Written by Natalia Muehlemann, Vice President, Clinical Development; Martin Frenzel, Research Principal, Statistical Consulting; and Michael Fossler, Vice President, Clinical Pharmacology
The importance of dose selection and early phase clinical trial design was on the scientific agenda of the ESMO (European Society of Medical Oncology) Congress, which took place on October 20–24, 2023, in Madrid, Spain. Speakers discussed investigator, regulatory (FDA), industry, and patient perspectives during the special symposium “Challenging the Status Quo of Early Phase Clinical Trial Design: Project Optimus.”
Highlight of ESMO symposium “Challenging the Status Quo of Early Phase Clinical Trial Design: Project Optimus”
Historically, the dose range of oncology drugs has been inadequately characterized prior to approval, leading to many post-approval dose changes in the labelling. Most of these post-approval changes have been overall decreases in dose. To address this challenge, the FDA Oncology Center of Excellence initiated Project Optimus. Since its launch in 2021, Project Optimus has been reforming the dose optimization and dose selection paradigm in oncology drug development. With consensus of multiple stakeholders on “why” the change is needed, the speakers focused on “how.” The key paradigm shift includes:
Dose selection should be driven by the totality of data, including dose and exposure response relationships for efficacy and safety.
Randomized comparison to support identification of optimized doses.
Safety assessment should include low-grade toxicities, which can impact treatment tolerability.
Project Optimus has had a significant impact on the early phase of drug development in oncology. Multiple dose evaluations and longer timelines are often required, leading to increased utilization of resources and potentially increased cost. The focus on finding the “optimal” dose requires early engagement with regulators and the consideration of modern designs, with a movement away from the classic “3+3” design for dose escalation. Backfilling of patients into lower or higher doses during the dose escalation phase of development may also be a very useful approach. Careful consideration should be given to randomized comparison, which may not be required in some specific situations. It is important to note that there is “no one size fits all” and specific development plans can benefit from early discussions with the FDA.
Modern designs with multidisciplinary approaches in early development
Development of adequate and efficient early phase trial programs for novel oncology drugs requires multidisciplinary clinical, statistical, and clinical pharmacology project teams. In contrast to traditional cytotoxic chemotherapy, many modern drugs, such as immune therapies, violate the assumption that efficacy and toxicity are monotonically increasing with dose and hence bring a challenge to the conventional 3+3 designs. Though most pharmaceutical companies, as well as emerging biotech companies, have already moved away from the classic 3+3 design, we still often get questions on the benefits of using more modern designs from companies used to the traditional 3+3 design. Modern designs, such as Bayesian Optimal Interval (BOIN), Modified Toxicity Probability Interval (mTPI), i3+3, or Bayesian Logistic Regression Model (BLRM) based designs, allow a more flexible sample size, using small numbers of patients when there is little toxicity but allowing for more patients once toxicity is observed. The algorithm that modern designs use to estimate the maximum tolerated dose (MTD) is more accurate than the 3+3 definition of the MTD, and because modern designs allow for additional patients at doses where toxicity has been observed, this enables a more precise estimate of toxicity at each dose level.
Studies performed under Project Optimus will benefit from increased attention to the pharmacokinetics and pharmacodynamics of the drug under study. Incorporating biomarkers that demonstrate target engagement into the study, along with exposure-response analyses that describe the change in target engagement with drug exposure, will add additional value to the study and allow a more objective perspective to choosing the optimal dose for Phase II. The addition of exposure-response analyses to these modern designs allows the determination of the full exposure-response curve, which will aid in the choice of the optimal dose for these compounds.
While modern dose escalation designs are a great improvement, dose optimization no longer ends following the dose escalation. In fact, FDA guidance recommends randomized comparisons of candidate dose levels for new oncology drugs whenever feasible. Dose expansion portions of Phase I studies have classically been focused on identifying the right indications to pursue for further development but have done so using a single dose. Modern expansion cohort designs, such as MATS or MERIT, can achieve both of these objectives, simultaneously evaluating multiple indications while including randomized dose optimization.
However, it is important to point out that there is no single design that outperforms all others in all scenarios. Therefore, no single design can be recommended as the preferred option. Analysis of probable scenarios and simulation-based evaluations of candidate designs can help select the design that performs best for each individual development plan.
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