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Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers
Open accessAbstract
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.
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PIM inhibitors have not met expectations in clinical trials.
“Although initially promising as therapeutic targets, PIM inhibitors have not met expectations in clinical trials15”
From Endothelial Pim3 kinase protects the vascular barrier during lung metastasis (2024) · cites this paper as [15]
The Results > Efficacy section reports no clinical responses to AZD1208 in the AML study and a 0% objective response rate in the solid-tumour study. But the Discussion also reports therapeutic efficacy for another PIM inhibitor, LGH447, so these findings do not establish that PIM inhibitors generally have fallen short in clinical trials. Page numbers were not provided in our copy. (LLM, conf=0.87)
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PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer
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Endothelial Pim3 kinase protects the vascular barrier during lung metastasis
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Metadata
- Authors
- 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.
- Affiliations
- National Cancer Center Hospital (JP)
- Dana-Farber Cancer Institute (US)
- Royal Marsden NHS Foundation Trust (GB)
- Princess Margaret Cancer Centre (CA)
- Washington University in St. Louis (US)
- The University of Texas MD Anderson Cancer Center (US)
- AstraZeneca (United States) (US)
- AstraZeneca (United Kingdom) (GB)
- The Christie NHS Foundation Trust (GB)
- Corresponding author
- Dean, Emma
- ORCID
- Venue
- British Journal of Cancer
- Published
- 2018-05
- Volume
- 118
- Issue
- 11
- Pages
- 1425-1433
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC5988656
- OpenAlex
- W2803557794
- Cited by
- 120
- References
- 25
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 15 · 2023: 19 · 2022: 17 · 2021: 14 · 2020: 16 · 2019: 7 · 2018: 1
- FWCI
- 7.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- British Journal of Cancer (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- AstraZeneca (CA016672)
- Leukemia and Lymphoma Society (P30 CA016672)
- National Cancer Institute (P01CA066996)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- AZD1208, PIM kinase inhibitors, acute myeloid leukemia, solid tumors, hematologic malignancies, dose-limiting toxicity, gastrointestinal adverse effects, CYP3A4 induction, pharmacokinetics, pharmacodynamics, maximum tolerated dose, ATP-competitive kinase inhibitors
- MeSH terms
- Adult, Aged, Aged, 80 and over, Biphenyl Compounds, Female, Humans, Male, Middle Aged, Neoplasms, Up-Regulation, Gene Expression Regulation, Neoplastic, Hematologic Neoplasms, Maximum Tolerated Dose, Protein Kinase Inhibitors, Cytochrome P-450 CYP3A, Thiazolidines, Young Adult
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