Phase 1 First-in-Human Trial of AMV564, a Bivalent Bispecific (2:2) CD33/CD3 T-Cell Engager, in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)
Authors: Westervelt Peter , Cortes Jorge E. , Altman Jessica K. , Long Meixiao , Oehler Vivian G. , Gojo Ivana , Guenot Jeanmarie , Chun Patrick , Roboz Gail J. 
Published: February 2020

Background: AMV564 is a novel bivalent, bispecific (2:2) CD33/CD3 T-cell engager that binds CD33 on target cells and CD3 on T-cells leading to T-cell-directed lysis of CD33+ leukemic blasts and myeloid derived suppressor cells (MDSCs), as well as T-cell expansion, differentiation and proliferation. By design, AMV564 has reduced clearance and therefore has a longer half-life (t1/2) than monovalent, bispecific T-cell engagers. In preclinical investigations using both leukemic cell lines and primary cells from AML patients, AMV564 eliminated myeloid blasts with picomolar potency and broad activity independent of cytogenetic or molecular abnormalities, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res. 2016;22:5829-38).
Methods: This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), cytokine changes, and immunophenotyping are secondary objectives. Key inclusion/exclusion criteria are: adults with relapsed/refractory AML after 1-2 prior induction regimens (with a standard anthracycline-based regimen or hypomethylating agent) and no more than 2 prior salvage regimens. AMV564 is administered by continuous intravenous infusion (CIV) for 14 consecutive days over a 28 day cycle, with prophylactic antiemetics, antipyretics, and antihistamines. AMV564 and cytokine (IL2, IL4, IL6, IL8, IL10, TNF-α, and IFN-γ) concentrations were measured by validated immunoassays. T-cell activation was measured using flow cytometry to quantify T cells expressing CD25, CD38, CD69, or HLA-DR.
Results: To date, 36 patients (20 male/16 female) with a median age of 71 years (range 24-85 years) have been enrolled in 10 dose cohorts from 0.5 to 300 mcg/day. Twenty-four patients (67%) had secondary AML and/or adverse cytogenetics, including 9 patients (25%) with a TP53 mutation. Fourteen patients (39%) had received at least 1 prior salvage regimen and 23 (64%) had received prior intensive chemotherapy, including 13 patients (36%) who had received a high-dose (≥ 1 g/m2) cytarabine-based regimen and 1 patient (3%) with prior allogeneic stem cell transplant. At the time of this analysis, 36 patients were evaluable for safety and 35 patients were evaluable for activity. No dose-limiting toxicities were reported. Median duration of treatment was 20 days (range 3-204 days). Using a lead-in dose escalation schedule, no Grade 3 or higher cytokine release syndrome has been observed. The most common Grade ≥3 treatment-emergent AE has been anemia, reported in 4 (11%) patients. No patient has died within 30 days of treatment initiation. Bone marrow blast reductions have been observed in 17 (49%) of 35 efficacy evaluable patients. Objective responses have been observed including 1 complete response (CR) during cycle 1 at the 200 mcg/day assigned dose, 1 CRi (CR with incomplete hematologic recovery) during cycle 2 at the 150 mcg/day assigned dose, and 1 partial response (PR) during cycle 1 at the 100 mcg/day assigned dose. In addition, 3 patients had hematologic improvement in neutrophil counts. AMV564 PK was dose proportional through the 100 mcg/day dose level with a terminal half-life of 2-3 days. Serum concentrations increased gradually, with times to steady-state concentration of 3-7 days. T-cell redistribution from the periphery upon initiation of dosing (consistent with T-cell activation) was observed, as was evidence of increased bone marrow T-cells with repeated cycles of treatment.
Conclusions: AMV564 is well-tolerated and demonstrates anti-leukemic activity through T-cell engagement.

Disclosures
Cortes: Sun Pharma: Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Altman:Novartis: Consultancy; Cancer Expert Now: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PeerView: Speakers Bureau; prIME Oncology: Speakers Bureau; France Foundation: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy; NCCN: Consultancy. Gojo:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Merck: Research Funding; Juno: Research Funding; Amgen Inc: Consultancy, Honoraria, Research Funding; Amphivena: Research Funding. Guenot:Amphivena Therapeutics, Inc.: Employment. Chun:Amphivena Therapeutics, Inc: Employment. Roboz:Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees.