A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Fatih M Uckun, Tara L Lin, Alice S Mims, Prapti Patel, Cynthia Lee, Anoush Shahidzadeh, Paul J Shami, Elizabeth Cull, Christopher R Cogle, Justin Watts, Fatih M Uckun, Tara L Lin, Alice S Mims, Prapti Patel, Cynthia Lee, Anoush Shahidzadeh, Paul J Shami, Elizabeth Cull, Christopher R Cogle, Justin Watts

Abstract

APVO436 is a recombinant T cell-engaging humanized bispecific antibody designed to redirect host T cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). In this first-in-human (FIH) multicenter phase 1B study, we sought to determine the safety and tolerability of APVO436 in R/R AML/myelodysplastic syndrome (MDS) patients and identify a clinically active recommended phase 2 dose (RP2D) level for its further clinical development. A total of 46 R/R AML/MDS patients who had failed 1-8 prior lines of therapy received APVO436 as weekly intravenous (IV) infusions at 10 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.3 mcg to 60 mcg. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). The single dose RP2D level was identified as 0.2 mcg/kg. Preliminary efficacy signals were observed in both AML and MDS patients: Prolonged stable disease (SD), partial remissions (PR), and complete remissions (CR) were observed in R/R AML patients as best overall responses to APVO436 at the RP2D level. Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential.

Keywords: AML; APVO436; CD123; MDS; T cells; bispecific antibody; clinical study; leukemia.

Conflict of interest statement

T.L.L., P.P., P.J.S., E.C., C.R.C. and J.W. and their institutions received research funding in the form of investigative site awards from Aptevo Therapeutics for conducting the study. F.M.U., A.S. and C.L. received compensation from Aptevo Therapeutics as a consultant. No other disclosures are reported.

Figures

Figure 1
Figure 1
Simplified schematic explaining the mode of action of APVO436. APVO436 targeting CD123 on AML cells and redirecting CD3+ T cells to the close vicinity of the target leukemia cells. APVO436 is a humanized bispecific antibody that targets both CD123 and CD3. It is composed of two sets of binding domains linked to a human IgG1 Fc domain. The CD123 binding domain is a fully human scFv directed against human CD123. The CD3 binding domain is a humanized scFv that binds human CD3. The Fc region has been engineered to minimize complement fixation and interaction with Fcγ receptors.
Figure 2
Figure 2
Swimmer plot of best overall responses of the eight-patient favorable response population of R/R AML patients. The onset and duration of SD, PR, CR, clearance of peripheral blasts (PBB-C), bone marrow relapse (BM REL), and onset of PD are indicated with specific symbols. Arrow: alive. See Table 4 and text for additional details.
Figure 3
Figure 3
Survival outcome of AML patients according to response to APVO436. Depicted are the overall survival curves of the 8 patients’ favorable responses, 31 patients who did not respond, and all 39 patients combined. Favorable responses of CR, PR, or SD ≥ 3 months was associated with improved overall survival in R/R AML patients treated with APVO436 monotherapy.

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