PII-103 - CLINICAL PHARMACOLOGY CHARACTERIZATION OF BLINATUMOMAB FROM SUBCUTANEOUS (SC) DOSING IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL)

H. Wong¹, F. Chandra², G. Zugmaier³, P. Gordon², H. Penny², S. Doshi², V. Upreti¹; ¹Amgen, South San Francisco, CA, USA, ²Amgen, Thousand Oaks, CA, USA, ³Amgen, Munich, Bayern, Germany.

Background: Blinatumomab is a CD19-CD3 bispecific T-cell engager (BiTE®) molecule approved for treatment of R/R B-ALL by continuous intravenous infusion (cIV). SC delivery simplifies treatment administration and improves convenience for pts. Here, we present the clinical pharmacology results for SC blinatumomab in pts with R/R B-ALL.

Methods: In a Phase 1 study (NCT04521231), pts with R/R B-ALL received SC blinatumomab once daily (QD) in week (wk) 1 followed by 3 times weekly (TIW) in wks 2-4 of cycle 1 and wks 1-4 of later cycles. Doses in cohorts 1, 2, 3, and 4 of dose escalation were 40 µg QD/250 µg TIW (n=6 subjects), 120 µg QD/250 µg TIW (n=3), 250 µg QD/500 µg TIW (n=5), and 500 µg QD/1000 µg TIW (n=8), respectively. Exposure metrics including maximum concentration and area under the concentration-time curve were estimated using noncompartmental and population PK methods. Exposure-response analyses were conducted to assess the relationships between exposure metrics and efficacy (complete remission with full or partial hematologic recovery [CR/CRh]) and safety (cytokine release syndrome [CRS] and neurologic events [NE]) endpoints.

Results: SC blinatumomab administration in pts with R/R B-ALL exhibited an encouraging PK/PD profile. Consistent SC bioavailability with dose-related increase in exposures was observed without any treatment-emergent immunogenicity. Relative to cIV, the SC PK profile results in a slow gradual increase in exposure that allows for achieving early efficacious exposures from the first wk of dosing that is consistent with preliminary efficacy results at doses with a manageable safety profile. Also, increase of apparent elimination half-life relative to cIV allows for convenience in administration. Exposure-response analyses for efficacy and safety indicated exposure-related increase in CR/CRh and no clear relationships observed between exposure and grade ≥3 adverse events of interest, CRS and NE.

Conclusion: Encouraging SC blinatumomab PK/PD results supported selection of doses for dose expansion. They also contributed to securing Food and Drug Administration agreement for recommended Phase 2 dose selection in the Project Optimus era using non-randomized dose finding, instead of a randomized design, for dose expansion, which provided more flexibility for study conduct.