Abstract
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.
Highlights
Anticancer agents used in combination are fundamental to successful cancer treatment
Instead of a simple unidimensional dose–safety profile, both drug dosages can be changed resulting in a continuum of potential MTD, meaning that multiple potential Recommended Phase 2 Doses (RP2Ds) can be defined
The use of the model-based adaptive optimal design (MBAOD) concept in the context of dose finding of combination therapy was exemplified by the association of a marketed drug and a hypothetical compound in development to be added on top of paclitaxel
Summary
Anticancer agents used in combination are fundamental to successful cancer treatment. The association of different therapies can target tumor cells with different sensitivities and improve the response to treatment. These combination therapies often involve a marketed drug and a new drug. In these associations, the characteristics of the marketed drug (pharmacokinetic– pharmacodynamic relationships (PKPD), maximal tolerated. Compared to the development of a single drug, development of combination therapies is complex. Instead of a simple unidimensional dose–safety profile, both drug dosages can be changed resulting in a continuum of potential MTD, meaning that multiple potential Recommended Phase 2 Doses (RP2Ds) can be defined
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