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A novel clinical trial design is being tested to streamline cancer trials and allow quicker follow up of promising results. The Pragmatica-Lung study is a Phase III trial of a combination of ramucirumab and the imunotherapy pembrolizumab for advanced non-small cell lunger cancer (NSCLC). Both drugs are already FDA approved and promising data emerged last summer from a Phase II study of this combination in advanced non-small cell lung cancer (NSCLC).
What’s unusual about this Phase III study, is that it aims to recruit a broad real-world population. It will also have less strict rules about participants’ diagnoses, medical conditions, functional status, and other factors. Further, it will focus on survival improvements.
“For patients with cancer, survival is the gold standard,” said Karen L. Reckamp, MD, associate director for Clinical Research in Cedars-Sinai Cancer, and principal investigator for Pragmatica-Lung. “The design of this clinical trial could change the paradigm for how some drugs undergo approval, ultimately increasing the number of participating medical centers and the number of participants who are able to enroll.”
She points to three major factors that slow trials:
- Burdensome enrollment criteria
- The need to report every side effect
- Evaluation of multiple outcomes
Lung cancer treatment is rapidly evolving. Over ten thousand trials for this form of cancer are listed at clinicaltrials.gov. In this case in particular, “To wait many years to start a trial to confirm the results of this well-designed Phase II trial didn’t seem to make a lot of sense,” Reckamp said.
The Phase II showed the combination of Lilly’s VEGF-inhibitor ramucirumab and Merck’s immunotherapy pembrolizumab seemed safe and promising. There was evidence that adding ramucirumab helped extend the lives of patients who had become resistant to the immunotherapy.
The science backs this up.
“VEGF is important in modulating the tumor immune microenvironment, and can induce PD-L1 expression on dendritic cells, and impedes T cell extravasation, inhibits the proliferation and cytotoxicity of T Lymphocytes, stimulates the proliferation of T regulatory cells, and mediates effects on myeloid-derived suppressor cells,” Reckamp explains. This is particularly important because “Acquired resistance to immunotherapy is a major area of unmet need for patients with NSCLC,” Reckamp added.
The Phase II data was presented last June, and by November the Pragmatica-Lung protocol was reviewed by the NCI Central Institutional Review Board. “This is breakneck speed not generally seen in developing a new trial.” Reckamp said. “Development of a new clinical trial, especially a study intended for FDA registration, would take more than 18 months of planning and activation.”
To speed recruitment, the team simplified the eligibility criteria, allowing most patients with recurrent non-small cell lung cancer to enroll, whatever prior therapy they received. As a result, many more National Clinical Trial Network (NCTN) institutions could participate.
“It empowers investigators to treat as they would in the real world and allows a much broader population to go on the trial,” Reckamp said. “By opening this up and making it simpler, we hope to increase the diversity of our study sample, and we have a plan, in conjunction with SWOG and other groups, to reach out to underrepresented groups to further extend our reach.”
Once the trial is underway, investigators will collect data only on serious and unexpected side effects, and the trial will only look at overall survival rates.
Collaborators on the Pragmatica-Lung Study include the SWOG Cancer Research Network, which designed and is leading the trial in collaboration with the Alliance for Clinical Trials in Oncology.
