A Phase I Study of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia, Blastic Plasmacytoid Dendritic Cell Neoplasm, and Other CD123-Positive Hematologic Malignancies

Background: Overexpression of CD123, the alpha subunit of the IL-3 receptor, occurs in multiple hematological malignancies, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute lymphoblastic leukemia (ALL) and others, thus making this antigen an attractive target for the development of new therapeutics. 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 cytotoxic payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class. Preclinically, IMGN632 has demonstrated potent activity against AML, BPDCN and ALL models, with a wide therapeutic index in animal models, as well as a 150-fold differential cytotoxicity in AML patient samples compared to normal hematopoietic progenitors (PMIDs: 29661755, 30361418). Remarkable sensitivity of BPDCN patient derived xenografts to IMGN632 has been demonstrated (Blood 2018 132:3956). These findings suggest a potential profile of robust efficacy and favorable tolerability in multiple hematologic malignancies. Study Design and Methods: This open-label Phase 1 study comprises a dose escalation phase designed to establish the maximum tolerated dose (MTD) for IMGN632 administered using two dosing schedules, as well as subsequent dose expansion cohorts to further explore the safety and preliminary anti-leukemia activity of IMGN632 in relapsed AML and BPDCN. Adult patients with CD123-positive, relapsed or refractory AML or BPDCN, may be eligible to enroll. Additional inclusion criteria include up to 3 prior lines of therapy (which may include transplant) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Patients with active central nervous system disease, history of veno-occlusive disease of the liver, or history of grade 3-4 capillary leak syndrome or non-cardiac grade 3-4 edema are ineligible. Two schedules have been evaluated during dose escalation: Schedule A, IMGN632 administered intravenously on Day 1 of a 21-day cycle (Q3W); and Schedule B, fractionated dosing (i.e. one-third total dose) of IMGN632 administered on Days 1, 4, and 8 of a 21-day cycle. IMGN632 was escalated from 0.015 to 0.45 mg/kg on Schedule A in both AML and BPDCN patients, and from 0.015 to 0.06 mg/kg on schedule B in patients with AML. Escalation on both schedules is complete. Currently, two expansion cohorts have been opened, with patients receiving IMGN632 at 0.0