First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity
<strong>Background:</strong> Bromodomain and extraterminal motif (BET) protein inhibition is a promising cancer treatment strategy, notably for targeting MYC- or BRD4-driven diseases. A first-in-human study investigated the safety, pharmacokinetics, maximum tolerated dose and recommended...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
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Elsevier
2019
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| _version_ | 1797103590846758912 |
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| author | Postel-Vinay, S Herbschleb, K Massard, C Woodcock, V Soria, J-C Walter, AO Ewerton, F Poelman, M Benson, N Ocker, M Wilkinson, G Middleton, MR |
| author_facet | Postel-Vinay, S Herbschleb, K Massard, C Woodcock, V Soria, J-C Walter, AO Ewerton, F Poelman, M Benson, N Ocker, M Wilkinson, G Middleton, MR |
| author_sort | Postel-Vinay, S |
| collection | OXFORD |
| description | <strong>Background:</strong> Bromodomain and extraterminal motif (BET) protein inhibition is a promising cancer treatment strategy, notably for targeting MYC- or BRD4-driven diseases. A first-in-human study investigated the safety, pharmacokinetics, maximum tolerated dose and recommended phase II dose of the BET inhibitor BAY 1238097 in patients with advanced malignancies. <strong>Material and methods:</strong> In this phase I, open-label, non-randomised, multicentre study, patients with cytologically or histologically confirmed advanced refractory malignancies received oral BAY 1238097 twice weekly in 21-day cycles using an adaptive dose-escalation design at a starting dose of 10 mg/week. Model-based dose–response analysis was performed to guide dose escalation. Safety, pharmacokinetics, pharmacodynamics and tumour response were evaluated. <strong>Results:</strong> Eight patients were enrolled at three dose levels (10 mg/week, n = 3; 40 mg/week, n = 3; 80 mg/week, n = 2). Both patients receiving 80 mg/week had dose-limiting toxicities (DLTs) (grade 3 vomiting, grade 3 headache and grade 2/3 back pain). The most common adverse events were nausea, vomiting, headache, back pain and fatigue. Pharmacokinetic analysis indicated a linear dose response with increasing dose. Two patients displayed prolonged stable disease; no responses were observed. Biomarker evaluation of MYC and HEXIM1 expression demonstrated an emerging pharmacokinetic/pharmacodynamic relationship, with a trend towards decreased MYC and increased HEXIM1 expression in response to treatment. <strong>Conclusion:</strong> The study was prematurely terminated because of the occurrence of DLTs at a dose below targeted drug exposure. Pharmacokinetic modelling indicated that an alternate dosing schedule whereby DLTs could be avoided while reaching efficacious exposure was not feasible. Registration number: NCT02369029. |
| first_indexed | 2024-03-07T06:22:13Z |
| format | Journal article |
| id | oxford-uuid:f3140d62-513a-4c8e-baf4-76f987509c4d |
| institution | University of Oxford |
| last_indexed | 2024-03-07T06:22:13Z |
| publishDate | 2019 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:f3140d62-513a-4c8e-baf4-76f987509c4d2022-03-27T12:09:11ZFirst-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f3140d62-513a-4c8e-baf4-76f987509c4dSymplectic Elements at OxfordElsevier2019Postel-Vinay, SHerbschleb, KMassard, CWoodcock, VSoria, J-CWalter, AOEwerton, FPoelman, MBenson, NOcker, MWilkinson, GMiddleton, MR<strong>Background:</strong> Bromodomain and extraterminal motif (BET) protein inhibition is a promising cancer treatment strategy, notably for targeting MYC- or BRD4-driven diseases. A first-in-human study investigated the safety, pharmacokinetics, maximum tolerated dose and recommended phase II dose of the BET inhibitor BAY 1238097 in patients with advanced malignancies. <strong>Material and methods:</strong> In this phase I, open-label, non-randomised, multicentre study, patients with cytologically or histologically confirmed advanced refractory malignancies received oral BAY 1238097 twice weekly in 21-day cycles using an adaptive dose-escalation design at a starting dose of 10 mg/week. Model-based dose–response analysis was performed to guide dose escalation. Safety, pharmacokinetics, pharmacodynamics and tumour response were evaluated. <strong>Results:</strong> Eight patients were enrolled at three dose levels (10 mg/week, n = 3; 40 mg/week, n = 3; 80 mg/week, n = 2). Both patients receiving 80 mg/week had dose-limiting toxicities (DLTs) (grade 3 vomiting, grade 3 headache and grade 2/3 back pain). The most common adverse events were nausea, vomiting, headache, back pain and fatigue. Pharmacokinetic analysis indicated a linear dose response with increasing dose. Two patients displayed prolonged stable disease; no responses were observed. Biomarker evaluation of MYC and HEXIM1 expression demonstrated an emerging pharmacokinetic/pharmacodynamic relationship, with a trend towards decreased MYC and increased HEXIM1 expression in response to treatment. <strong>Conclusion:</strong> The study was prematurely terminated because of the occurrence of DLTs at a dose below targeted drug exposure. Pharmacokinetic modelling indicated that an alternate dosing schedule whereby DLTs could be avoided while reaching efficacious exposure was not feasible. Registration number: NCT02369029. |
| spellingShingle | Postel-Vinay, S Herbschleb, K Massard, C Woodcock, V Soria, J-C Walter, AO Ewerton, F Poelman, M Benson, N Ocker, M Wilkinson, G Middleton, MR First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity |
| title | First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity |
| title_full | First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity |
| title_fullStr | First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity |
| title_full_unstemmed | First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity |
| title_short | First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity |
| title_sort | first in human phase i study of the bromodomain and extraterminal motif inhibitor bay 1238097 emerging pharmacokinetic pharmacodynamic relationship and early termination due to unexpected toxicity |
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