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

Background: Overexpression of CD123, the alpha subunit of the IL-3 receptor, is characteristic of a number of hematological malignancies, including acute myeloid leukemia (AML), thus providing an attractive candidate for targeted therapeutic approaches in this disease. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprising a novel anti-CD123 antibody coupled, via a peptide linker, to a unique DNA-alkylating payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class of cytotoxic compounds. Preclinically, IMGN632 exhibited potent antitumor tumor activity, with a wide therapeutic index, in models of AML. Confirming preclinical expectations, encouraging single-agent activity and manageable tolerability have emerged for IMGN632 in the ongoing Phase I trial in patients with CD123-positive AML (NCT03386513). Recently, preclinical data from AML mouse models were presented demonstrating synergy in combinations with azacitidine or venetoclax (EHA 2019), supporting the exploration of these combinations in this upcoming clinical trial. Study Design and Methods: This Phase 1b/2 study is designed to determine the safety, tolerability, and preliminary antileukemia activity of IMGN632 when administered in combination with azacitidine and/or venetoclax to patients with relapsed and frontline CD123-positive AML. Building on the encouraging activity observed in the Phase I study, the single-agent activity of IMGN632 in patients with minimal residual disease (MRD)-positive AML after frontline treatment will be assessed. Three combination regimens will be evaluated: Regimen A, IMGN632 plus azacitidine (632+AZA); Regimen B, IMGN632 plus venetoclax (632+VEN); and Regimen C, IMGN632 plus azacitidine and venetoclax (632+AZA+VEN). For each regimen, a Phase 1b dose escalation cohort (~24 patients) will determine the recommended Phase 2 dose (RP2D) of IMGN632 for the specific combination. This will be followed by a Phase 2 dose expansion stage to further characterize the safety profile and assess antileukemia activity of each combination (~35 patients/cohort). In addition, IMGN632 monotherapy will be explored in an expansion cohort of MRD-positive patients to assess conversion rate from MRD+ to MRD-. Adult patients with CD123-positive, relapsed or refractory AML, an Eastern Cooperative Group (ECOG) performance status ≤ 1, and who are deemed appropriate for experimental therapy, are eligible to enroll as part of the dose escalation phase. Key exclu