@article{d0109d06bdbd435791cf75687c7c7617,
title = "Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA",
abstract = "APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients{\textquoteright} T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.",
keywords = "AML – acute myeloid leukaemia, CD123 expression, bispecific antibody (bsAb), myelodysplastic and myeloproliferative syndromes, venetoclax (BCL2 inhibitor)",
author = "Justin Watts and Lin, {Tara L.} and Alice Mims and Prapti Patel and Cynthia Lee and Anoush Shahidzadeh and Paul Shami and Elizabeth Cull and Cogle, {Christopher R.} and Eunice Wang and Uckun, {Fatih M.}",
note = "Funding Information: This study received funding from Aptevo Therapeutics. The funder had the following involvement with the study: 1. Provided funding to a clinical research organization for the operationalization of the study by clinical monitoring, medical monitoring, pharmacovigilance, and data management; 2. Provided site awards to the investigative sites to compensate the sites for their clinical research expenses; and 3. Sponsored the IND, funded the regulatory affairs and quality assurance activities to ensure ICH/GCP compliance. The sponsor did not Funding Information: The authors thank the patients who participated in this trial and their families, the coinvestigators, nurses, and study coordinators at each of the participating sites. The study was performed at the following 10 centers in the US as an open-label study sponsored by Aptevo Therapeutics: (1) Greenville Health System, Institute for Translational Oncology Research, Greenville, South Carolina, United States, 29605; (2) The University of Kansas Clinical Research Center, Westwood, Kansas, United States, 66205; (3) Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States, 33136; (4) University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah, United States, 84112; (5) The Ohio State University Wexner Medical Center/James Cancer Hospital; Columbus, Ohio, United States, 43210; (6) Roswell Park Cancer Institute; Buffalo, New York, United States, 14263; (7) Fred Hutchinson Cancer Research Center; Seattle, Washington, United States, 98109; (8) University of Texas Southwestern Medical Center, Dallas, Texas, United States, 75390; (9) University of Florida College of Medicine, Gainesville, Florida, United States, 32610; (10) University of California, San Francisco Medical Center, San Francisco, California, United States, 94143. This study was sponsored by Aptevo Therapeutics, which provided APVO436 and worked with investigators to design the study, as well as collect, analyze, and interpret the data. We thank our preferred provider for Clinical Research Organization (CRO) services, Lab Corp Drug Development Team for the medical monitoring, clinical monitoring, program management, data management, and pharmacovigilance services. We thank the Aptevo Lab Personnel for centralizes laboratory services for immunophenotyping by flow cytometry. We thank the research coordinators from the participating clinical sites for their assistance with study coordination and data management. Publisher Copyright: Copyright {\textcopyright} 2022 Watts, Lin, Mims, Patel, Lee, Shahidzadeh, Shami, Cull, Cogle, Wang and Uckun.",
year = "2022",
month = jan,
day = "13",
doi = "10.3389/fonc.2021.806243",
language = "English (US)",
volume = "11",
journal = "Frontiers in Oncology",
issn = "2234-943X",
publisher = "Frontiers Media S. A.",
}