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

doi:10.3390/cancers13164113

Abstract

Simple SummaryAML is a common form of blood cancer in adults. This study was undertaken to evaluate if AML patients who have failed the available standard treatment options could tolerate and potentially benefit from a new form of therapy. This new therapy activates patients’ own immune system against AML cells. The findings from this research may provide the foundation for a potentially more effective future form of standard therapy that is less likely to fail.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.

Highlights

acute myeloid leukemia (AML) is the most common form of adult acute leukemia, with >20,000 estimated new cases and >11,000 deaths in the United States (US) for 2021 (SEER Program, www.seer.cancer.gov; last accessed on 13 August 2021)
Forty-six patients with R/R AML or myelodysplastic syndrome (MDS) were enrolled in the study between 15/05/18 and 04/06/21
APVO436 was generally well tolerated in the older adults with relapsed AML with manageable toxicity and a promising benefit to risk profile

Summary

Introduction

AML is the most common form of adult acute leukemia, with >20,000 estimated new cases and >11,000 deaths in the United States (US) for 2021 (SEER Program, www.seer.cancer.gov; last accessed on 13 August 2021). 100,000 men and women per year, and the death rate is 2.8 per 100,000 men and women per year Several targeted medicines, such as FLT3 inhibitors, IDH1/2 inhibitors, and BCL-2 inhibitor Venetoclax, as well as biotherapeutics (e.g., antibody-drug conjugates) for AML therapy have been developed and approved by the FDA over the last 10 years [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. There is an urgent and unmet need for effective new treatment modalities for relapsed AML [8,9,10,11,12,13,14,15,16]

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