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
Authors: Daver Naval G. , Montesinos Pau , DeAngelo Daniel J. , Wang Eunice S. , Papadantonakis Nikolaos , Deconinck Eric , Erba Harry P. , Pemmaraju Naveen , Lane Andrew A. , Rizzieri David A. , Sweet Kendra L. , Martinelli Giovanni , Tarella Corrado , Todisco Elisabetta , Konopleva Marina Y , Sloss Callum M. , Culm-Merdek Kerry , Wang Jiuzhou , Malcolm Kara E. , Zweidler-McKay Patrick A. , Kantarjian Hagop M. 
Published: November 2019

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 0.045 mg/kg IV Q3W. In cohort 1, a total of 50 relapsed/refractory BPDCN patients are planned to assess the activity of IMGN632 in this population; prior SL-401 is allowed. In cohort 2, 20 relapsed AML patients (1 or 2 prior lines of therapy, and who have previously achieved a complete response) will be enrolled to aid in the design of future monotherapy and combination studies.
Given the rarity of BPDCN, and the lack of therapeutic options for relapsed/refractory patients, enrollment of these patients continues with high priority. Clinical results from this study and the design of the phase 1b/2 combination study are reported in separate abstracts.
Clinical trial information: NCT03386513.

Disclosures
Daver: Agios: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Abbvie: Consultancy, Research Funding; NOHLA: Research Funding; Jazz: Consultancy; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; Astellas: Consultancy; BMS: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Otsuka: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Abbvie: Consultancy, Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Sunesis: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Servier: Research Funding; NOHLA: Research Funding; Celgene: Consultancy; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Research Funding. Montesinos:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. DeAngelo:Abbvie: Research Funding; Glycomimetics: Research Funding; Blueprint: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Papadantonakis:Agios: Consultancy, Honoraria. Erba:Pfizer: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy. Pemmaraju:mustangbio: Consultancy, Research Funding; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Lane:AbbVie: Research Funding; Stemline Therapeutics: Research Funding; N-of-One: Consultancy. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Konopleva:Agios: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Astra Zeneca: Research Funding. Sloss:ImmunoGen: Employment. Culm-Merdek:ImmunoGen Inc: Employment. Wang:ImmunoGen Inc: Employment. Malcolm:ImmunoGen Inc: Employment. Zweidler-McKay:ImmunoGen: Employment. Kantarjian:Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding.