Determining drug dose in the era of targeted therapies: playing it (un)safe?
Abstract Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously u...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-08-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-022-00720-7 |
| _version_ | 1817998986132324352 |
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| author | Sigrid S. Skånland Geir E. Tjønnfjord |
| author_facet | Sigrid S. Skånland Geir E. Tjønnfjord |
| author_sort | Sigrid S. Skånland |
| collection | DOAJ |
| description | Abstract Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously under development. While these therapies act on well-characterized molecular targets, this knowledge is only to some extent taken into consideration when determining their dose in phase I trials. For example, BTK occupancy has been assessed in dose-finding studies of various BTK inhibitors, but the minimum doses that result in full BTK occupancy were not determined. Although targeted agents have a different dose–response relationship than cytotoxic agents, which are more effective near the maximum tolerated dose, the traditional 3 + 3 toxicity-driven trial design remains heavily used in the era of targeted therapies. If pharmacodynamic biomarkers were more stringently used to guide dose selection, the recommended phase II dose would likely be lower as compared to the toxicity-driven selection. Reduced drug doses may lower toxicity, which in some cases is severe for these agents, and are supported by retrospective studies demonstrating non-inferior outcomes for patients with clinically indicated dose reductions. Here, we review strategies that were used for dose selection in phase I studies of currently approved and select investigational targeted therapies in CLL, and discuss how our initial clinical experience with targeted therapies have pointed to dose reductions, intermittent dosing, and drug combinations as strategies to overcome treatment intolerance and resistance. |
| first_indexed | 2024-04-14T03:01:46Z |
| format | Article |
| id | doaj.art-9b49410398f8460089f156da1c1d247e |
| institution | Directory Open Access Journal |
| issn | 2044-5385 |
| language | English |
| last_indexed | 2024-04-14T03:01:46Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj.art-9b49410398f8460089f156da1c1d247e2022-12-22T02:15:53ZengNature Publishing GroupBlood Cancer Journal2044-53852022-08-011281710.1038/s41408-022-00720-7Determining drug dose in the era of targeted therapies: playing it (un)safe?Sigrid S. Skånland0Geir E. Tjønnfjord1Department of Cancer Immunology, Institute for Cancer Research, Oslo University HospitalThe K. G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of OsloAbstract Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously under development. While these therapies act on well-characterized molecular targets, this knowledge is only to some extent taken into consideration when determining their dose in phase I trials. For example, BTK occupancy has been assessed in dose-finding studies of various BTK inhibitors, but the minimum doses that result in full BTK occupancy were not determined. Although targeted agents have a different dose–response relationship than cytotoxic agents, which are more effective near the maximum tolerated dose, the traditional 3 + 3 toxicity-driven trial design remains heavily used in the era of targeted therapies. If pharmacodynamic biomarkers were more stringently used to guide dose selection, the recommended phase II dose would likely be lower as compared to the toxicity-driven selection. Reduced drug doses may lower toxicity, which in some cases is severe for these agents, and are supported by retrospective studies demonstrating non-inferior outcomes for patients with clinically indicated dose reductions. Here, we review strategies that were used for dose selection in phase I studies of currently approved and select investigational targeted therapies in CLL, and discuss how our initial clinical experience with targeted therapies have pointed to dose reductions, intermittent dosing, and drug combinations as strategies to overcome treatment intolerance and resistance.https://doi.org/10.1038/s41408-022-00720-7 |
| spellingShingle | Sigrid S. Skånland Geir E. Tjønnfjord Determining drug dose in the era of targeted therapies: playing it (un)safe? Blood Cancer Journal |
| title | Determining drug dose in the era of targeted therapies: playing it (un)safe? |
| title_full | Determining drug dose in the era of targeted therapies: playing it (un)safe? |
| title_fullStr | Determining drug dose in the era of targeted therapies: playing it (un)safe? |
| title_full_unstemmed | Determining drug dose in the era of targeted therapies: playing it (un)safe? |
| title_short | Determining drug dose in the era of targeted therapies: playing it (un)safe? |
| title_sort | determining drug dose in the era of targeted therapies playing it un safe |
| url | https://doi.org/10.1038/s41408-022-00720-7 |
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