Developing Clinical Trials to Advance Care for Brain and Spine Cancers

Clinical trials are vital to improving care and treatment for central nervous system (CNS) cancers. These rare cancers represent 1.3% of all new cancer cases in the United States. The overall five-year relative survival rate is 32.6%, and even lower for patients with the most malignant tumors. Clinical trial development can help advance treatments and improve outcomes for people and families impacted by brain and spine tumors.

Clinical trial development is the process that determines which therapies should be tested in humans and how. The NCI’s Neuro-Oncology Branch (NOB) is taking a comprehensive approach to designing clinical trials that includes a robust clinical research and translational laboratory program. This often starts with basic research in areas that show promise for developing new treatments. Promising therapies are then tested in diverse laboratory model systems, and finally translated into clinical studies.

Yet, developing successful clinical trials for brain and spine cancers has unique challenges. Mark Gilbert, M.D., and Terri Armstrong, Ph.D., chief and deputy chief of the Neuro-Oncology Branch, hope to overcome these challenges through education and innovative approaches and designs. These include measuring the impact of a treatment on the person and eliminating barriers to participation.

Unique Challenges

Unique challenges can include those related to the relative rarity of these tumors and also characteristics of these tumors. The low incidence and prevalence of CNS tumors also result in geographical barriers that make it extremely challenging to find people to enroll in clinical trials. Study design and participation can be even more challenging for studies that look at specific molecular tumor subtypes.

Enthusiasm and interest for brain and spine cancers are often not a high priority for drug developers or pharmaceutical companies due to the low incidence and prevalence, and funding opportunities are limited for rare cancers. However, the U.S. Food and Drug Administration (FDA) Rare Disease Program encourages research in the area of rare diseases. 

Clinical trials that require frequent visits, in person treatments, and long travel may prevent a person from being able or willing to participate. Such logistics can also place additional strain on caregivers and families.

“A unique challenge that researchers face when developing neuro-oncology trials is drug delivery that crosses the blood-brain barrier,” Dr. Gilbert says. The blood-brain barrier is a protective layer that allows certain substances to reach the brain but prevents others that it thinks are harmful, such as cancer-treating drugs. Researchers must either select drugs that are able to cross or find innovative ways to get a treatment to reach the brain. Once there is a portfolio of drugs that are able to cross the blood-brain barrier and reach the tumor, the next challenge is to determine which drug or drug combinations are best for each patient. This requires extensive research looking for targets in the tumors that are likely to respond to available therapies. This process is often referred to as Precision Medicine.

Approach to Development

Clinical trial development starts with the researcher asking an important question. This helps to formulate the hypothesis and is the reason for developing a trial.

“Clinical trials need to be driven by a hypothesis that is testable,” Dr. Gilbert says. “Everything builds on the hypothesis, including the patient population, eligibility criteria, and statistical analysis.”

It is also important to evaluate background information by asking such questions as:  

• Is the clinical trial a good option for patients? Is it going to provide robust or meaningful information?
• What is the likelihood of answering the research question or hypothesis?
• Is the study designed with appropriate statistics?
• Is the eligibility criteria suitable or is it providing unnecessary risk to patients?

When considering a clinical trial, researchers should also review trials that are currently available and determine what is missing for people with brain and spine tumors. “A researcher should also investigate what is available outside of neuro-oncology to see if there is a drug in development that could potentially be beneficial,” says Dr. Armstrong.

The Neuro-Oncology Branch researchers primarily focus on novel ideas for early phase clinical trials, such as phase I, phase II, or first-in-human trials.

Clinical Trials for Brain and Spine Tumors

Importance of Patient Outcome Measures

Brain and spine tumors are unique because they are both a cancer and a neurologic illness. Dr. Armstrong’s research shows that people with brain and spine tumors are symptomatic and have functional limitations often from the time of diagnosis. Patient outcome measures are important because researchers are able to capture the impact of the disease. These reports help researchers learn how a person functions at the time of diagnosis and additionaly, provides insight into their well-being and treatment impact. “Treatments that extend time to progression or extend survival affect how the person feels and functions and is critical to truly understanding the impact of a therapy,” says Dr. Armstrong.

Besides living longer, patients reported that they want to be able to walk, do usual activities, and reduce their symptoms. These results are the driving force behind Dr. Armstrong’s work and have led to the integration of patient-reported outcomes in clinical trial development.

Patient-reported outcomes allow researchers to systematically capture data on the symptoms and experiences of patients in clinical trials and should be included when developing trials. Patient outcome measures can provide powerful insight into the patient experience even if a treatment does not shrink a tumor.

The FDA also encourages including clinical outcome assessments in clinical trial development. A new treatment can be approved by the FDA if the treatment improves survival or if it improves how a person feels or functions.

Measuring Success

A successful clinical trial advances the field by acquiring new knowledge. A clinical trial can be defined as successful if it improves survival. However, a study can also be deemed successful if it advances the understanding of the disease or leads to improvements in the approach and design of trials.

For example, a randomized trial of dose-dense temozolomide in newly diagnosed glioblastoma found no difference in overall or progression-free survival between treatment groups. However, it was one of the first studies to require a tumor tissue sample as part of eligibility, and 97% of participants complied showing the feasibility of obtaining tissue to confirm prognosis and further research.

Additionally, a trial of dose-dense temozolomide and lapatinib in recurrent ependymoma included patient-reported outcome measures and found that patients with stable disease reported significant improvements in their symptoms and function. This study led to this treatment being approved as a standard treatment because it improves how patients feel and function and highlights the importance of capturing a comprehensive picture of the patient experience.

Advancing Education and the Future

Researchers and neuro-oncology providers can join the Society for Neuro-Oncology’s two-day virtual clinical trials course on November 17 to 18, 2020 to learn the principles and future direction of CNS trials and to better understand barriers to patient participation.

Drs. Gilbert and Armstrong will be providing their perspective and expertise during the course. Dr. Gilbert will share how to successfully navigate the clinical trial environment, while Dr. Armstrong teaches about the importance of including patient outcome assessments.

“It is important that investigators learn the scientific method to research, including hypothesis-driven trials that use appropriate tools to measure patient outcomes,” Dr. Armstrong says.

The Neuro-Oncology Branch leads a network of investigators across the nation called the Brain Tumor Trials Collaborative as a means to advance treatments for primary brain and spine tumors through smart and novel clinical trial development.

When thinking about future directions of clinical trials in neuro-oncology, both Drs. Gilbert and Armstrong emphasize the importance of pragmatic clinical trial design. This can include designing trials using oral treatments that patients can take at home, partnering with a local provider to administer treatments, broadening eligibility criteria, or requiring infrequent visits.