title: KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study.
abstract: EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.
authors.affiliation: Leukemia Program, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL, United States. Electronic address: rswords@med.miami.edu.
authors.forename: Ronan T
authors.initials: RT
authors.lastname: Swords
authors.affiliation: Stanford Cancer Institute, Stanford, CA, United States.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Greenberg
authors.affiliation: The Alfred Hospital and Monash University, Melbourne, Australia.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Wei
authors.affiliation: The Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Durrant
authors.affiliation: Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Anjali S
authors.initials: AS
authors.lastname: Advani
authors.affiliation: Westmead Hospital, Westmead, Australia.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hertzberg
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis School of Medicine, UC Davis Comprehensive Cancer Center, United States
authors.forename: Brian A
authors.initials: BA
authors.lastname: Jonas
authors.affiliation: The Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
authors.affiliation: Stanford Cancer Institute, Stanford, CA, United States.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rivera
authors.affiliation: Stanford Cancer Institute, Stanford, CA, United States.
authors.forename: Dita
authors.initials: D
authors.lastname: Gratzinger
authors.affiliation: Stanford Cancer Institute, Stanford, CA, United States.
authors.forename: Alice C
authors.initials: AC
authors.lastname: Fan
authors.affiliation: Stanford Cancer Institute, Stanford, CA, United States.
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Leukemia Program, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL, United States.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Watts
authors.affiliation: KaloBios Pharmaceuticals, Inc., South San Francisco, CA, United States.
authors.forename: Geoff T
authors.initials: GT
authors.lastname: Yarranton
authors.affiliation: KaloBios Pharmaceuticals, Inc., South San Francisco, CA, United States.
authors.forename: Jackie M
authors.initials: JM
authors.lastname: Walling
authors.affiliation: H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lancet
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D036121:Receptor, EphA3; D016879:Salvage Therapy; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C000621320:KB004; D047428:Protein Kinase Inhibitors; C491718:EPHA3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D036121:Receptor, EphA3
keywords: Acute myeloid leukemia; EphA3; Ephrin receptor tyrosine kinase; KB004; Myelodysplastic syndromes; Myelofibrosis