TPS7564 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 have emerged for IMGN632 in the ongoing Phase I trial in patients with CD123-positive AML (ASH 2019, NCT03386513). Preclinical data from AML xenograft models have demonstrated synergy in IMGN632 combinations with azacitidine and venetoclax (EHA 2019), supporting the exploration of these combinations in AML patients. Methods: This Phase Ib/II study is designed to determine the safety, tolerability, and preliminary anti-leukemia activity of IMGN632 when administered in combination with azacitidine and/or 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 after frontline 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. Three combination regimens are being 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 Ib dose escalation cohort will determine the recommended Phase II dose (RP2D) of IMGN632 for the specific combination. This will be followed by a Phase II dose expansion stage to further characterize the safety profile and assess antileukemia activity in frontline or relapsed AML patients, depending on combination regimen. In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD+ to MRD-, in fit and unfit AML subpopulations. Clinical trial information: NCT04086264 .
A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia
