Contributions
Abstract: S859
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 16:30 - 16:45
Location: Room A2
Background
AMV564 is a novel bivalent, bispecific (2x2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T-cell receptors with strong avidity, thus creating an immune synapse between CD33-expressing cells and T cells, initiating T-cell directed lysis of CD33 expressing cells, and inducing expansion, differentiation and proliferation of T cells. By design, AMV564 has reduced renal 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 risk, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res 2016;22:5829-38). AMV564 also selectively eliminated myeloid-derived suppressor cells (MDSC) in myelodysplastic bone marrows at low doses with restoration of immune homeostasis and hematopoiesis (Cheng P et al. Blood 2017;130:51).
Aims
The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of AMV564 pharmacokinetics (PK) is a secondary objective.
Methods
This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). Key inclusion/exclusion criteria are: adults with relapsed and/or 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 for up to 2 induction cycles.
Results
Twelve patients (7M/5F) with a median age of 71 years (range 24-84) have been enrolled in 1 of 4 dosing cohorts: (0.5, 1.5, 5.0, and 15 mcg/day x 14 days). Overall, 83% (10/12) had secondary AML and/or adverse cytogenetics, 75% (9/12) had received at least one prior salvage regimen, and 58% (7/12) had received one or more prior intensive chemotherapy-based regimens. No dose-limiting toxicity, cytokine release syndrome, or treatment-related grade ≥3 adverse events (AE) have been reported. The most common treatment-emergent grade ≥ 3 AE has been febrile neutropenia in 25% (3/12) of patients, but each case was considered unrelated to study drug. The 30-day mortality rate is 0% (0/12). AMV564 PK were linear with a terminal t1/2 of 2-3 days. Plasma concentrations increased gradually, with time to steady-state concentrations of 3-7 days. Reductions in bone marrow blasts ranging from 13% to 38% were observed in 6 of 9 evaluable patients. Two of 3 patients with progression after cycle 1 had a reduction in bone marrow blasts after cycle 2. One patient with prior myelodysplastic syndrome had stable disease with a significant rapid rise in hemoglobin (>4 g/dL), achievement of transfusion-independence, and a rise in the absolute neutrophil count to >2,400/mm3. Preliminary data demonstrated clearing of MDSC from the peripheral blood.
Conclusion
AMV564 is well-tolerated and can be administered without the need for incremental dosing and/or pre-medication. AMV564 has a unique PK profile compared to monovalent T-cell engagers, demonstrating a gradual increase in drug concentration and thus the potential for controlled T-cell activation. In a limited number of patients at the lowest dose levels, AMV564 demonstrated anti-leukemic activity. Dose escalation continues and correlation with T-cell expansion, T-cell activation, cytokine release, and other pharmacodynamic endpoints is ongoing.
Session topic: 4. Acute myeloid leukemia - Clinical
Keyword(s): Acute Myeloid Leukemia, CD33, Immunotherapy, Pharmacokinetic
Abstract: S859
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 16:30 - 16:45
Location: Room A2
Background
AMV564 is a novel bivalent, bispecific (2x2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T-cell receptors with strong avidity, thus creating an immune synapse between CD33-expressing cells and T cells, initiating T-cell directed lysis of CD33 expressing cells, and inducing expansion, differentiation and proliferation of T cells. By design, AMV564 has reduced renal 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 risk, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res 2016;22:5829-38). AMV564 also selectively eliminated myeloid-derived suppressor cells (MDSC) in myelodysplastic bone marrows at low doses with restoration of immune homeostasis and hematopoiesis (Cheng P et al. Blood 2017;130:51).
Aims
The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of AMV564 pharmacokinetics (PK) is a secondary objective.
Methods
This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). Key inclusion/exclusion criteria are: adults with relapsed and/or 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 for up to 2 induction cycles.
Results
Twelve patients (7M/5F) with a median age of 71 years (range 24-84) have been enrolled in 1 of 4 dosing cohorts: (0.5, 1.5, 5.0, and 15 mcg/day x 14 days). Overall, 83% (10/12) had secondary AML and/or adverse cytogenetics, 75% (9/12) had received at least one prior salvage regimen, and 58% (7/12) had received one or more prior intensive chemotherapy-based regimens. No dose-limiting toxicity, cytokine release syndrome, or treatment-related grade ≥3 adverse events (AE) have been reported. The most common treatment-emergent grade ≥ 3 AE has been febrile neutropenia in 25% (3/12) of patients, but each case was considered unrelated to study drug. The 30-day mortality rate is 0% (0/12). AMV564 PK were linear with a terminal t1/2 of 2-3 days. Plasma concentrations increased gradually, with time to steady-state concentrations of 3-7 days. Reductions in bone marrow blasts ranging from 13% to 38% were observed in 6 of 9 evaluable patients. Two of 3 patients with progression after cycle 1 had a reduction in bone marrow blasts after cycle 2. One patient with prior myelodysplastic syndrome had stable disease with a significant rapid rise in hemoglobin (>4 g/dL), achievement of transfusion-independence, and a rise in the absolute neutrophil count to >2,400/mm3. Preliminary data demonstrated clearing of MDSC from the peripheral blood.
Conclusion
AMV564 is well-tolerated and can be administered without the need for incremental dosing and/or pre-medication. AMV564 has a unique PK profile compared to monovalent T-cell engagers, demonstrating a gradual increase in drug concentration and thus the potential for controlled T-cell activation. In a limited number of patients at the lowest dose levels, AMV564 demonstrated anti-leukemic activity. Dose escalation continues and correlation with T-cell expansion, T-cell activation, cytokine release, and other pharmacodynamic endpoints is ongoing.
Session topic: 4. Acute myeloid leukemia - Clinical
Keyword(s): Acute Myeloid Leukemia, CD33, Immunotherapy, Pharmacokinetic