ASH 2018 | AMG 330, a BiTE® construct, in patients with relapsed/refractory acute myeloid leukemia

Therapeutically targeting immune pathways has radically changed the treatment paradigm for many diseases. At the 60^th Annual Meeting and Exposition of the American Hematology Society, there was an oral abstract session which focused on the new novel immunotherapeutic agents in acute myeloid leukemia (AML). The session was co-chaired by Peter Paschka, MD, from the University Hospital of Ulm and Adriano Venditti, MD, from the University of Rome Tor Vergata.

At this oral session, Farhad Ravandi from the MD Anderson Cancer Center, Houston, TX, presented data from a phase I first-in-human-study (NCT02520427) of AMG 330 in patients with relapsed or refractory (R/R) AML.

AMG 330 is a novel CD33/CD3-directed bispecific T-cell engaging (BiTE®) antibody construct, that can bind to CD33 and CD3 on T cells, facilitating T-cell destruction of CD33+ cells. AMG 330, have been shown to be highly active against CD33+ AML cell lines and can potently lyse leukemic blasts from AML patients. CD33, a 67-kDa type I transmembrane receptor, is expressed by cells of myeloid origin but not by normal hematopoietic cells. In AML, CD33 surface antigen is expressed in approximately 90% of leukemic blast cells.

The phase I dose-escalation study evaluated AMG 330 as a continuous intravenous infusion in patients with R/R AML, with single-patient cohorts for the first 3 doses and subsequently 3–6 patients per cohort. The objectives of this phase I study were to evaluate the safety, pharmacokinetics, and pharmacodynamics of AMG 330 in R/R AML and to estimate the maximum tolerated dose.

Forty patients (median = 58.5 years; range: 18–80) with R/R AML have been enrolled in 12 dose cohorts with a target dose range of 0.5–480 μg/d. After the 30 μg/day cohort, risk mitigation measures for cytokine release syndrome (CRS) were put in place, including step‑dosing and pretreatment with a single dose of corticosteroids. The median number of prior therapies in this group of patients was 4 (range: 1–15).

Key findings:

Safety

• Eighty-eight percent of patients (35/40) discontinued treatment due to disease progression (n = 27), adverse events (AEs; n = 6, 2 treatment-related), and patient request (n = 2)
• Serious AEs (SAEs) were seen in 73% (29/40) of patients; treatment-related in 17
• SAEs occurring in > 1 patient include CRS (n = 11), febrile neutropenia (n = 7), pneumonia (n = 4), leukopenia (n = 4), thrombocytopenia (n = 3), and subdural hematoma (n = 2)
• One patient each in the 10 μg/d and 30 μg/d cohorts (no lead-in) experienced grade 4 CRS, respectively
• Dose-limiting toxicities of grade 2 CRS and grade 4 ventricular fibrillation occurred at the target dose of 480 μg/d
• The target dose was decreased to 240 μg/d

Efficacy

• Two patients achieved complete response (CR) at a target dose of 240 μg/d (lead-in of 10 μg/d→60 μg/d)
  • Patients with CR had a decrease in bone marrow blasts
  • The CRs observed were not sustained beyond one cycle of treatment
• One patient each at target doses of 120 μg/d and 240 μg/d achieved a CR with incomplete count recovery (CRi)
• One patient who received 1.5 μg/d had a morphologic leukemia-free state, < 5% blasts, no hematologic recovery)

The speaker, Farhad Ravandi concluded by stating that the “preliminary data of AMG 330 dosed up to 480 μg/d provide encouraging early evidence of tolerability and anti-leukemic activity in heavily pre-treated patients with R/R AML.” Importantly, expected CRS was alleviated through “step-up dosing, corticosteroid pretreatment, IV fluids, tocilizumab, and drug interruption if needed”. He further added that the findings of the phase I study validate the use of BiTE® platform in targeting CD33 in AML.