A Phase 1b/2 Study of the CD123-Targeting Antibody-Drug Conjugate IMGN632 As Monotherapy or in Combination with Venetoclax and Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia

Background: Overexpression of CD123 is characteristic of a number of hematological malignancies, including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) with a novel anti-CD123 antibody coupled to a unique DNA-alkylating payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class of payloads. In preclinical models of AML, IMGN632 exhibited potent anti-leukemia activity, with a wide therapeutic index. Confirming preclinical expectations, encouraging single-agent activity and favorable tolerability were observed in the Phase I trial (Daver ASH 2019, Blood 2019, vol 134, suppl 1, 734). Preclinical data from AML xenograft models have demonstrated synergy in IMGN632 combinations with azacitidine and venetoclax (Kuruvilla ASH 2020, Blood 2020, vol 136, suppl 1, 32-33), supporting the exploration of these combinations in AML patients. Methods: This Phase 1b/2 study is designed to determine the safety, tolerability, and preliminary anti-leukemia activity of IMGN632 when administered in combination with azacitidine and venetoclax to patients with relapsed and frontline CD123-positive AML, and the single-agent activity of IMGN632 in patients with minimal residual disease (MRD)-positive AML in frontline or 1 st salvage treatment. Study Design: Adult patients with CD123-positive relapsed or refractory AML, who are deemed appropriate for experimental therapy, are eligible to enroll as part of the dose escalation phase. Key exclusion criteria for all regimens include active central nervous system disease, and history of sinusoidal obstruction syndrome/venous occlusive disease of the liver. Current enrollment is focused on the triplet, IMGN632 plus azacitidine and venetoclax (IMGN632+AZA+VEN). Once an RP2D is selected, Phase 2 dose expansion will further characterize the safety profile and assess antileukemia activity in frontline or relapsed AML patients. In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD+ to MRD- and RFS in both fit and unfit AML subpopulations (NCT04086264). IMGN632 is also being tested as a monotherapy in a pivotal cohort for adults with frontline BPDCN (NCT03386513, https://BPDCNtrial.com). Daver: FATE Therapeutics: Research Funding; Sevier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Hanmi: Research Funding; Genentech: Consul