Abstract
Background: Overexpression of CD123 occurs in multiple hematological malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), 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. Preclinically, IMGN632 has demonstrated potent activity against BPDCN, AML, and ALL models, with a wide therapeutic index in animal models, as well as 150-fold differential cytotoxicity in AML patient-derived samples compared to normal hematopoietic progenitors (Kovtun. Blood Adv (2018) 2(8):848, Angelova. Haematologica (2019) 104(4):749). In particular, remarkable sensitivity of BPDCN patient-derived xenografts to IMGN632 was demonstrated (Zhang Blood (2018) 132:3956). The clinical safety profile of IMGN632 in BPDCN is characterized by low-grade peripheral edema and infusion reactions, and reversible veno-occlusive disease in < 5%; there have been no capillary leak syndrome and no treatment-related deaths. Data in relapsed or refractory BPDCN led to FDA granting of Breakthrough Therapy Designation for IMGN632 (October 2020). We have previously reported three of three frontline BPDCN patients achieved clinical complete responses (CRc) with duration of response (DOR) of up to 10.7 months without transplant (Pemmaraju. ASH 2021 Abstract #1284). Aims: This study is designed to determine the safety, tolerability, and activity of IMGN632 when administered to patients with frontline BPDCN. Methods: The dose escalation phase identified a recommended phase 2 dose of 0.045 mg/kg given intravenously every 3 weeks. Expansion cohorts include a pivotal cohort for frontline/untreated BPDCN (no prior systemic therapy), and exploratory cohorts for patients with relapsed or refractory BPDCN. Patients with central nervous system disease are not eligible in the frontline BPDCN cohort. Results: N/A Summary/Conclusion: Enrollment continues in the pivotal cohort for frontline/untreated BPDCN patients. CADENZA, https://BPDCNtrial.com, NCT03386513
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