Treatment with the CD33/CD3 bivalent, bispecific antibody AMV564 demonstrated clinical activity in patients with relapsed and refractory acute myeloid leukemia (AML) with a tolerable safety profile, according to results from a first-in-human trial presented by lead investigator Peter Westervelt, MD, PhD, at the 23rd Congress of the European Hematology Association.
Even at low doses (≤50 mcg), the agent showed evidence of reducing bone marrow (BM) blasts, activating T cells, and reducing spleen size, the researchers reported. “AMV564 has distinctive pharmacokinetic features, compared with smaller monovalent bispecific agents,” Dr. Westervelt, from the Washington University School of Medicine in St. Louis, told ASH Clinical News. “In this ongoing trial, we observed a prolonged half-life of approximately two days that was associated with gradual drug accumulation and manageable cytokine release syndrome (CRS) at higher doses.”
The early-phase trial enrolled 17 patients with AML who had received one or two prior induction regimens consisting of a hypomethylating agent or standard anthracyclinebased therapy. Most (83%) had secondary AML and/or adverse cytogenetics and a history of receiving at least one salvage regimen (75%). Seven patients also had received one or more intensive chemotherapybased regimens (58%).
Over 14 consecutive days, the investigators administered AMV564 through continuous intravenous infusion for up to two cycles of induction at the following dosing levels:
- 0.5 mcg/day
- 1.5 mcg/day
- 5.0 mcg/day
- 15 mcg/day
- 50 mcg/day
The most common grade 1 or 2 adverse events (AEs) included peripheral edema, pyrexia, cough, nausea, pneumonia, and fatigue. During and following therapy, there were no reports of treatment-related grade ≥3 AEs through the 50-mcg dose. Although four patients (20%) reported grade 3 febrile neutropenia, the investigators found no association between AMV564 therapy and these events. There also were no observations of CRS in the ≤15 mcg/day dose levels, but one patient experienced manageable grade 2 CRS in the 50 mcg/day dose cohort.
In 10 of the 16 patients who were considered evaluable at the data cutoff point, investigators observed reductions in BM blasts ranging from 13 to 38 percent. Among patients whose disease progressed following cycle one (n=3), two showed reductions in BM blasts following the second cycle.
One patient with a history of myelodysplastic syndromes experienced a rapid hemoglobin increase of >4 g/dL. This patient also achieved transfusion independence and experienced an increase in absolute neutrophil count to >2,400/mm3, suggesting evidence of AMV564 clearing myeloid-derived suppressor cells from the peripheral blood; however, these data are preliminary, Dr. Westervelt noted.
“Overall, the drug was well tolerated as a 14-day continuous infusion, with no dose-limiting toxicity or off-target effects, and [there was] no mortality at 30 days,” he added. “Modest evidence of activity was observed, manifested by inflammatory cytokine profiles, T-cell activation markers, and reductions in BM blast counts, demonstrating ‘proof of biology’ even at the relatively low doses studied to date.”
“T-cell mediated immunotherapies, such as T-cell engagers, have the potential for broad activity to overcome resistance to chemotherapy,” Dr. Westervelt concluded. “If the ongoing study confirms a wide therapeutic window and lack of non-hematologic toxicity, AMV564 may be an ideal partner for use with other anti-leukemic agents, including standard chemotherapy or targeted agents such as inhibitors of FLT3 and IDH1/2.”
Dr. Westervelt reports a financial relationship with Amphivena, the manufacturer of AMV564 and sponsor of the trial.
Westervelt P, Roboz GJ, Cortes JE, et al. 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). Abstract #S859. Presented at the 23rd Congress of the European Hematology Association, June 16, 2018; Stockholm, Sweden.