WALTHAM, Mass.—A new paper authored by statistical experts at Cytel Inc. has been published in CA: A Cancer Journal for Clinicians. Cytel hopes that the paper, entitled “An Overview of Precision Oncology Basket and Umbrella Trials for Clinicians,” will be a valuable resource for increasing master protocol trial literacy among the many clinicians and researchers who may not be familiar with these types of trials.
DDNews spoke with several Cytel spokespersons: Ed Mills, vice president of real-world evidence; Jay Park, director; Kristian Thorlund, vice president of real-world analytics; Grace Hsu, a senior statistician; and Ellie Siden, a former research associate.
According to the researchers, “Basket and umbrella trials are two types of master protocols, also commonly referred to as complex innovative trial designs (CIDs). Master protocols generally refer to a single overarching protocol developed to evaluate multiple hypotheses with the general goal of improving efficiency and uniformity through standardized procedures. These trials have been motivated by advancements in ‘omics’ technologies and improvements in biomarker research, particularly in oncology, that allow us to better understand how cancers work and how we could potentially treat them.”
“In contrast to conventional clinical trials, ‘basket trials’ aim to identify therapies that are agnostic to tumor or histology (i.e. tumor-agnostic therapies) by testing them on multiple diseases that have common targets for treatment,” the researchers continue. “By matching these molecular targets with the intervention’s mechanism of action, these therapies can help predict whether a patient will respond to a particular treatment. ‘Umbrella trials,’ on the other hand, aim to identify targeted therapies but for the same cancer. Here, a single disease is stratified into multiple groups, usually based on their molecular alterations, and multiple targeted therapies are tested in these cancer subgroups.”
“These trials require a common molecular screening tool with standardized biomarker assays established with the master protocol. This is the key difference from conventional trials, where different molecular subgroups would be investigated as different sub-studies, each with different assays and procedures,” say the researchers.
Basket and umbrella trials offer considerable potential value in more rapidly bringing new oncology therapeutics to patients, but there’s a critical need for improved understanding in order to optimize their use.
“At first glance, these methods might appear to be overwhelming to trial investigators. We need to show the power of these strategies in the hands of experienced problem-solvers,” noted co-author Edward Mills, who in addition to his vice president role is also senior principal scientist at Cytel.
An increased ability to classify tumors at the genomic level has led to an ever-greater need for highly targeted cancer therapies. Accordingly, there has been a rapid rise in the use of biomarker-guided trials under the master protocol framework in recent years—including both basket and umbrella trials.
“Given that these trials tend to be of a larger scale, it will be difficult for individual companies—especially for small biotechs—to undertake them without collaboration. Collaboration will be a key component to serving the patients ... The regulators, particularly the FDA [U.S. Food and Drug Administration], in our opinion, have been very welcoming of these new changes,” add the researchers. “Their recognition of the dire need to improve the efficiency and quality of clinical trial research cannot be left unnoticed.”
The researchers state that “Discussions on precision medicine, master protocols, and CIDs have been largely limited to high-income countries. There is critical importance in ensuring that the master protocol framework is not just being limited to the U.S. and other high-income countries.”
Such trials enable expedited development timelines, reduced costs and improved patient safety. But current understanding of such trials is not widespread among clinicians and researchers outside of the National Cancer Institute, and a select number of organizations in the private sector, slowing their adoption.
“With such a wide spectrum of cancer subpopulations, it’s simply not feasible to pursue targeted therapies using traditional clinical development approaches. Under the master protocol framework, we have an economically streamlined and statistically rigorous way to examine multiple interventions across multiple disease sub-types in parallel,” explained Cyrus Mehta, president and co-founder of Cytel. “Such approaches show promise in ensuring cancer patients receive the most efficacious new medicines in the shortest possible time.”
The investigators note in particular the ACTG A5288 trial, an umbrella trial in HIV that was recently published in The Lancet HIV.
“Here, the trial investigators used the history of antiretroviral therapy (ART) and real-time drug resistance genotype monitoring to develop new third-line ART strategies for people living with HIV at 19 urban sites in 10 low- and middle-income countries in Africa (Kenya, Malawi, South Africa, Uganda and Zimbabwe), Latin America (Brazil, Haiti and Peru) and Southeast Asia (India and Thailand),” explain the researchers. “These patients were failing their second-line treatment and were differentiated into four cohorts, based on varying resistance and susceptibility to a different ART. To our knowledge, this is the first umbrella trial to be conducted in low- and middle-income countries. It is promising that these trials aim to evaluate new approaches for differentiated care in settings where they have not been routinely used before.”
Park, Thorlund and Mills have signed a book deal with Cambridge University Press for an educational book on master protocols. The book, called “Introduction to Adaptive Trial Designs and Master Protocols,” is slated to be published in 2021.
“This book was motivated and shaped by our experience in educating the students at McMaster University, which also parallels the target audience of the book. We believe that our book will provide a clear understanding of master protocols and adaptive trial designs, even to those without a background in clinical research. It will also offer answers to those concerned about how master protocols differ from conventional trial designs. The book will help readers recognize the strengths and limitations of these novel trial designs, and apply them to their own areas of research and clinical practice,” conclude the researchers.