In 2021, the Project Optimus initiative was launched by the US Food and Drug Administration’s (FDA) Oncology Center of Excellence, with the aim of reforming the dose selection paradigm in oncology drug development[i]. The goal was to address concerns with the traditional Maximum Tolerated Dose (MTD) approach to dose selection, which may lead to insufficiently characterised doses and schedules for molecularly targeted therapies before pivotal trials commence.
According to the National Cancer Institute, the MTD is ‘the highest dose of a drug or treatment that does not cause unacceptable side effects.[ii]’ However, the new FDA guidelines[iii] say that this paradigm does not adequately consider data such as low-grade symptomatic toxicities (i.e., grade 1-2), dose modifications, drug activity, pharmacokinetics (PK), pharmacodynamics (PD), and dose- and exposure-response relationships, when selecting dosages for subsequent trials[iv].
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Project Optimus emphasises the importance of maximising the safety and tolerability of treatments, with the FDA urging pharmaceutical companies to conduct detailed analyses of randomised dose-ranging studies to select the right dose based on biological activity rather than just tolerability. However, implementing this initiative presents increased complexity in clinical trial delivery and creates additional operational challenges, in terms of recruiting more patients early on and gathering correlative analysis of more diverse data including safety and PK/PD insights – all while maintaining a focus on fast decision making.
As oncology drug development evolves, Project Optimus is becoming increasingly vital in refining dosing strategies, for example, in therapies that engage or inhibit specific biological targets such as cell functionality, including receptor modulators like PDL-1 or enzyme targets such as K Ras or B Raf. These pathways are at the forefront of cancer treatment due to their ability to directly drive cancer growth or to harness the immune system to target and destroy cancer cells. However, they come with distinct challenges related to PK, PD and safety, which necessitate precise dose selection to maximise therapeutic efficacy while minimising adverse effects.
The impact of Project Optimus
With the FDA guidelines emphasising more comprehensive dose optimisation studies, Project Optimus has created additional development pressures that can be effectively managed through partnering with a highly experienced cross-functional oncology team, who can mitigate the risk.
Extension of Phase I trial timelines
One of the primary impacts of Project Optimus is the extension of Phase I trial timelines. Sponsors may need to conduct additional studies or recruit more patients within a study to provide more diverse data demonstrating that the selected doses optimise efficacy while minimising toxicity. This creates the risk of prolonged timelines necessary to move from Phase I to later stages of development, extending the overall development timeline for new oncology therapies.
Increased complexity in trial designs
Project Optimus encourages a more nuanced understanding of dose-response relationships, which often necessitates the inclusion of multiple study arms in trials, and/or data analysis and reporting. This approach aims to evaluate various doses and their biological and tolerability profile more thoroughly, ensuring the most appropriate dose is used in the next stage of development. However, it also complicates trial design and execution, which can further risk extension in timelines and increase costs associated with trial management and monitoring. This risk comes with an opportunity to better select the appropriate patient population that will react positively to the drug by narrowing the biological target, therefore potentially avoiding high numbers of Phase III failures.
Challenges in patient recruitment and retention
As trials become more intricate, they may require a larger and more diverse patient population to adequately assess the efficacy and safety of multiple doses across biologically diverse cancer patient populations defined in various study arms. Extended timelines for access to trial participation and additional patient selection requirements can deter potential participants and/or further exacerbate patient retention challenges due to the balance of efficacy and tolerability. This can be mitigated with appropriate patient and site information and the support of a CRO partner accustomed to identifying specific cancer populations with diverse biomarker mutations or biological targets.
Financial and resource constraints
The cumulative effects of extended Phase I timelines, increased study arms, and recruitment challenges means a significant rise in research and development costs, increasing the risks of budget overruns and potentially affecting the financial viability of ongoing oncology projects and asset development. Smaller biotech companies may feel these impacts more acutely. Financial constraints can be alleviated with early planning of the entire drug development process, along with clear and detailed communication with investors on critical milestones and key interactions with regulatory bodies.
