Determining drug dose in the era of targeted therapies: playing it (un)safe?
Sigrid S Skånland1,2, Geir E Tjønnfjord3,4
1Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. sigrid.skanland@ous-research.no.
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.
Insights
Optimizing targeted therapy for chronic lymphocytic leukemia (CLL) requires prioritizing pharmacodynamic biomarkers over traditional toxicity-driven trials. Lowering doses based on biomarkers can reduce severe side effects and maintain treatment efficacy.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Targeted therapies including PI3K, BTK, and BCL-2 inhibitors are approved for chronic lymphocytic leukemia (CLL).
- Next-generation targeted agents are continually developed, yet dose selection in early trials often overlooks molecular target engagement.
- Traditional toxicity-driven trial designs persist despite the distinct dose-response of targeted agents.
Purpose of the Study:
- To review dose selection strategies in phase I trials of targeted therapies for CLL.
- To discuss the underutilization of pharmacodynamic biomarkers in determining optimal doses.
- To explore strategies like dose reduction and intermittent dosing to manage intolerance and resistance.
Main Methods:
- Review of phase I trial designs for approved and investigational targeted therapies in CLL.
- Analysis of dose-finding studies, focusing on BTK occupancy and pharmacodynamic biomarker integration.
- Examination of clinical experience with dose reductions, intermittent schedules, and combination therapies.
Main Results:
- Current phase I trials for targeted CLL therapies often do not determine minimum effective doses based on target occupancy.
- Pharmacodynamic biomarker-guided dose selection could lead to lower recommended phase II doses compared to toxicity-driven approaches.
- Retrospective data suggest non-inferior outcomes with clinically indicated dose reductions.
Conclusions:
- Relying on toxicity-driven designs for targeted therapies may lead to suboptimal dosing.
- Integrating pharmacodynamic biomarkers can potentially lower doses, reduce toxicity, and maintain efficacy in CLL treatment.
- Dose reduction, intermittent dosing, and combination strategies are crucial for managing treatment intolerance and resistance in CLL.
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