In the world of cancer drug development, finding the right dose is a crucial step that can make a significant difference in how well a treatment works for patients. Traditionally, oncology dose-finding studies for systemic chemotherapies focused on calculating the maximum tolerated dose (MTD), defined as the highest dose a patient can handle without causing toxicity or unacceptable adverse effects. However, this approach has known limitations as it can result in significant toxicity without necessarily improving efficacy.
With the increasing number of novel targeted therapies and immunotherapies in development, the U.S. FDA Oncology Center of Excellence created the Project Optimus initiative to reform the dose optimization and dose selection process. The FDA provided further guidance in its document, “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases.”
To support oncology drug development sponsors, this article shares how Project Optimus encourages the use of alternative approaches to find a dose that maximizes therapeutic benefit while minimizing adverse effects.
Recognizing the Limitations of the MTD Approach
Defining the MTD doesn’t necessarily translate to improved patient outcomes in a Phase I oncology trial. For oncology treatments that alter molecular pathways, the FDA guidance notes that “doses below the MTD may have similar activity to the MTD with fewer toxicities.”
Targeted therapies, for example, often have a flat exposure-response relationship. Increasing the dose beyond a certain point doesn’t always improve the treatment’s effectiveness, but it can cause more side effects. As a result, patients might be given higher doses without seeing any additional benefits, which can be risky and unnecessary.
Understanding Dosing Terms
The use of effect markers, such as target engagement, pharmacodynamic, or disease progression markers, can help understand how the drug works in the body and find the best and safest doses. Here, several key concepts are important to understand:
- Minimum effective dose (MED): The MED is the lowest dose that still provides a therapeutic benefit. This approach ensures that patients receive the minimum amount of the drug needed to see an effect, reducing the risk of side effects.
- Minimal immunologically active dose (MIAD): As a concept in development, the MIAD is particularly relevant for immunotherapies that activate the immune system to fight cancer. The MIAD represents the lowest amount of a treatment that can still trigger a meaningful immune response.
- Optimal biological dose (OBD): The OBD provides the best balance between efficacy and safety, ensuring the drug is as effective as possible while minimizing side effects.
Informing Dosing Optimization with Comprehensive Data
Effective dose selection strategies start with a robust trial design, which incorporates a wide range of data to make informed decisions.
- Pharmacokinetic (PK) data, which looks at how the drug moves through the body
- Pharmacodynamic (PD) data, which examines how the drug affects the body
- Pharmacogenomic data, which considers how a patient’s genetic makeup influences their response to the drug
- Therapeutic drug monitoring involves regularly measuring the drug levels in a patient’s system to ensure that they are receiving the right dose.
Incorporating Patient-Centric Practices
Patient factors are also vital to consider in early phase development as the overall success of the therapy can be affected by the convenience of the dosing schedule, patients’ ability to adhere to the treatment plan, and the timing of doses. A dose that is too complex or difficult to manage can lead to poor adherence, undermining the treatment’s effectiveness.
Focusing on Dose Optimization to Improve Patient Outcomes
A personalized approach to dose optimization can help tailor treatments, making them safer and more effective. As the drug development industry shifts toward more biologically informed dose selection strategies and integrates comprehensive data, researchers can not only impact patient outcomes but also improve the overall efficiency and success of drug development in the fight against cancer.
Rely on our experience navigating complex oncology studies to guide your dose escalation/expansion studies: https://www.caidya.com/what-we-do/therapeutic-areas/oncology/