentrations of GO using data from a post marketing requirement study (NCT03727750).

Methods: This was a Phase 4, single arm, open-label study to evaluate the effect of GO on QTc, PK, safety, immunogenicity and efficacy in 50 AML adult patients treated with the fractionated regimen of GO at 3 mg/m2 on days 1, 4, and 7. The concentration-QT analysis was performed using nonlinear mixed effects modeling (version 7.5.0).

Results: There was no observed relationship between GO concentrations (either unconjugated calicheamicin or total hP67.6 antibody) and heart rate. QTcF (corrected for heart rate using Fridericia’s formula) and QTcS (corrected for heart rate using study specific formula) were determined to be the most appropriate and used as the primary endpoints. No observed relationship was found between GO concentrations and QTc intervals. None of the tested population covariates (e.g., age, race and gender) had a statistically significant impact on QTc interval. The expected median change in QTcF from baseline was 0.842 msec (95% CI: -1.93, 3.51 msec) and 0.602 msec (95% CI: -2.17, 2.72) at the mean observed plasma Cmax of total hP67.6 antibody and unconjugated calicheamicin, respectively.

Conclusion: The upper bound of 95% CI for the model predicted changes in QTc at the mean observed plasma Cmax were less than 5 msec, suggesting that GO is not expected to present a clinically meaningful QT prolongation at the recommended dosing regimen.