Getting the Dose Right in Oncology

By: Alison Betts, PhD

Project Optimus is an initiative from the FDA’s Oncology Center of Excellence (OCE) aiming to reform the dose optimization and selection process in oncology to be more appropriate for targeted therapies such as biotherapeutics.

Why the need for change?

Traditionally, dose finding clinical studies in oncology are conducted with the objective of identifying the maximum tolerated dose (MTD), which establishes the dose for pivotal clinical studies. This approach originates from chemotherapeutics, where higher doses are generally associated with more anti-tumoral activity, and the strategy is to get drugs to patients as quickly as possible. However, advances in cancer research have shifted the therapeutic paradigm to targeted therapies such as kinase inhibitors, monoclonal antibodies, antibody drug conjugates (ADCs) and cell therapies. These drugs have extended survival amongst patients with various cancers, and their introduction in the adjuvant setting provides potential for a cure. They require more chronic administration with less tolerance of toxicity, and increasing doses beyond certain levels may not enhance anti-tumor efficacy and will simply increase the risk of toxicity. A more mechanistic approach needs to be taken based on understanding of target occupancy and the relationship between exposure and response for both efficacy and safety.

Mylotarg story

The industry has already been finding this out in clinical trials, with many examples of drug development impacted due to lack of robust dose exploration (Shah et al., 2021). For example, Mylotarg, a CD33 targeting ADC, received accelerated approval in 2000 as a stand-alone treatment for older patients with CD33+ acute myeloid leukemia (AML) who had experienced a relapse. It was subsequently voluntarily withdrawn from the market by Pfizer in 2010 due to safety concerns (veno-occlusive disease and treatment-related mortality). The original dose of Mylotarg was established to be 9 mg/m2 IV (days 1 and 15) based on the MTD in pivotal clinical trials. However, target receptor saturation studies indicated doses of 2 mg/m2 or higher would achieve >90% saturation of CD33 receptors. In essence, the approved dose of Mylotarg was greater than that required for efficacy. A single phase III, randomized clinical trial confirmed the fractionated dosing regimen of 3 mg/m2 (days 1, 4, and 7) for Mylotarg in combination with chemotherapy had statistically better event‐free survival and higher overall survival in de novo AML patients, compared with chemotherapy alone. Mylotarg was relaunched in 2017 at this new lower dose and schedule, with additional approval in pediatrics.

A more mechanistic approach needs to be taken based on understanding of target occupancy and the relationship between exposure and response for both efficacy and safety.

What does Project Optimus mean for me?

It is not completely clear yet what the recommendations from Project Optimus will be. However, it is clear that more rational dose optimization strategies will be required for oncology drugs, considering therapeutic properties and the patient population for both original submissions and supplemental applications. A recent Whitepaper on “Optimizing Dosing of Oncology Drugs” by key representatives from the FDA outlined potential strategies for use at different stages of drug development, acknowledging key challenges and considerations. These included:

  • Dose selection for registration trials should be guided by pharmacokinetic and pharmacodynamic (PD) data collected early in drug development.
  • Recommendations to approach the FDA early in clinical development to discuss dose finding trial design.
  • After an initial dose-escalation trial, 2 or more doses should be selected on the basis of exposure and other PD markers and subsequently evaluated in a randomized trial.

We are here to help

At Applied BioMath we have the scientific expertise to develop mechanistic models which evaluate doses and regimens of oncology drugs for optimal efficacy and safety. These models integrate preclinical in vitro and in vivo data, in addition to known clinical data on the molecule or competitors as well as relevant dynamics of downstream biology. We have rigorous QC and validation of these models to ensure they are appropriate for regulatory submission. We have significant experience of submitting these analyses to the FDA with our clients in regulatory documents.


The MTD approach in oncology is no longer an acceptable means of selecting doses for Oncology therapies. A more informed method based on understanding target coverage and exposure response relationships is recommended. This will open the door for precision medicine approaches tailored to specific patient populations and will expedite rational combination therapy selection, ultimately bringing more benefit to patients.


About the Author

Dr. Alison Betts, Vice President of Scientific Collaborations & Fellow of Modeling & Simulation at Applied BioMath