LB-007 - A POPULATION PHARMACOKINETIC/PHARMACODYNAMIC MODEL FOR CARFILZOMIB IN COMBINATION WITH IFOSFAMIDE, CARBOPLATIN AND ETOPOSIDE IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA.

L. Lin^1,2, M. Ghasemi^2,2, S. Burke², C. Mavis², J. Nichols², P. Torka², D. Mager¹, F. Hernandez-Ilizaliturri², A. Goey^2,2; ¹The State University of New York at Buffalo, Buffalo, NY, United States, ²Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.

Background: In patients (pts) with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL), salvage chemotherapy regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide, R-ICE) yield poor outcomes. Carfilzomib (CFZ), an irreversible proteasome inhibitor, can overcome acquired rituximab-chemotherapy resistance and, when combined with R-ICE, improves outcomes in pts with R/R DLBCL.1 This analysis aims to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for CFZ in R/R DLBCL pts.

Methods: In this single-center, open-label, prospective phase 1 study (NCT01959698), pts received CFZ (10, 15, or 20 mg/m2) on Days 1, 2, 8, and 9, and standard doses of R-ICE on Days 3–6 q21day (maximum of 3 cycles). CFZ plasma concentrations up to 24 h post infusion were measured by LC-MS/MS. Proteasome activity (PD biomarker) in peripheral blood mononuclear cells was assessed on Days 1–2 with sparse sampling. PK/PD models were developed using FOCEI in NONMEM 7.4 interfaced with Finch Studio and PsN 4.7.0. Model selection was guided by objective function value, goodness‐of‐fit, and visual predictive checks. Stepwise covariate modeling was used for covariate selection.

Results: 28 patients were enrolled in the PK/PD analysis from whom 217 PK samples and 127 PD samples were included. CFZ PK was best described by a 2-compartment model with linear disposition. Proteasome activity was best characterized using a turnover model with irreversible inactivation. All parameters were estimated with good precision. No statistically significant covariates were identified.

Conclusion: A population-based PK/PD model of carfilzomib, which was successfully developed and validated, may be suitable for future individualization of carfilzomib dosing in this patient population.

1. Torka, P. et al. A Phase I Study of Carfilzomib Combined with Rituximab, Ifosfamide, Carboplatin and Etoposide (C-RICE) in Transplant-Eligible Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL). Blood Adv., 2022. Accepted for publication.