167: Pharmacokinetics, Pharmacodynamics & Exposure- Response for Neurotoxicity Adverse Events in a Phase Ib/II CARTITUDE-1 Open-Label Study

Statement of Purpose: Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen (BCMA)-directed CAR-T indicated for the treatment of relapsed/refractory multiple myeloma. This study aimed to investigate the pharmacokinetic (PK), pharmacodynamic (PD) profiles and exposure-response (E-R) for neurotoxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS), and Other CAR-T Neurotoxicities (including movement and neurocognitive treatment emergent adverse events [MNTs] defined as “Other Neurotoxicities”) in a Phase Ib/II CARTITUDE-1 study (NCT03548207) using the database for the 2-year-post Last Patient Dosed (LPD) analysis (11 January 2022). Among 97 subjects who received a single intravenous infusion administration of cilta-cel with a targeted dose of 0.75 × 10^6 (range 0.5–1.0 × 10^6) CAR positive viable T-cells per kg body weight, blood CAR transgene levels which were measured by quantitative polymerase chain reaction (qPCR) were used for characterizing PK. PD was measured by serum soluble BCMA (sBCMA) level using ligand binding assay.

Description of Methods & Materials: The non-compartmental analysis (NCA) using Phoenix™ WinNonlin® (Copyright ©1998 - 2018, Certara LP, USA) and summary statistics using SAS (SAS Institute Inc., Cary, NC, USA)/R programming were used for analyzing PK and PD bioanalytical results from subjects’ blood samples. The AUC values were calculated using the linear up-logarithmic down calculation method. Individual t_max, C_max and other PK parameters were derived from actual sampling times. E-R relationship for subjects encountering neurotoxicity AE (categorized by events or grades) was analyzed based on the observed individual PK metrics (C_max and AUC_0-28d, and AUC_0-last) and neurotoxicity AEs (ICANS and Other Neurotoxicities). The results were presented in scatter box plots.

Data & Results: Following a single infusion, cilta-cel exhibited an initial expansion phase (median t_max =12.7 days after infusion) followed by a rapid decline (mean t_1/2 = 23.5 days after infusion) and then a slower decline exhibiting transgene persistence over months (median tbql = 100.0 days after infusion). Among 97 subjects, mean (SD) PK metrics values were 48,692 (27,174) copies/μg genomic DNA for C_max, 504,496 (385380) copies/μg genomic DNA for AUC_0-28d and 1,098,030 (1,387,010) copies/μg genomic DNA for AUC_last. Reduced mean serum sBCMA concentrations reached nadir levels around the lower quantifiable concentration (LLOQ) between Day 78 and Day 100 after a single infusion among 97 subjects. High interindividual variability was observed in both PK and PD results.

Interpretation, Conclusion or Significance: The observed median CAR transgene PK metrics (C_max and AUC_0-28d) in subjects with these neurotoxicity AEs were higher than those in subjects without neurotoxicity AEs. However, there is no clear evidence to draw any conclusion on the association between cilta-cel kinetic or persistence and neurotoxicity AEs in comparison to subjects without neurotoxicity AEs, with the consideration of wide overlapping ranges of PK transgene levels and high interindividual variability. sBCMA increased from nadir were seen in some subjects among 97 subjects, but levels remained lower than baseline sBCMA levels. This reversal of sBCMA levels likely reflects the proliferation of normal BCMA+ plasma cells.

Disclosures: