S877 SAFETY AND CLINICAL ACTIVITY OF AMV564, A CD33/CD3 T‐CELL ENGAGER, IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA (AML): UPDATED RESULTS FROM THE PHASE 1 FIRST‐IN‐HUMAN TRIAL

Background: AMV564 is a novel bivalent, bispecific (2:2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T‐cell receptors. AMV564 creates an immune synapse between CD33‐expressing cells and T cells, initiating T‐cell directed lysis of CD33 expressing cells, and inducing activation, differentiation and proliferation of T cells. In preclinical studies, AMV564 eliminated myeloid blasts with picomolar potency and demonstrated 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). Aims: The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti‐leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), assessment of cytokine changes, and immunophenotyping of T cells and myeloid cells are secondary objectives. Methods: This is an ongoing Phase 1 study with a 3+3 dose‐escalation followed by a dose expansion (NCT03144245). The 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 in a 28 day cycle. Responding patients are eligible to receive additional cycles until disease progression or unacceptable toxicity. AMV564 and cytokine concentrations are measured by validated immunoassays and immunophenotyping is performed by flow cytometry. Results: To date, 30 patients (16 male/14 female) with a median age of 72 years (range 24–84 years) have been enrolled in 8 dose cohorts from 0.5 to 200 mcg/day. Twenty‐two patients (73%) had secondary AML and/or adverse cytogenetics, including 9 patients (30%) with a p53 mutation. Nineteen patients (63%) had received at least 1 prior salvage regimen and 18 (60%) had received prior intensive chemotherapy, including 9 patients (30%) who had received a high‐dose (≥ 1 g/m 2 ) cytarabine‐based regimen. At the time of this analysis, 28 patients were evaluable for safety and 27 patients were evaluable for activity. No dose‐limiting toxicity or treatment‐related Grade ≥ 3 adverse events (AE) were reported. Using a lead‐in dose regimen, Grade 2 CRS was observed in 1 patient (treated at 200 mcg/day) and no Grade 3 or higher CRS has been observed. The most common Grade ≥3 treatment‐emergent AE has been febrile neutropenia, reported in 9 (30%) of 30 patients. No patient has died within 30 days of treatment initiation. Bone marrow blast reductions were observed in 17 (63%) of 27 efficacy evaluable patients. At doses of 100 mcg or higher, objective responses (1 complete response [CR], 1 CR with incomplete hematologic recovery, and 1 partial response) were observed in 3 of 9 evaluable patients. AMV564 PK was dose proportional with a terminal half‐life of 2–3 days. Serum concentrations increased gradually, with times to steady‐state concentration of 3–7 days. Marked increases in serum IL6, IL8, and IL10 were observed with evidence of T‐cell activation in both blood and bone marrow. Summary/Conclusion: AMV564 is well‐tolerated and demonstrates anti‐leukemic activity through T‐cell engagement using a 14‐day administration schedule. AMV564 has a unique PK profile with a gradual increase in drug concentrations and thus the potential for better controlled T‐cell activation.