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What Does Immunotherapy Mean for Trial Design?

It has now been a year since we first posted about immunotherapy on this blog, and several years since the first FDA approval of an immunotherapy treatment for cancer. For anyone paying attention, it’s difficult to avoid the conclusion that immunotherapy is one of today’s hottest topics not only in oncology, but in healthcare at large. Still, the treatment has had ups and downs, and much remains to be seen regarding its viability as a replacement for traditional cancer therapy. While it famously led former president Jimmy Carter, who had been diagnosed with melanoma that had metastasized to his liver and brain, into remission, it hasn’t been successful across the board.

These uncertainties surrounding immunotherapy have extended into the clinical research arena. In addition to the search for consensus on whether it has potential as a mainstream cancer therapy, researchers have struggled to determine the ideal design for immunotherapy clinical trials, particularly in Phase I, with some calling for a change in how such trials are conducted today. Immunotherapy drugs affect the body in different ways than traditional cancer treatments; why, these researchers wonder, shouldn’t the trials that test those drugs be different as well?


Design dilemmas in Phase I

As cancer research shifts its focus more and more toward the immune system, immunostimulatory monoclonal antibodies (imAbs) are coming to play an increasingly large role in oncology clinical trials.1 However, researchers have found it particularly difficult to determine safety and dosage profiles in Phase I clinical trials for these antibodies, raising the question of whether a reassessment of study design is needed. Here are some of the characteristics of imAbs and immunotherapy treatments in general that have presented challenges in Phase I:

  • Where’s the maximum tolerated dose?
    In many trials involving imAbs, researchers have been unable to confidently determine a maximum tolerated dose of the tested compound. In fact, in a review of 13 Phase I studies, only one study was able to do so.2
  • Dosage now, reaction later
    Like any compound in a clinical trial, immunotherapy drugs carry the risk of adverse events. But adverse events caused by immune drugs can take weeks to manifest.2 Researchers run the risk of establishing a safety profile that is later rendered obsolete by adverse events that don’t appear until later.
  • Looking for a connection
    With most treatments in clinical trials, there is a clear correspondence between dosage size and the toxicity or efficacy level experienced by the patient. imAbs appear to be an anomaly in this regard: researchers have struggled to find a direct relationship between dosage level and the degree of toxicity or efficacy.2

So what’s the alternative?

Phase I oncology trials commonly employ what is colloquially known as the 3+3 trial design to guide its dose escalation process. However, the elusiveness of dosage- and toxicity-related conclusions associated with immunotherapy treatments has challenged this convention. Andrew Zupnick of the CRO Novella Clinical, writing for Applied Clinical Trials, discusses several alternatives to this common trial design. These alternatives stop short of abandoning 3+3 altogether; rather, most either use the 3+3 design in combination with other designs, or use an alternative design in the earlier stages of a trial and revert to 3+3 later.

Of course, the most modern approaches to immunotherapy constitute largely new territory in oncology. Immunotherapy has defied conventions related to how treatments affect the body, and how those effects manifest, that oncology researchers have long deferred to in designing Phase I clinical trials. As ideas for alternative trial designs become more refined and are implemented, will we get closer to a consensus on the viability of immunotherapy as a mainstream cancer treatment?


1 Postel-Vinay, S.; Aspeslagh, S.; Lanoy, E.; Robert, C.; Soria, J.C.; Marabelle, A.; Challenges of Phase 1 clinical trials evaluating immune checkpoint-targeted antibodies.; Oxford University Press on behalf of the European Society for Medical Oncology; 16 November 2015
2 Menis, Jessica; Litiere, Saskia; Tryfonidis, Konstantinos; Golfinopoulos, Vassilis; The European Organization for Research and Treatment of Cancer perspective on designing clinical trials with immune therapeutics; Annals of Translational Medicine; July 2016

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