A Review of Early-Phase Trial Design in the Era of Project Optimus
Deepak Bhamidipati, MD, discusses a review conducted to investigate how the design of early-phase clinical trials has evolved.
Deepak Bhamidipati, MD, assistant director, drug development, Sarah Cannon Research Institute (SCRI), discusses a review conducted to investigate how the design of early-phase clinical trials has evolved.1,2
“Historically, early-phase clinical trials were designed in such a way to identify the maximally tolerated dose, especially in the era of chemotherapy. But with emerging classes of therapies, such as targeted therapies, immunotherapies, antibody-drug conjugates, that typical paradigm of finding the maximally tolerated dose may not necessarily end up resulting in finding the optimal dose for patients when considering both toxicity and efficacy,” says Bhamidipati.
This particular review is in response to the emergence of new cancer therapies like targeted therapies, immunotherapies, and antibody-drug conjugates. Historically, these trials have focused on identifying the maximum tolerated dose (MTD), a paradigm more suited for chemotherapy. However, Bhamidipati explains that the MTD may not always represent the optimal dose for newer agents, where balancing toxicity and efficacy is crucial.
“In response to this, the FDA has taken this issue seriously and has developed some guidance, called Project Optimus, which was initially developed in 2021 but has since been finalized in 2024,” adds Bhamidipati.
The impetus for this review stems from the FDA's "Project Optimus" initiative, which emphasizes finding a dose that is both safe and effective by considering the totality of toxicity and efficacy data.2 Given Sarah Cannon's extensive network conducting numerous phase 1 trials annually, the researchers aimed to determine if and how this FDA guidance has influenced the design of these early-phase studies.
The key aspects evaluated included the design of both the dose escalation and dose expansion phases of the trials. For dose escalation, the review examined whether studies employed rule-based designs to identify the maximal or best dose. Regarding dose expansion, particularly in the context of Project Optimus, the researchers assessed if studies explored multiple doses (two or three) and whether they did so in a randomized manner.
Additionally, the review considered other elements of protocol development, such as efforts to enroll more diverse patient populations, the inclusion of patient-reported outcomes, and the requirement for mandatory biopsies. These latter points reflect broader interests within the FDA and the drug development community.
“We also looked at whether these protocols include patient-reported outcomes and also mandatory biopsies. I think those are some other areas that are certainly of interest to the FDA and the drug development community in general. We are kind of curious to take a look at those as well,” he adds.
