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
Autor: | Ronan T, Swords, Peter L, Greenberg, Andrew H, Wei, Simon, Durrant, Anjali S, Advani, Mark S, Hertzberg, Brian A, Jonas, Ian D, Lewis, Gabriel, Rivera, Dita, Gratzinger, Alice C, Fan, Dean W, Felsher, Jorge E, Cortes, Justin M, Watts, Geoff T, Yarranton, Jackie M, Walling, Jeffrey E, Lancet |
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Rok vydání: | 2016 |
Předmět: |
Adult
Male 0301 basic medicine Oncology Cancer Research medicine.medical_specialty Maximum Tolerated Dose Salvage therapy Pharmacology Drug Administration Schedule 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Refractory hemic and lymphatic diseases Internal medicine medicine Humans Infusions Intravenous Myelofibrosis Protein Kinase Inhibitors Aged Aged 80 and over Salvage Therapy business.industry Myelodysplastic syndromes Receptor EphA3 Antibodies Monoclonal Receptor Protein-Tyrosine Kinases Hematology Middle Aged medicine.disease Treatment Outcome 030104 developmental biology Tolerability Hematologic Neoplasms 030220 oncology & carcinogenesis Pharmacodynamics Female business Tyrosine kinase |
Zdroj: | Leukemia Research. 50:123-131 |
ISSN: | 0145-2126 |
Popis: | 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. |
Databáze: | OpenAIRE |
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