Fewer than 5% of all adult patients with cancer participate in a clinical trial, a rate that has remained stubbornly stable over an extended period of time. Participation for certain subgroups, such as young adults, are similarly low, whereas participation of children younger than age 15 is much higher. Conducting large efficacy trials remains time consuming, costly, and, in some ways, such trials are becoming more difficult as molecular pathways and biomarkers have further differentiated patient groups. Several Education Sessions this year will examine the current state and future directions of clinical trials.
“Clinical trial participation is a foundational issue with respect to advancing new treatments from the experimental to clinical practice settings,” said Joseph Unger, PhD, of the Fred Hutchinson Cancer Research Center, who will chair the Education Session “Removing Barriers to Clinical Trial Participation” on June 4.
Dr. Joseph Unger Photo courtesy of Fred Hutchinson Cancer Research Center
“The barriers to trial participation are numerous and often self-reinforcing,” he said. “Perhaps for that reason, the low rate of trial participation for adult patients with cancer has been fairly stable for an extended period.”
Such barriers take a number of forms: they can be structural, clinical, and attitudinal in nature, and the resulting low rates of participation can have clear effects on the progress toward disease management.
Enrollment of children younger than age 15 has historically been far better than enrollment of adults, a fact that is reflected in the much more rapid decrease in mortality rates for childhood malignancies compared with adult cancers over the last several decades. In other words, greater access to patients means better research progress. Or, as Dr. Unger put it, “our ability to answer important clinical research questions is very much constrained by the limited number of available patients.”
Dr. Unger will speak during the session about ways that this issue might be addressed in future clinical trials. For example, he noted that there is often a “surfeit of unnecessary eligibility criteria in trials.” Although appropriate eligibility criteria are important, studies have indicated that cancer histology and disease stage are the primary determinants of outcome1; with that in mind, cutting some unnecessary eligibility criteria could increase trial participation and maintain safety without reducing the validity of clinical trial treatment results.
“I believe more effort should be put into relaxing or eliminating eligibility criteria, where possible,” Dr. Unger said. “Some examples include laboratory cutoff values that may exclude patients, or eligibility criteria that preclude the participation of cancer survivors, which is increasingly an issue given the growing cancer survivor population.”
Dr. Archie Bleyer
He also will discuss how extending the upper age limit of mandated health care insurance on parents’ policies could benefit this patient population. Elise D. Cook, MD, of The University of Texas MD Anderson Cancer Center, will also participate in this Education Session, giving a presentation on global and local strategies to improve clinical trial enrollment.
Evolving Trial Design Philosophies
In another Education Session, experts will focus specifically on eligibility issues in clinical trial design. The session, titled “Clinical Trial Eligibility Criteria: Tradition Versus Reality,” will be chaired by Edward S. Kim, MD, of the Levine Cancer Institute, Carolinas HealthCare System, and will be held on June 4.*
Dr. Edward S. Kim
“We urgently need to reassess the actual nuts and bolts of clinical trial protocols and try to include as many people who want the opportunity to participate in these trials,” Dr. Kim said. “Modernizing eligibility criteria is critically important. When research studies don’t reflect actual clinical practice, then you’re not doing anyone a service. Trials must be representative of the patient population in the real world, the majority of whom never participated in a clinical trial.”
The session will involve discussion of how the classical model of clinical trials—comparing a new drug’s efficacy to the standard of care—does not necessarily fit for modern-day targeted therapies, as the understanding of molecular pathways in oncology has evolved. As biomarkers and associated diagnostic testing become increasingly common across many malignancies, and as we subdivide those malignancies into more and more types with different treatment strategies, new therapies with specific targets are appropriate for fewer and fewer patients. This has obvious implications for trial design.
The increasing understanding of druggable molecular targets and pathways has already allowed changes, in particular, to early-phase clinical trial design. According to Dr. Kim, relaxing the eligibility requirements could further lead to better trial accrual and faster drug development. “One could make the argument that if your tumor contained a promising target, then maybe having a hemoglobin level above 9 g/dL, a performance status of 1 compared with 2, or other criteria, are less important than the biomarker,” he said. “We have all encountered patients in the clinic who may have poorer functional status but whose tumor contains a druggable biomarker and has benefited greatly from molecularly targeted therapy.”
Gwynn Ison, MD, of the U.S. Food and Drug Administration, will also speak during this Education Session. Dr. Kim said she will focus on the regulatory issues related to changing clinical trial designs and criteria. Finally, Jeffrey R. Infante, MD, of the Sarah Cannon Research Institute, will speak on brain metastases as a barrier for enrollment.
Cooperative Group Trials, Past and Future
An Extended Education Session will examine one specific branch of the clinical trial milieu: cooperative group trials.
“Cooperative groups have a unique niche in that they can design trials that otherwise would not be done,” said Razelle Kurzrock, MD, of the University of California, San Diego, who will speak during the session. “These include important questions that a drug company may not have an interest in, as well as trials in rare disorders or genomic subsets that require numerous sites.”
Dr. Razelle Kurzrock Photo courtesy of MDACC Barry G. Smith
The session, “On the Shoulders of Giants: Cooperative Groups and Clinical Trial Design—Past, Present, and Future,” will be chaired by ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO, and will take place on June 3.*
Dr. Kurzrock said that designing trials in the modern era of cancer therapy and research depends hugely on the ability to adapt to fit changes in knowledge. “Customized therapy is the wave of the future,” she said. “There will need to be drastic changes in trial design to accommodate the revelations of genomics.” More specifically, new N-of-1 trial designs—in which customized combinations of drugs are matched to variables such as the individual’s characteristics or risk factors—will be needed in order to move the field forward quickly.
Dr. Travis J. Osterman
Photo courtesy of Todd Buchanan
The session will also cover the background and design of the ambitious NCI-MATCH trial, which began enrolling in August 2015. The trial, which is coordinated by ECOG and the American College of Radiology Imaging Network, will incorporate 10 treatment arms assigned based on the molecular mutations present in each patient’s tumor. Any type of malignancy is eligible for the trial, and the investigators hope to have at least 25% of participants with a malignancy considered rare.
“It is important that we all support these large efforts and discuss enrolling in clinical trials with our patients,” Dr. Osterman said. “We have seen tremendous therapeutic breakthroughs in the past 10 years largely due to our patients’ and their families’ willingness to participate in clinical trials.”
In general, clinical trial design and execution remains an active area of discussion and research in oncology. Adjusting to the new era of molecular targets and more customized, personalized treatments and working to diminish or eliminate barriers to participation would allow trials to be streamlined, testing promising agents in a far more timely and relevant fashion than in the past.