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

British Journal of Cancer
Jorge CortesEmma Dean

Abstract

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. 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. 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. Despite the lack of single-agent clinical efficacy with AZD1208, P...Continue Reading

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Citations

Dec 4, 2019·British Journal of Cancer·Paniz Tavakoli ShiraziDeborah L White
Sep 24, 2020·Future Oncology·Athanasios Mavratzas, Frederik Marmé
Oct 30, 2018·Journal of Cancer Prevention·Xinning ZhangZhen-Zhen Liu
Apr 25, 2019·Nature Communications·Kei MiyakawaAkihide Ryo
Feb 7, 2020·Signal Transduction and Targeted Therapy·Sabina LuszczakSusan Heavey
Aug 28, 2020·Expert Opinion on Therapeutic Targets·Pavel Klener
Sep 26, 2020·Nucleic Acids Research·Derrick J Y TanAnh Tuân Phan
Dec 12, 2020·Molecular Cancer Therapeutics·Rachel K Toth, Noel A Warfel
Feb 11, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bruno OyallonCaroline Denevault-Sabourin
Apr 17, 2020·Signal Transduction and Targeted Therapy·Sabina LuszczakSusan Heavey
Feb 14, 2021·Cancer Immunology Research·Gang XinWeiguo Cui
Mar 30, 2021·Arthritis & Rheumatology·Nicola J ManeyArthur G Pratt
Aug 30, 2021·Biochimica Et Biophysica Acta. General Subjects·Aanchal RathiMd Imtaiyaz Hassan

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Methods Mentioned

BETA
ELISA
electrophoresis
protein array
xenograft

Clinical Trials Mentioned

NCT01489722
NCT01588548
NCT01456689
NCT00848601
NCT02144038

Software Mentioned

GraphPad Prism
RECIST

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