P555: A PHASE 1B/2 STUDY OF THE CD123-TARGETING ANTIBODY-DRUG CONJUGATE PIVEKIMAB SUNIRINE (IMGN632) IN COMBINATION WITH VENETOCLAX (VEN) AND AZACITIDINE (AZA) FOR PATIENTS WITH CD123-POSITIVE AML

Abstract

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. With limited expression on normal hematopoietic progenitor cells, the CD123 antigen is an attractive target for 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 IGN (indolinobenzodiazepine pseudodimer) class. In preclinical models of AML, IMGN632 exhibited potent anti-leukemia activity, with a wide therapeutic index. Confirming preclinical expectations, encouraging single-agent activity has emerged for IMGN632 in the ongoing Phase I trial in patients with CD123-positive BPDCN and AML (Daver. Blood (2019) 134 (Supplement_1):734.). Preclinical data have demonstrated increased activity with the addition of IMGN632 to AZA alone and to AZA+VEN in multiple AML xenograft and PDX models, leading to improved survival in these models (Kuruvilla. Blood (2019) 134 (Supplement_1):1375.). We have reported compelling activity (ORR 59% and CCR rate 38%) of the IMGN632 triplet in relapsed or refractory AML patients (Daver. ASH 2021 Abstract #372). The safety profile of the triplet included rates of cytopenias similar to those observed with AZA+VEN; additional low-grade adverse events included infusion-related reactions, dyspnea, fatigue, gastrointestinal toxicities, electrolyte imbalances, and pneumonia. Aims: This Phase 1b/2 study is designed to determine the safety, tolerability, and preliminary anti-leukemia activity of IMGN632 when administered in combination with AZA and VEN to patients with relapsed and frontline CD123-positive AML. Methods: Dose escalation for the IMGN632+AZA+VEN triplet is complete. The Recommended Phase 2 Dose levels are: IMGN632 45 mcg/kg given on day 7 with 14 days of VEN, and either AZA 50 OR 75 mg/m2 for 7 days of a 28-day cycle. Results: N/A Summary/Conclusion: Phase 2 expansion cohorts for patients with untreated/frontline and relapsed AML are enrolling to further characterize the safety profile and assess the antileukemic activity. NCT04086264