Adaptive Two-Stage Dose-Finding Designs for Combined Drugs(2/2)

Project Details


In order to improve the drug efficacy for cancer treatment, the drug development recently considers the combination of two or more anticancer drugs, especially when individual drugs target different pathways and/or inhibit resistance mechanisms in the tumor-malignant process. Although the efficacy of the combined drugs could be improved due to the expected synergistic treatment effects, the toxicity of the combined drugs may be enhanced when individual drugs possibly have overlapping dose-limiting toxicities (DLTs). Therefore, it is important to have well-designed phase I/II trials for finding the optimal combination doses (OCD) so that the combined drugs preserve the maximum efficacy, while maintaining allowable toxicity. Note that the dose-finding study for combined drugs majorly focus on sequentially and adaptively searching for a better drug combination for next cohort of patients based on both the completely observed responses of toxicity and efficacy. However, when the efficacy response takes a long time to observe, the trial time of the sequential dose-finding design would be too lengthy. Therefore, in this project, innovative two-stage designs are considered in which admissible dose combinations with allowable toxicity are identified in the first stage, and, in the second stage, batches of more patients are adaptively and randomly allocated to receive more effective yet admissible dose combinations. Finally, the OCD is identified based on all the available toxicity and efficacy responses. Note that the toxicity response in clinical trial is usually the binary variable, but the type of efficacy response may be binary variable or survival time. Also, note that combined drugs under study recently include a combination of two chemotherapies or two molecular targeting agents (MTAs), a combination of a chemotherapy and an MTA, or a combination of an MTA and immunotherapy (IMT), where one of the two drugs may serve as the standard therapy with a fixed dose and the other is the additive drug, or the two therapies under current use are combined. Therefore, in the first year of the subproject, novel two-stage early clinical trial designs are constructed for finding the OCD with different types of efficacy response when two anti-cancer therapies are combined. In the second year, novel two-stage phase I/II trial designs are developed for finding the OCD with different types of efficacy response when a standard therapy is combined with an additive drug. In fact, the optimal dose of the additive drug is determined so that the combined drug is more effective than the standard therapy while maintains the allowable toxicity.
Effective start/end date1/08/2131/10/22

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being
  • SDG 11 - Sustainable Cities and Communities
  • SDG 17 - Partnerships for the Goals


  • Combined drug
  • maximum tolerated combination
  • optimal drug combination
  • two-stage early clinical trial design
  • Bayesian method


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