A Phase 1b/2 Study of the CD123-Targeting Antibody-Drug Conjugate IMGN632 As Monotherapy or in Combination with Venetoclax and/or Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia
Authors: Daver Naval G. , Erba Harry P. , Papadantonakis Nikolaos , DeAngelo Daniel J. , Wang Eunice S. , Konopleva Marina Y , Sloss Callum M. , 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, is characteristic of a number of hematological malignancies, including acute myeloid leukemia (AML), thus providing an attractive candidate for targeted therapeutic approaches in this disease. 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 payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class of cytotoxic compounds. Preclinically, IMGN632 exhibited potent antitumor tumor activity, with a wide therapeutic index, in models of AML. Confirming preclinical expectations, encouraging single-agent activity and manageable tolerability have emerged for IMGN632 in the ongoing Phase I trial in patients with CD123-positive AML (NCT03386513). Recently, preclinical data from AML mouse models were presented demonstrating synergy in combinations with azacitidine or venetoclax (EHA 2019), supporting the exploration of these combinations in this upcoming clinical trial.
Study Design and Methods: This Phase 1b/2 study is designed to determine the safety, tolerability, and preliminary antileukemia activity of IMGN632 when administered in combination with azacitidine and/or venetoclax to patients with relapsed and frontline CD123-positive AML. Building on the encouraging activity observed in the Phase I study, the single-agent activity of IMGN632 in patients with minimal residual disease (MRD)-positive AML after frontline treatment will be assessed.
Three combination regimens will be evaluated: Regimen A, IMGN632 plus azacitidine (632+AZA); Regimen B, IMGN632 plus venetoclax (632+VEN); and Regimen C, IMGN632 plus azacitidine and venetoclax (632+AZA+VEN). For each regimen, a Phase 1b dose escalation cohort (~24 patients) will determine the recommended Phase 2 dose (RP2D) of IMGN632 for the specific combination. This will be followed by a Phase 2 dose expansion stage to further characterize the safety profile and assess antileukemia activity of each combination (~35 patients/cohort). In addition, IMGN632 monotherapy will be explored in an expansion cohort of MRD-positive patients to assess conversion rate from MRD+ to MRD-.
Adult patients with CD123-positive, relapsed or refractory AML, an Eastern Cooperative Group (ECOG) performance status ≤ 1, and who are deemed appropriate for experimental therapy, are eligible to enroll as part of the dose escalation phase. Key exclusion criteria for all regimens include prior treatment with HMAs for myelodysplastic syndrome, active central nervous system disease, or history of sinusoidal obstruction syndrome/venous occlusive disease of the liver. Escalation will follow a standard 3+3 design, with a starting dose for IMGN632 of 0.015 mg/kg administered intravenously on Day 7 of a 21- (632+VEN) or 28-day cycle (632+AZA, 632+AZA+VEN). In the MRD-positive cohort, frontline AML patients must be in complete remission (CR/CRi) for no more than 6 months and be MRD-positive, confirmed by central laboratory testing. IMGN632 monotherapy dosing in this cohort will be 0.045 mg/kg once every 3 weeks. The study is planned to open in October 2019.

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