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

Ronan T. Swords, Peter L. Greenberg, Andrew H. Wei, Simon Durrant, Anjali S. Advani, Mark S Hertzberg, Ian D. Lewis, Gabriel Rivera, Dita Gratzinger, Alice C. Fan, Dean W. Felsher, Jorge Eduardo Cortes, Justin M. Watts, Geoff T. Yarranton, Jackie M. Walling, Jeffrey E Lancet

Research output: Contribution to journalArticleResearchpeer-review

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 250 mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190 mg. 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.

Original languageEnglish
Pages (from-to)123-131
Number of pages9
JournalLeukemia Research
Volume50
DOIs
Publication statusPublished - 1 Nov 2016

Keywords

  • Acute myeloid leukemia
  • EphA3
  • Ephrin receptor tyrosine kinase
  • KB004
  • Myelodysplastic syndromes
  • Myelofibrosis

Cite this

Swords, Ronan T. ; Greenberg, Peter L. ; Wei, Andrew H. ; Durrant, Simon ; Advani, Anjali S. ; Hertzberg, Mark S ; Lewis, Ian D. ; Rivera, Gabriel ; Gratzinger, Dita ; Fan, Alice C. ; Felsher, Dean W. ; Cortes, Jorge Eduardo ; Watts, Justin M. ; Yarranton, Geoff T. ; Walling, Jackie M. ; Lancet, Jeffrey E. / 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. In: Leukemia Research. 2016 ; Vol. 50. pp. 123-131.
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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 250 mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190 mg. 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.",
keywords = "Acute myeloid leukemia, EphA3, Ephrin receptor tyrosine kinase, KB004, Myelodysplastic syndromes, Myelofibrosis",
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Swords, RT, Greenberg, PL, Wei, AH, Durrant, S, Advani, AS, Hertzberg, MS, Lewis, ID, Rivera, G, Gratzinger, D, Fan, AC, Felsher, DW, Cortes, JE, Watts, JM, Yarranton, GT, Walling, JM & Lancet, JE 2016, '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', Leukemia Research, vol. 50, pp. 123-131. https://doi.org/10.1016/j.leukres.2016.09.012

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. / Swords, Ronan T.; Greenberg, Peter L.; Wei, Andrew H.; Durrant, Simon; Advani, Anjali S.; Hertzberg, Mark S; Lewis, Ian D.; Rivera, Gabriel; Gratzinger, Dita; Fan, Alice C.; Felsher, Dean W.; Cortes, Jorge Eduardo; Watts, Justin M.; Yarranton, Geoff T.; Walling, Jackie M.; Lancet, Jeffrey E.

In: Leukemia Research, Vol. 50, 01.11.2016, p. 123-131.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies

T2 - Results from a phase 1 study

AU - Swords, Ronan T.

AU - Greenberg, Peter L.

AU - Wei, Andrew H.

AU - Durrant, Simon

AU - Advani, Anjali S.

AU - Hertzberg, Mark S

AU - Lewis, Ian D.

AU - Rivera, Gabriel

AU - Gratzinger, Dita

AU - Fan, Alice C.

AU - Felsher, Dean W.

AU - Cortes, Jorge Eduardo

AU - Watts, Justin M.

AU - Yarranton, Geoff T.

AU - Walling, Jackie M.

AU - Lancet, Jeffrey E

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Y1 - 2016/11/1

N2 - 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 250 mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190 mg. 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.

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KW - EphA3

KW - Ephrin receptor tyrosine kinase

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KW - Myelodysplastic syndromes

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