Improving Clinical Trials with a Simpler and More Inclusive Study Design

Investigators from Cedars-Sinai Cancer are collaborating on a streamlined clinical trial design in a study called Pragmatica-Lung. This randomized Phase 3 trial funded by the National Cancer Institute (NCI), part of the National Institutes of Health, will test a therapy for advanced non-small cell lung cancer in a real-world patient population.

The study will answer am important question: “Does this therapy help patients live longer?”

Participating patients inn the trial will be randomly assigned to receive either standard chemotherapy or a combination of the drugs ramucirumab (Cyramza®; Eli Lilly and Company)*, recombinant human antibody that inhibits the angiogenesis pathways involved in the development and progression of cancer, and pembrolizumab (Keytruda®; Merck & Co)*, an immunotherapy that binds to the PD⁠-⁠1 receptor and blocks its interaction with PD‑L1 and PD‑L2, which helps restore the immune response. [1]

Answering the question
Although answering the question (Does this therapy help patients live longer?), is important, researchers are watching the trial for its practical design as a clinical study open to a broad patient population with non-small cell lung cancer. Most new drug clinical trials have strict rules about participants’ diagnoses, medical conditions, functional status and other factors.

“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,” said Karen L. Reckamp, MD, associate director for Clinical Research in Cedars-Sinai Cancer, director of Medical Oncology in the Department of Medicine and principal investigator for Pragmatica-Lung. “This may open the doors to patients who might not otherwise be offered clinical trials.” [1]

SWOG Cancer Research Network
NCI collaborators for 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, and the pharmaceutical companies Merck & Co (known as MSD outside the U.S. and Canada) and Eli Lilly and Company.

The study will be conducted with participation of the four U.S. NCI National Clinical Trials Network (NCTN) groups that focus on cancer in adults. The trial opened nationwide in March.

The therapy being tested was most recently examined in a SWOG randomized Phase II clinical trial funded by the NCI that was led by Reckamp. The study, known as S1800A, was part of Lung-MAP, a lung cancer precision medicine trial supported by the National Cancer Institute, part of the National Institutes of Health and focused on patients whose cancer had returned after chemotherapy and immunotherapy. Based on the outcome of the study, the investigators concluded that the combination therapy significantly extended the lives of patients with one of the most common forms of lung cancer.[2][3]

The results of that trial, presented in June at the 2022 annual meeting of the American Society of Clinical Oncology (ASCO), were promising enough for a Phase 3 trial to follow. But the design, execution and completion of a Phase 3 trial can take many years.

“We know that treatments for non-small cell lung cancer are evolving rapidly, so 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 explained.

“We have safe, FDA-approved drugs. We wanted to create a simple trial that would quickly tell us whether this combination improves patient survival over standard of care,” she added.

Addressing barriers
There are three major factors that can cause a trial to lag, all of which Pragmatica-Lung aims to address:

• Burdensome enrollment criteria that require patients to submit imaging, tissue samples and other labs in order to ensure only ideal participants are included
• The requirement that research staff collect and report every side effect occurring in every patient, even if that side effect is not serious or unexpected
• Evaluation of multiple outcomes, such as whether or not a patient’s tumor continues to progress, regardless of how that affects patient survival

Based on available data, investigators concluded that the combination of ramucirumab and pembrolizumab seemed a good candidate for a new trial design that trims data collection requirements to a minimum.

More streamlined, more practical
“The FDA and the Clinical Trials Advisory Board have recently been exploring the idea of more streamlined, more practical clinical trials, and this is a good opportunity to move this idea into practice,” Reckamp said.

Reckamp and a team of others involved with the Phase 2 study began discussions with the NCI and members of the NCTN.

“We presented the Phase 2 data in June, and by November we had the Pragmatica-Lung protocol reviewed by the NCI Central Institutional Review Board,” Reckamp said.

“This is breakneck speed not generally seen in developing a new trial,” Reckamp added.

“This pragmatic approach could really speed up clinical trials and decrease the cost of trials,” said James H. Doroshow, MD, director of NCI’s Division of Cancer Treatment and Diagnosis.

“We can do more studies that provide more answers for patients more quickly,” Doroshow added.

Simplified eligibility criteria
The team simplified the eligibility criteria of the Pragmatica-Lung study, remove many of the barriers that prevent people from joining clinical trials. This approach allowed most patients with non-small cell lung cancer that had recurred despite chemotherapy and immunotherapy to be enrolled, and means that virtually any NCTN institution in the U.S. treating lung cancer could participate.

While the so called ‘side studies’ and additional tests may help investigators learn a lot beyond the core study, they also tend to place a large burden on the study investigators and patients.

“[This approach] 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.”

Data collection
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.

“For patients with cancer, survival is the gold standard,” Reckamp said. “And if this simplified trial produces a reasonable outcome, other groups may start to follow this model.”

Reckamp noted that this type of trial isn’t right for therapies where safety data hasn’t previously been collected, but that the FDA and the NCI are highly invested in making these types of trials work where appropriate.

“The Pragmatica-Lung should ease the burden on sites interested in conducting clinical research in non-small cell lung cancer while steadfastly improving outcomes for patients and ushering in new treatment paradigms,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair.

“And thanks to the streamlined trial design, whether the outcome is positive or negative, the findings will have an impact,” Theodorescu concluded.

Note: * Merck & Co and Eli Lilly & Company each contributed one of the study drugs provide and additional trial funding.

Clinical trial
Ramucirumab Plus Pembrolizumab vs Usual Care for Treatment of Stage IV or Recurrent Non-Small Cell Lung Cancer Following Immunotherapy, Pragmatica-Lung Study – NCT05633602
Lung-MAP: A Master Screening Protocol for Previously-Treated Non-Small Cell Lung Cancer – NCT03851445

Highlights of Prescription Information
Ramucirumab (Cyramza®; Eli Lilly and Company) [Prescription Information]
Pembrolizumab (Keytruda®; Merck & Co) [Prescribing Information]

Reference
[1] Pragmatica-Lung Cancer Treatment Trial. National Cancer Institute. Online.Last accessed on April 21, 2023
[2] Lung-MAP: Master Protocol for Lung Cancer. National Cancer Institute. Online. Last accessed on April 21, 2023
[3] Steuer CE, Papadimitrakopoulou V, Herbst RS, Redman MW, Hirsch FR, Mack PC, Ramalingam SS, Gandara DR. Innovative Clinical Trials: The LUNG-MAP Study. Clin Pharmacol Ther. 2015 May;97(5):488-91. doi: 10.1002/cpt.88. PMID: 25676724.