PI-011 - CHARACTERIZING THE RELATIONSHIP BETWEEN CELLULAR KINETICS AND RESPONSE TO SUPPORT DOSING RECOMMENDATIONS FOR CD19-TARGETED 19(T2)28Z1XX CELL THERAPY.

J. Li¹, R. Singh¹, A. Dey¹, L. Sellner¹, R. Liu¹, A. Dash¹, J. Park², M. Palomba², J. Mansilla-Soto², B. Senechal², X. Wang², D. Sikder², V. Bermudez², I. Riviere², M. Sadelain², G. Mugundu¹; ¹Takeda Development Center Americas, Inc., Lexington, MA, USA, ²Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Determining the most optimal dose instead of conventional maximum tolerable dose is promoted for immune-oncology trials by FDA Project Optimus. 19(T2)28z1xx is an autologous chimeric antigen receptor (CAR) T-cell therapy targeted CD19 and with an optimized 1XX CD3 ζ signaling domain. A total of 16 relapsed or refractory diffuse large B-Cell lymphoma adult patients were dosed across 4 dose escalation levels: 25, 50, 100 and 200 million CAR+ T cells. With a 3+3 dose escalation design, the primary objective of phase 1 study was to evaluate tolerability and determine the recommended phase 2 dose.

Methods: Cellular kinetics (CK) in peripheral blood was monitored by flow cytometry and quantitative polymerase chain reaction. CK parameters were calculated using noncompartmental CK analysis; power model and logistic regression model were used for dose proportionality test and exposure-response (E-R) analysis. Multivariate analysis was used to assess the effect of patient and product related factors on E-R relationship.

Results: Robust expansion of CAR+ T cells across dose levels were observed after 19(T2)28z1xx infusion supporting the benefit of enhanced potency due to 1XX CD3 ζ signaling domain. Median time to peak expansion was 14 days (range,7-83.3 days) with persistence of up to 1 year. No dose-exposure relationship was observed with responses seen across all dose levels. Lower LDH and CRP level were associated with better response. No other baseline variables or product characteristics was identified as a significant predictor for response. Onset of higher grade of cytokine release syndrome was observed in patients with higher exposure.

Conclusion: Based on the integrated exposure response analysis, lowest dose (25 million) was identified as expansion cohort dose.