Seeking to Make Clinical Trials More Efficient

A Cedars-Sinai biostatistician has been awarded $1.7 million from the National Cancer institute to study how to make cancer clinical trials safer and more effective for patients.

Mourad Tighiouart, PhD, associate director of the Biostatistics and Bioinformatics Research Center at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, will focus on Phase I and II clinical trials that simultaneously test two or more chemotherapy and/or biologic agents — an increasingly common therapy for cancer patients. His goal is to better identify dose combinations that are safe and tolerable for patients and have good treatment efficacy.

"More and more physicians are combining known drugs," Tighiouart said. "But the question is how to explore the effects of these combinations safely and efficiently. It is a complicated process, both statistically and clinically, to evaluate each individual agent as well as the combination of agents."

Existing drug-combination designs have important shortcomings because they recommend a single tolerable dose combination selected from a pre-specified, small number of dose combinations to be studied for treatment efficacy, Tighiouart said. This approach can be inefficient if the pre-specified dose combinations are poorly selected by the clinicians or the recommended Phase II dose combination is suboptimal, he explained. His research proposal aims to develop designs that overcome these limitations by allowing all agents to vary during the trial and the search for tolerable and effective dose combinations to be carried out adaptively from a continuum space of dose combinations.

The five-year grant will help Tighiouart and his collaborators further develop the application of adaptive designs based on Bayesian statistics to multi-agent trials. These methods allow investigators to continually update doses based on patients' responses, previous experiments, expert medical opinion and the acceptable risk level for overdose, as determined by the investigators. Tighiouart and his colleague, André Rogatko, PhD, director of the Biostatistics and Bioinformatics Research Center, have spent many years refining a design called Escalation With Overdose Control (EWOC) for single-agent trials.

Currently, fewer than 10 percent of published Phase I trials use the Bayesian method, Tighiouart said. He is hoping that his grant-funded research will help expand use of this method. Among the project's goals are the following:

  • To develop several methods using Escalation With Overdose Control and the Continual Reassessment Method to estimate the maximum tolerated dose curve or surface of two or more cytotoxic/biologic agents
  • To develop Bayesian adaptive design Phase I and II cancer clinical trials to estimate the optimal toxicity and efficacy contour of two or more cytotoxic/biologic agents
  • To deploy software packages and web applications to implement these designs
  • To apply these statistical designs to prospective Phase I and II trials combining two or more drugs

As part of the project, Tighiouart, who also is an associate professor of medicine, said he plans to further expand his ongoing collaborative work with Cedars-Sinai investigators to develop investigator-initiated clinical trials using these Bayesian designs.

Tighiouart is principal investigator for the grant. His co-investigators are Rogatko and Steven Piantadosi, MD, PhD, director of the Samuel Oschin Comprehensive Cancer Institute and professor of medicine. Other Cedars-Sinai collaborators include senior biostatisticians Galen Cook-Wiens, Quanlin Li and Sungjin Kim and Web application developers Shao-Chi Huang and Harold Moyse.