Clinical Trial Scenarios Help to Appropriately Include Patients With Brain Metastases

New guidelines may help to include patients with cancer who also have central nervous system (CNS) involvement, in appropriate clinical trials of anti-cancer drugs.

Clinical trials designed to evaluate the use of anti-cancer drugs for the treatment of cancer typically exclude patients whose disease has spread to the brain or CNS for a number of reasons, including the misperception that they are poor clinical trial candidates. And if patients with these metastases do make it in to a clinical trial, such studies fail to clearly capture information on a drug’s effect on the brain.

“It’s not really about why should we have inclusion, it’s about appropriate inclusion or exclusion,” lead author D. Ross Camidge, M.D., Ph.D., the Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center and director of Thoracic Oncology at the Colorado University School of Medicine, said in an interview with CURE.

Camidge noted this is also important because the spread of solid tumors to the brain has become an increasing problem, especially among lung cancer, melanoma and breast cancer.

“As we have gotten better at controlling advanced cancers, the need to address the CNS directly in clinical trials led to these guidelines,” he added. “[These guidelines are] also about drawing attention to how we have done things in the past and how we need to do better — shifting the field through a shared desire to improve.”

The guidelines — issued in Lancet Oncology — were developed by an expert working group called the Response Assessment in Neuro-Oncology - Brain Metastases (RANO-BM) group. This group included researchers from Dana-Farber Cancer Institute, City of Hope National Medical Center, Cleveland Clinic, University of Heidelberg in Germany, University of California at San Francisco, Queen's University in Canada, University of Groningen and Erasmus University Medical Center in the Netherlands, University of Turin in Italy, Massachusetts General Hospital, University of Virginia, The University of Texas MD Anderson Cancer Center and Columbia University Medical Center.

The researchers aimed to find a way to appropriately include these patients in clinical trials so that the trials could accurately capture that benefit, and to limit any risks to patients and to the drug development process of drugs that would be unlikely to work in the brain.

To do this, the researchers created three scenarios, based on initial understanding of a drug’s potential activity in the brain, to help with the “how-to-do-it” approach, Camidge said.

The first scenario is for when a new drug is considered “unlikely” to have activity in the brain, for which the guidelines suggest that patients with stable CNS disease should be permitted, while those with active CNS disease should be excluded from trials of systemic therapy.

“It is about protecting patients and the drug development process appropriately, but not in too draconian a manner,” said Camidge. “So, treated and stable are OK, with clear definitions of both key words, but ideally not excluding anyone with any history of CNS disease in some blanket way.”

The second scenario is for when there may be some initial evidence that a drug may actually have activity in the brain, for which the guidelines recommend to include patients with both stable and active CNS disease in a way that will capture data that will define the drug’s activity in the brain, separate from its activity in the rest of the body.

“It is about capturing the data appropriately: how to scan, measure and present CNS data so it is interpretable,” Camidge explained.

The final scenario is for when it is unclear whether a drug has activity in the brain, for which the guideline proposed to include a dedicated cohort of patients with brain metastases early in the drug’s development to generate data that could allow researchers to adopt one of the first two scenario trial designs.

“We described including dedicated CNS sub-studies within trials to generate these data early and then adapting the trial design in the future per [the first two scenarios] as the data emerge,” said Camidge.

The researchers highlighted their desire for these guidelines to represent a turning point in cancer drug development. “Guidelines are just that — they are not laws – but these were written to make pragmatic ‘how-to-do-it’ suggestions,” Camidge said. “And as doctors, scientists and all the consumers of the trial data increasingly demand data to make informed decisions in the future, we hope the adoption of the suggestions in this paper will happen organically, driven by that shared desire to improve.”