A phase I/II 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.

Abstract

TPS7563 Background: Overexpression of CD123 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). Methods: This Phase I/II study comprises a dose escalation phase designed to establish the recommended phase II dose (RP2D) for IMGN632, as well as dose expansion cohorts to further explore the safety and preliminary anti-leukemia activity of IMGN632. Expansion cohorts were designed to evaluate the following patient populations: adult patients with relapsed or refractory BPDCN or patients with untreated BPDCN who are inappropriate for available therapies, patients with relapsed or refractory AML, or with other CD123+ relapsed or refractory hematologic malignancies including ALL. Inclusion criteria include up to four prior lines of therapy which may include transplant. Patients with active central nervous system disease, history of veno-occlusive disease of the liver, or history of grade IV capillary leak syndrome or non-cardiac grade IV edema are ineligible. Expansion cohorts for unfit frontline and relapsed/refractory BPDCN, and relapsed/refractory ALL continue to enroll at the RP2D (0.045 mg/kg Q3W). Clinical trial information: NCT03386513 .