The American Society of Clinical Oncology has hailed immunotherapy, also known as immuno-oncology, as one of the more transformative advances in recent years. But with the inherent novelty of immunotherapies comes unique challenges in their development. Many traditional clinical trial parameters common to chemotherapy – or even the more recent targeted antibodies or kinase inhibitors – must be revisited for their application to examining the safety and effectiveness of immunotherapies.

Small and mid-sized biopharmaceutical companies play significant, pioneering roles in innovating and adapting existing drug designs to create new immunotherapies. Because immunotherapy endpoints are not traditional, and oncology practitioners are still gaining experience with this class of drugs, a well-written protocol can guide the investigators and trial staff as they adapt to this new class of treatment. The protocol design is particularly important because of the emerging popularity of testing combinations of drugs within the same protocol.  

In part one of this two-part Q&A series, we spoke with Andrew Zupnick, Ph.D., Vice President, Oncology Division with Novella Clinical to provide insights into protocol designs for immunotherapy studies that are of particular interest to small and mid-sized oncology companies.

Protocol Design

Contract Pharma: What are the more common endpoints for the more recent studies getting started?

Andrew Zupnick: For early phase studies, primary endpoints almost always focus on safety and pharmacokinetics ( PK ) – generally, ensuring the drug is engaging its target in vivo , and selecting a dose that balances safety with anticipated efficacy .  It is also fairly common now that early phase studies include efficacy endpoints as secondary or exploratory measures: overall response rate, progression-free survival, etc. The intent is to capture early hints at efficacy to help inform future development, though the results with some products of late, including a wave of immunotherapies, have been so striking that it has been possible to go straight to an approval based on early efficacy.  In late phase programs we are seeing a shift away from overall survival as a primary endpoint , in favor of surrogate endpoints such as progression-free survival, response rate, and duration of response. Overall survival is almost always included, but more often as a secondary endpoint. Endpoints are also selected specific to the indication or mechanism of action of the drugs. For example, normalization of cancer markers such as CA125 in ovarian cancer, or prostate-specific antigen (PSA) levels in prostate cancer.  

CP: What are the challenges you’ve had to face in managing global checkpoint inhibitor trials?

AZ: The emergence of checkpoint inhibitors is one of the most significant advances in oncology drug development that we have seen in some time. With this advance comes a number of new hurdles, however. The first challenge is finding the patients to meet enrollment targets. A large proportion of new drugs are being developed in combination with PD-1 and other checkpoint inhibitors, creating a significant number of potentially competing trials. Additionally, many new combination trials exclude prior checkpoint inhibitor treatment, and with the shift in standards of care to utilize checkpoint inhibitors in earlier lines of therapy, fewer patients are available for studies who have not already been exposed to a checkpoint inhibitor. Also, many of these studies are targeted to a discreet population of patients with rare biomarkers, further reducing the potentially eligible patient pool at a given site, and thus creating more risk to enrollment timelines. Detailed and current feasibility becomes even more critical with so much competition in a rapidly changing landscape. Additionally, new checkpoint inhibitor trials are usually designed to be administered in combination with approved treatments. The question of the sourcing of these drugs can pose a risk and large expense to checkpoint inhibitor studies. Especially for global trials, access to commercial lots via prescription with standard reimbursement is not a reliable solution .  

CP: What use case scenarios would you consider using a master protocol (or all-in-one designs)?

AZ: The concept of a “master protocol” is a common core design study that allows patients to be screened for specific biomarkers and assigned to treatments most likely to be effective for them. The American Society of Clinical Oncology (ASCO) recently launched the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. This is a non-randomized clinical trial that aims to describe the performance of commercially available, targeted anticancer drugs prescribed for treatment of patients with advanced cancer that has a potentially actionable genomic variant. TAPUR’s goals are to collect data on clinical outcomes to help expand the indications of approved drugs, to get real-world practice experience in targeted therapy, to spread the word about targeted therapy in clinical practice, and to expand our knowledge of genomic profiling tests.

These master protocol studies are an effective way to expand the labeling of approved drugs, but are not likely to replace the focus and fine tuning required in early to mid-phase studies to establish proof-of-concept and confirm basic efficacy.