Integration of biomarker and pharmacodynamic data (PD)
Project Optimus requires leveraging biomarkers and PD data insights through integration with PK data to guide dose-response relationships. However, not all oncology drugs have well-defined biomarkers or assays for assessing PD in humans, complicating dose selection. In addition, predictive modelling especially in defining the starting dose, machine learning for extrapolation within or across drug classes, and advanced PK/PD analyses, must be integrated into study designs, highlighting the requirement for advanced analytical tools. Finally, using exploratory biomarkers to inform dose selection may necessitate further validation and discussion with regulatory authorities[v].
Thus, it is critical that the scientific requirements and study endpoints which will dictate continued study progress are discussed early with regulatory authorities, and that appropriate time is invested for planning data analysis and preparing for possible outcomes.
For example:
- Any technology transfers required for vendor inclusion for PK and PD should be mapped into the clinical data analysis timelines, together with turnaround timeS for ongoing analysis and reporting.
- A dry run of the integrated data analysis plan from all vendors is necessary for ensuring efficient reporting and enabling real-time analysis and nimble decision making.
- Planning scenarios for the acceleration of a specific arm based on close monitoring and control of study site activation and patient recruitment could be required.
Future challenges while developing advanced therapies
These new complexities mean careful consideration is required when implementing Project Optimus into drug development programmes. Modern oncology trials often involve multiple treatment arms, including dose-finding studies and clinical pharmacology studies for investigating food effect and drug-drug interactions, in addition to progressing to combinations and biomarker-driven cohorts.
For example, many oncology treatments now involve several combinations, such as:
- T-cell engagers (CAR-T, bispecifics) + checkpoint inhibitors (PD-1, CTLA-4)
- Targeted therapies + chemotherapy, or antibody-drug conjugates (ADCs)
- Multiple immune-modulating agents (e.g., IL-2 variants + CAR-T cells)
These combinations often lead to nonlinear PK/PD interactions, making dose optimisation more challenging and including issues such as toxicity overlap and synergistic effects. Many combinations increase adverse event risks, requiring lower starting doses than monotherapy and ongoing dose titration. Additionally, some drugs enhance each other’s activity, meaning a lower dose may be just as effective. While the order and timing of drug administration can significantly impact efficacy and safety.
Project Optimus thus encourages extensive PK/PD modelling including use of preclinical primate data to better understand human drug-drug interactions affecting metabolism, clearance and target engagement; exposure-response relationships to determine the lowest effective dose for each drug; and real-time biomarker tracking to identify responders and optimise dosing per patient.
For example, in CAR-T or bispecific T cell engager + PD-1 inhibitor combinations, PD-1 blockade may enhance T-cell persistence, reducing the need for high CAR-T doses, while bispecific antibody and chemotherapy combinations may require adjusting of chemo intensity to prevent excessive immune activation.
All of this must begin in the preclinical stage. Approaches for PK/PD modelling in combination trials could include:
- Mechanism-based PK/PD models to simulate drug synergy and toxicity thresholds
- Bayesian adaptive dose-finding designs for flexible dosing adjustments
- AI-driven patient profiling to predict optimal responders
How Fortrea can support your oncology trial
Fortrea is a global CRO with an oncology dedicated cross-functional team that delivers strategic insights to enable efficient, cost-effective development of immune-oncology assets, including cell and gene therapies. Fortrea’s global expertise and innovation spans more than 30 years across multiple first-in-class modalities, providing clinical insights in study conduct, implementing operational solutions throughout early phase, and including selection of customised cross-functional teams to meet development. This covers protocol design to meet Project Optimus’s need, including biostats, regulatory (strategy, clinical, nonclinical) to support interactions with regulatory bodies, and medical and operational expertise.
To learn more about the key challenges and considerations involved in operationalising (and optimising) Project Optimus, please register your interest for the webinar below.
[i] https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus
[ii] https://www.cancer.gov/publications/dictionaries/cancer-terms/def/maximum-tolerated-dose
[iii] Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases | FDA
[iv] https://www.fda.gov/media/164555/download
[v] Use of Circulating Tumor DNA for Curative-Intent Solid Tumor Drug Development Guidance for Industry FDA Nov 2024
