Optimizing Therapeutic Outcome of CD19(T2)28z1XX Chimeric Antigen Receptor (CAR) T in Adult Patients with Large B-Cell Lymphoma through a Quantitative Medicine Approach

Background:

CD19(T2)28z1xx is an autologous CD19-targeting CAR-T cell therapy consisting of CD28 and optimized 1XX CD3ζ signaling domains with the hypothesis being 1XX CAR-T cells are more potent and will display promising efficacy profile with a lower infusion dose. Non-linear mixed effects modeling was used to characterize the cellular kinetics (CK). The developed CK model was further leveraged to assess the impact of various patient characteristics on CD19(T2)28z1xx kinetics. Exposure-response (E-R) relationships were evaluated for safety (probability of high-grade (>1) cytokine release syndrome (CRS)) and efficacy (rate of overall response (ORR) and complete response (CR)) to support dose recommendation.

Methods:

Analysis presented here was performed using data from the clinical study for four dose levels (25 x 10⁶, 50 x 10⁶, 100 x 10⁶, 200 x 10⁶ CAR-T cells). For E-R efficacy analyses, ORR and rate of CR were evaluated across all dose levels against exposure metrics (C_max and AUC) using logistic regression. Similarly, for E-R safety analysis, rate of high-grade CRS was evaluated against the exposure metrics. Population CK model was developed using piecewise functions embodying an initial cellular expansion followed by bi-phasic contraction. A forward selection and backward elimination stepwise covariate modelling approach was used to add covariates to the model. The focus of covariate modelling was to identify parameter-covariate relationships that can potentially explain the inter-individual variability observed with CK data.

Results:

The exposure-response analyses for ORR indicated that the probability of ORR was around 85% and probability of CR was around 74% across all dose levels and observed range of exposure. The relationship between exposure metrics and efficacy was flat. While the relationship between the incidence of high-grade CRS and exposure was not deemed statistically significant, a higher likelihood of experiencing high-grade CRS was noted with an increase in exposure. Therefore, the lowest dose level of 25 x 10⁶ CAR-T cells was selected as the recommended phase 2 dose (RP2D) for CD19(T2)28z1xx. Developed population CK model was able to effectively characterize multiphasic kinetics estimating parameters such as doubling time, initial decline half-life, and terminal half-life (representing long-term persistence). A covariate search of forward addition and backward elimination on the population CK model indicated that ECOG (Eastern Cooperative Oncology Group) score and transduction efficiency may potentially explain some of the variabilities observed in cellular kinetics. Adequacy of model fitting was further verified by population weighted residuals (PWRES) against population-predicted and time. No values fell outside |PWRES| > 3, indicating that no data points were classified as outliers.

Conclusions:

CD19(T2)28z1xx demonstrated promising efficacy profile across various dose levels and exposure ranges. Selection of the lowest dose (25 x 10⁶ CAR-T cells) for RP2D was supported by exposure response analyses, emphasizing the importance of optimizing strategies for efficacy and safety. While there is no ongoing clinical trial with CD19(T2)28z1xx, this recommended dose has the potential for further development.

Dey:Takeda Development Center Americas, Inc.: Current Employment. Li:Takeda Development Center Americas, Inc.: Ended employment in the past 24 months. Park:Autolus, Fate Therapeutics, Genentech, InCyte, Servier, Sobi, Takeda (Institution): Research Funding; Curocell: Current equity holder in publicly-traded company; Takeda: Consultancy; Adaptive Biotechnologies, Affyimmune, Allogene, Amgen, Artiva Biotherapeutics, Autolus, Bright Pharmaceutical Services, BMS, Caribou Biosciences, Curocell, Galapagos, Gilead Sciences, Intellia, In8Bio, Kite, Novartis, Pfizer, Servier, Sobi, Synthekine: Consultancy. Sellner:Takeda Development Center Americas, Inc.: Current Employment. Sundaresan:Takeda Development Center Americas, Inc.: Current Employment; Rubius Therapeutics, Inc: Ended employment in the past 24 months; Moderna, Inc: Current Employment. Palomba:Cellectar: Consultancy; Synthekine: Consultancy; Novartis: Consultancy; Bristo Meyer Squibb: Consultancy. Dash:Takeda Development Center Americas, Inc.: Current Employment. Riviere:Takeda Development Center Americas, Inc.: Current Employment, Current equity holder in publicly-traded company. Sadelain:Takeda Development Center Americas, Inc.: Patents & Royalties: Licensed patents and Research Funding ; Mnemo Therapeutics: Current equity holder in publicly-traded company, Patents & Royalties: Licensed Patients and Research Funding ; Fate Therapeutics: Patents & Royalties: Licensed Patents and Research Funding ; Atara Bio: Patents & Royalties: Licensed Patents and Research Funding . Mugundu:Takeda Development Center Americas, Inc.: Current Employment.