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Model-Based Adaptive Optimal Design (MBAOD) Improves Combination Dose Finding Designs: an Example in Oncology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
Servier, Clin Pharmacokinet & Pharmacometr Div, Paris, France.
Servier, Clin Pharmacokinet & Pharmacometr Div, Paris, France.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)ORCID iD: 0000-0002-2676-5912
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2018 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 2, article id UNSP 39Article in journal (Refereed) Published
Abstract [en]

Design of phase 1 combination therapy trials is complex compared to single therapy trials. In this work, model-based adaptive optimal design (MBAOD) was exemplified and evaluated for a combination of paclitaxel and a hypothetical new compound in a phase 1 study to determine the best dosing regimen for a phase 2 trial. Neutropenia was assumed as the main toxicity and the dose optimization process targeted a 33% probability of grade 4 neutropenia and maximal efficacy (based on preclinical studies) by changing the dose amount of both drugs and the dosing schedule for the new drug. Different starting conditions (e.g., initial dose), search paths (e.g., maximal change in dose intensity per step), and stopping criteria (e.g., "3 + 3 rule") were explored. The MBAOD approach was successfully implemented allowing the possibility of flexible designs with the modification of doses and dosing schedule throughout the trial. The 3 + 3 rule was shown to be highly conservative (selection of a dosing regimen with at least 90% of the possible maximal efficacy in less than 21% of the cases) but also safer (selection of a toxic design in less than 2% of the cases). Without the 3 + 3 rule, better performance was observed (>67% of selected designs were associated with at least 90% of possible maximal efficacy) while the proportion of DLTs per trial was similar. Overall, MBAOD is a promising tool in the context of dose finding studies of combination treatments and was showed to be flexible enough to be associated with requirements imposed by clinical protocols.

Place, publisher, year, edition, pages
2018. Vol. 20, no 2, article id UNSP 39
Keywords [en]
combination therapy, dose escalation, MBAOD, oncology, recommended dosing regimen
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-386312DOI: 10.1208/s12248-018-0206-9ISI: 000427539900002PubMedID: 29516207OAI: oai:DiVA.org:uu-386312DiVA, id: diva2:1327480
Available from: 2019-06-19 Created: 2019-06-19 Last updated: 2019-06-19Bibliographically approved

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