Joint TITE-CRM for Dual Agent Dose Finding Studies
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arXiv
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| Main Authors: | , , , |
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| Format: | Preprint |
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2025
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| _version_ | 1866910818756460544 |
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| author | Barnett, Helen Boix, Oliver Kontos, Dimitris Jaki, Thomas |
| author_facet | Barnett, Helen Boix, Oliver Kontos, Dimitris Jaki, Thomas |
| contents | Dual agent dose-finding trials study the effect of a combination of more than one agent, where the objective is to find the Maximum Tolerated Dose Combination (MTC), the combination of doses of the two agents that is associated with a pre-specified risk of being unsafe. In a Phase I/II setting, the objective is to find a dose combination that is both safe and active, the Optimal Biological Dose (OBD), that optimizes a criterion based on both safety and activity. Since Oncology treatments are typically given over multiple cycles, both the safety and activity outcome can be considered as late-onset, potentially occurring in the later cycles of treatment. This work proposes two model-based designs for dual-agent dose finding studies with late-onset activity and late-onset toxicity outcomes, the Joint TITE-POCRM and the Joint TITE-BLRM. Their performance is compared alongside a model-assisted comparator in a comprehensive simulation study motivated by a real trial example, with an extension to consider alternative sized dosing grids. It is found that both model-based methods outperform the model-assisted design. Whilst on average the two model-based designs are comparable, this comparability is not consistent across scenarios. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2502_05072 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Joint TITE-CRM for Dual Agent Dose Finding Studies Barnett, Helen Boix, Oliver Kontos, Dimitris Jaki, Thomas Applications Dual agent dose-finding trials study the effect of a combination of more than one agent, where the objective is to find the Maximum Tolerated Dose Combination (MTC), the combination of doses of the two agents that is associated with a pre-specified risk of being unsafe. In a Phase I/II setting, the objective is to find a dose combination that is both safe and active, the Optimal Biological Dose (OBD), that optimizes a criterion based on both safety and activity. Since Oncology treatments are typically given over multiple cycles, both the safety and activity outcome can be considered as late-onset, potentially occurring in the later cycles of treatment. This work proposes two model-based designs for dual-agent dose finding studies with late-onset activity and late-onset toxicity outcomes, the Joint TITE-POCRM and the Joint TITE-BLRM. Their performance is compared alongside a model-assisted comparator in a comprehensive simulation study motivated by a real trial example, with an extension to consider alternative sized dosing grids. It is found that both model-based methods outperform the model-assisted design. Whilst on average the two model-based designs are comparable, this comparability is not consistent across scenarios. |
| title | Joint TITE-CRM for Dual Agent Dose Finding Studies |
| topic | Applications |
| url | https://arxiv.org/abs/2502.05072 |