Phase i studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers

Jorge Cortes, Kenji Tamura, Daniel J. Deangelo, Johann De Bono, David Lorente, Mark Minden, Geoffrey L. Uy, Hagop Kantarjian, Lisa S. Chen, Varsha Gandhi, Robert Godin, Karen Keating, Kristen McEachern, Karthick Vishwanathan, Janet Elizabeth Pease, Emma Dean

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Background: Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours. Methods: Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208. Results: Sixty-seven patients received treatment: 32 in the AML study over a 120-900 mg dose range, and 25 in the solid tumour study over a 120-800 mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900 mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208. Conclusions: Despite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents.

Original languageEnglish (US)
Pages (from-to)1425-1433
Number of pages9
JournalBritish Journal of Cancer
Volume118
Issue number11
DOIs
StatePublished - May 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Cortes, J., Tamura, K., Deangelo, D. J., De Bono, J., Lorente, D., Minden, M., Uy, G. L., Kantarjian, H., Chen, L. S., Gandhi, V., Godin, R., Keating, K., McEachern, K., Vishwanathan, K., Pease, J. E., & Dean, E. (2018). Phase i studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers. British Journal of Cancer, 118(11), 1425-1433. https://doi.org/10.1038/s41416-018-0082-1