Introduction Blinatumomab has been approved to treat patients with B cell precursor acute lymphoblastic leukemia (B-ALL) with 28-day continuous IV infusion. However, the response rate to blinatumomab is unsatisfactory in patients with high tumor burden (NEJM 2017;376:836-847). The continuous dosing schedule is not only inconvenient to patients, but also it can lead to T cell exhaustion as shown by Philipp N. et al. (Blood 2022; 140:1104-1118). Therefore, “Bispecifics need a mindful pause” is proposed to overcome T cell exhaustion during treatment.

A-319 is a humanized CD19 x CD3 bispecific T cell engager (TCE) without Fc fragment. A-319 has the same mechanism of action as blinatumomab but with different pharmacological properties. We investigated if A-319 has the potential to treat r/r B-ALL patients with a dose schedule of “3-day dosing and 4-day pause”, especially for patients with high tumor burden. We report the safety and tolerability, the pharmacokinetics, biomarkers, anti-drug antibodies and efficacy of A-319 in r/r B-ALL patients in the phase I study.

Methods

Forty (Chinese) r/r B-ALL patients (19 male, 21 female), median age 43 yrs (18-65 yrs), were enrolled. Median baseline bone marrow blast was 69% (5-98%), with 83%, 15% and 3% patients being Ph-, Ph+ and Ph-like phenotype, respectively. Patients were enrolled into 6 sequential cohorts with 1 (or 3) + N design. In week (W) 1 (priming), all patients received A-319 at 0.1μg/kg, on days 1, 3 and 5 by 24 hours IV infusion. In W2-W4 (treatment), patients in cohort 1-4 received A-319 at 0.1, or 0.2, or 0.4, or 0.6μg/kg, on days 1, 3 and 5 by 6 hours IV infusion. Patients in cohort 5 (0.8μg/kg) and 6 (2.4μg/kg) were dosed by 24 hours IV infusion, respectively. One treatment cycle consists of 1-W priming and 3-W treatment plus 2-W break. Patients received 2-cycle of treatment. Responders may continue for additional 2 cycles. The study was approved by the local hospital IRBs and registered as CTR20210368 (www.chinadrugtrials.org.cn).

Results Maximum tolerated dose (MTD) was not reached for the study. One DLT occurred at cohort 5 (0.8 µg/kg) by 6 hours IV dosing. The most common (overall incidence ≥ 20%) TEAEs (Treatment Emergent Adverse Event) of grade 3 or higher were lymphopenia (60.5%), white blood cell counts decreased (52.6%), neutropenia (47.4%), thrombocytopenia (44.7%), anemia (28.9%) and pneumonia (28.9%). Grade 3 infections occurred in 15 patients (39.5%). Two infection-related deaths were reported, one in cohort 2 (last dosing on day 19, cycle 2) and the other in cohort 6 (last dosing on day 19, cycle 1). One disease progression-related death occurred in the Ph+ patient (day 20 after 2-cycle treatment). Grade 2 and 3 CRS (cytokine release syndrome) occurred in 24 (63.2%) and 2 (5.3%) patients, respectively. CRS mainly occurred following the first escalating dose. Grade 2 and 3 neurotoxicity or ICANs (immune effector cell associated neurotoxicity syndrome) occurred in 2 (5.3%) and 2 (5.3%) patients, respectively. One patient in cohort 2 reported grade 4 tumor lysis syndrome. No grade 3 CRS, and 1 grade 3 neurotoxicity were reported in cohort 6. No patient developed anti-A-319 antibodies during the study.

Overall, a total of 32 patients had completed at least one cycle treatment. No CR was observed from cohort 1-3. One CR reported each in cohort 4 and 5, In cohort 6 (n=19), 11/19 (57.9%) patients achieved CR, and 3/19 (15.8%) patients achieved CRi, and 13/14 (92.9%) responders achieved MRD-after one-cycle treatment. After 2-cycle treatment, 11/12 (91.7%) patients achieved CR and 10/11 (90.9%) patients achieved MRD-, respectively. In patients with high tumor burden (BM blast > 50%) in cohort 6, 9/13 (69%) patients achieved CR+CRi, while patients with lower tumor burden (BM blast < 50%) achieved 83% (5/6) CR+CRi after one cycle treatment.

Conclusions When administered at 3-day (D1, D3, D5) dosing with 4-day (D2, D4, D6-D7) pause schedule, A-319 (1.2μg/kg/day) demonstrated a tolerable safety profile with a high CR and MRD- rate in r/r B-ALL patients, especially for those patients with high tumor burden. Therefore, further clinical study is warranted.

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2025
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