Introduction: MK-1045 (CN201) is a humanized bispecific IgG4 CD19xCD3 T-cell engager that has shown encouraging safety, tolerability, and preliminary efficacy in participants with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) (Wang et al. J Clin Oncol. 2024;42(16_suppl):6505; data cutoff: April 22, 2024). Here we report updated safety and efficacy data for adult participants from dose escalation and expansion of the ongoing open-label, multicenter, phase 1b/2 study (NCT05579132).

Methods: Participants with R/R B-ALL, >5% bone marrow blasts and an ECOG PS of 0 to 2 were eligible. Escalating doses of MK-1045 were administered intravenously once per week with a 2-step, step-up dosing approach during cycle 1 comprising a priming dose on day 1 followed by the intermediate dose on day 8; the target dose was administered on day 15 and weekly thereafter, with a 28-day treatment cycle. Key primary objectives for phase 1b were to assess safety, tolerability, and dose-limiting toxicities (DLTs) and to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included assessment of efficacy (including rates for complete remission (CR), CR with incomplete hematologic recovery (CRi), CR with partial hematologic recovery (CRh), and minimal residual disease (MRD) negativity.

Results: As of the data cutoff date (April 25, 2025), 75 participants were enrolled and had been treated at 10 dose levels ranging from 0.15/0.3/0.6 mg (priming/intermediate/target dose) to 2/20/90 mg. The median follow-up time was 15.8 months (range, 0.5-29.7). Median age was 46.0 years (range, 18-73); 39 (52%) were male, 21 (28%) had a Ph-positive diagnosis, 33 (44%) relapsed within 12 months after first remission, and 52 (69%) had an ECOG PS of 1. The median number of prior lines of therapy was 2.0 (range, 1-8); 7 participants (9%) received blinatumomab, 5 (7%) CAR T-cell therapy, and 11 (15%) an allogeneic stem cell transplant. No DLTs occurred, and the MTD was not reached. Treatment-emergent adverse events (AEs) of any grade occurred in 75 participants (100%); grade 3-5 treatment-emergent AEs occurred in 67 participants (89%). Death due to an AE occurred in 1 participant (1%; due to hemoptysis), which was determined to be unrelated to MK-1045. Treatment interruption due to an AE occurred in 25 participants (33%, most commonly due to infections in 11% of participants). Dose reduction due to an AE occurred in 1 participant (1%; due to abnormal hepatic function), and no treatment discontinuations occurred due to an AE. The most frequent AEs were white blood cell decreased (80%; grade ≥3: 63%), neutrophil count decreased (72%; grade ≥3: 59%), platelet count decreased (65%; grade ≥3: 41%), and lymphocyte count decreased (60%; grade ≥3: 60%). Cytokine release syndrome occurred in 34 participants (45%) with 2 participants (3%) experiencing grade 3 events. Neurotoxicity AEs occurred in 11 participants (15%); all were grade 1 and 2 and the most frequent AE was headache (n = 6 [8%]). No immune effector cell-associated neurotoxicity syndrome was observed. Among 73 participants with sufficient follow-up to reach an efficacy evaluation, 40 participants (55%) achieved CR/CRi/CRh. For 24 participants who received target doses of ≥60 mg, 20 participants (83%) achieved CR/CRi/CRh and the median duration of complete remission (DoCR) was 11.3 months. A total of 18 of 20 participants who received target doses of ≥60 mg with a CR/CRi/CRh achieved MRD negativity. Among participants with prior exposure to blinatumomab or CAR T-cell therapy who had received a target dose ≥60 mg, 5 of 5 participants achieved CR/CRi/CRh and 4 achieved MRD negativity. Among participants treated at the highest dose level evaluated to date 2/20/90, 11 of 12 participants (92%) achieved a CR/CRi/CRh with median DoCR not reached. 10 of 11 (91%) of the participants with CR/CRi/CRh achieved MRD negativity. Evaluation of RP2D is ongoing.Conclusion: The safety profile of MK-1045 in adult participants with R/R B-ALL has been generally manageable with dose modifications and standard medical care. MK-1045 has shown encouraging single agent antitumor activity in adult participants with R/R B-ALL, achieving a CR/CRi/CRh rate of 92% at the 2/20/90 mg dose level.

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2025
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