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Updated: Feb 26, 2026

Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation
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Implementation of a Model-Based Design in a Phase Ib Study of Combined Targeted Agents

Nolan A Wages1, Craig A Portell2, Michael E Williams2

  • 1Division of Translational Research & Applied Statistics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia. nwages@virginia.edu.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 23, 2017
PubMed

Insights

This study introduces a new adaptive design for early-phase clinical trials evaluating combination targeted therapies. The model-based approach effectively identifies optimal treatment combinations with low toxicity and high efficacy in relapsed/refractory mantle cell lymphoma.

Area of Science:

  • Oncology
  • Clinical Trial Design
  • Pharmacology

Background:

  • Traditional early-phase clinical trial designs are inadequate for evaluating novel combination therapies, particularly targeted agents.
  • There is a need for adaptive designs that can efficiently identify optimal treatment combinations with both high efficacy and low toxicity.
  • Relapsed/refractory mantle cell lymphoma presents a challenge for standard treatment approaches, necessitating innovative therapeutic strategies.

Purpose of the Study:

  • To implement and evaluate a model-based adaptive design for identifying optimal treatment combinations in early-phase clinical trials.
  • To assess the design's ability to recommend combinations with low toxicity and high efficacy.
  • To demonstrate the applicability of this design to targeted therapies, including combinations of oral inhibitors and biological agents.

Main Methods:

  • A model-based adaptive design was implemented for an early-phase clinical trial involving a combination of two oral targeted inhibitors.
  • The design aimed to identify optimal treatment combinations based on predefined toxicity and efficacy endpoints.
  • Operating characteristics were used to evaluate the design's performance, including its ability to recommend combinations and its sample size efficiency.

Main Results:

  • The model-based adaptive design effectively identified optimal treatment combinations in a high percentage of simulated trials.
  • The design demonstrated reasonable sample size requirements for early-phase combination studies.
  • The approach proved practical for evaluating combinations of targeted therapies, as shown in the mantle cell lymphoma trial.

Conclusions:

  • The proposed adaptive design is a practical and effective method for early-phase clinical trials evaluating combination targeted therapies.
  • This design can be broadly applied to various early-phase combination studies, including those involving targeted agents and immunotherapies.
  • The method offers a flexible and efficient approach to optimizing treatment selection in early drug development.

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