Pharmacokinetics of ALETA-001, a CRUK first-in-human phase I/II trial in patients who have received anti-CD19 CAR T-cell therapy for B-cell malignancies

Background: Antigen loss or escape represents a primary mechanism of treatment failure of anti-CD19 CAR T-cell therapy and results in subsequent disease relapse. ALETA-001 is a first-in-class CAR T-cell engager protein that can bridge anti-CD19 CAR T-cells to cancer cells expressing CD20. Following successful preclinical studies, a first-in-human phase I/II trial of ALETA-001 was initiated in patients with B-cell malignancies. We report the pharmacokinetics of ALETA-001 in this ongoing Cancer Research UK phase I/II study. Methods: Eligible patients were diagnosed with B-cell malignancies and had undergone anti-CD19 CAR T-cell therapy. ALETA-001 was administered intravenously as a 2 hour infusion every 2 weeks, with patients receiving 0.4-2.0 mg/kg in cycle 1, and 2.0-6.0 mg/kg in subsequent cycles. Samples for pharmacokinetic analysis were obtained from cycles 1 and 2 at 0, 0.25, 2, 5, 24, 72 and 168 hours post-ALETA-001 administration, and analyzed using a validated ELISA assay. Pharmacokinetic analysis was carried out to determine parameters including C max , area under the curve (AUC), terminal elimination half-life (T 1/2 ), total body clearance (CL), and volume of distribution (Vz) of ALETA-001. Results: Table 1 provides a summary of the pharmacokinetic parameters obtained following ALETA-001 administration (data expressed as range or mean ± SD as appropriate). Comparison of pharmacokinetic data generated following ALETA-001 doses of 0.4 - 6.0 mg/kg suggests general dose proportionality in terms of observed C max and AUC values. Estimates of drug half-life in the current patient cohort indicate an elimination half-life of approximately 4-7 days. Conclusion: Novel pharmacokinetic data for the first-in-class CAR T-cell engager protein ALETA-001 have been generated as part of a first-in-human phase I/II clinical trial. Table 1: Summary of ALETA-001 pharmacokinetic data Group (No. Patients) Dose (mg/kg) Cycle No. of patients in cycle Cmax (µg/mL) AUC (µg/mL.h) T 1/2 (h) CL (mL/h) Vz (L) A (6) 0.4 1 6 5.31 - 13.70 826 ± 197 104.4 ± 7.8 34.2 ± 8.9 5.2 ± 1.6 2 2 6 24.4 - 40.4 5282 ± 592 136.3 ± 23.1 25.8 ± 5.1 5.17 ± 1.7 B (4) 2 1 4 29.5 - 41.4 5657.5 ± 536 170.3 ± 36.4 25.86± 6.0 6.3 ± 2.1 2 3 41.7 - 47.8 6470 ± 1878 133.4 ± 48.8 23.4 ± 5.2 4.3 ± 1.2 6 2 1 77.9 18601 312.5 21.5 9.7