A panel of experts at BIO 2025 explored the transformative impact of Project Optimus, a Food Drug Administration (FDA) Oncology Center of Excellence initiative reshaping early-phase oncology drug development. Moving beyond the traditional focus on maximum tolerated dose (MTD), Project Optimus emphasizes early dose optimization to better balance safety, tolerability, and efficacy.
Since the 2023 draft guidance, trials have adopted more complex designs, including larger cohorts, real-time pharmacokinetic/pharmacodynamic (PK/PD) sampling, and broader global access—enhancing data quality but also increasing costs. Despite these challenges, the initiative aims to streamline late-phase development and improve the likelihood of success.
This summary distills key takeaways and best practices shared by the panelists, offering actionable guidance for navigating the oncology drug development landscape.
Key takeaway 1: Enhanced FDA engagement for dose optimization
Project Optimus emphasizes the importance of early and frequent interactions with the FDA to align on dose optimization and development plans. This approach has transformed pre-IND and IND meetings from routine milestones into critical checkpoints for ensuring a smooth transition to clinical trials. Clear evidence of robust design—including safety and efficacy endpoints—a range of doses, and strong supporting data, are essential to avoid potential holds.
Regular meetings with health authorities, especially when holding Fast Track or Breakthrough Therapy designations, are crucial. Listening to and implementing FDA recommendations can significantly aid in developing and accelerating innovative cancer treatments.
Actionable insight: Schedule regular and proactive meetings with the FDA to present robust study designs and implement recommendations, ensuring a smooth transition to clinical trials and accelerating cancer treatment development.
Key takeaway 2: Finalized guidance on dose optimization
The FDA’s guidance on dose optimization, initially drafted in January 2023 and finalized in August 2024, reinforced its focus on patient-centric approaches to maximize efficacy while minimizing toxicity. The final guidance provided clearer expectations, emphasizing early engagement, optimal dose determination, comprehensive PK plans, patient-centered outcomes, and robust data packages to support decisions.
Actionable insight: Implement early engagement strategies, develop comprehensive PK plans, and consider patient reported outcome endpoints in early-phase trials to meet FDA expectations and support robust decision-making in dose optimization.
Key takeaway 3: Shift in study designs and sample sizes
Project Optimus has significantly altered early-phase study designs and sample sizes. Traditional algorithm-based designs, like the 3+3 model, have been replaced by model-based escalation schemes, such as the BOIN design, which allows for more continuous enrollment, dosing decisions based on the latest safety data, and backfilling to existing dose cohorts. This approach requires larger sample sizes and more upfront planning and resources.
While this shift has increased the number of subjects enrolled, extending timelines and raising costs, it also establishes a well-defined dose and schedule early on. This can potentially accelerate later phase studies, effectively doing away with the need for a standalone Phase II, and ultimately speeding up the overall development program.
Actionable insight: Adopt model-based escalation schemes and plan for larger sample sizes early on to establish a well-defined dose and schedule, potentially accelerating late-phase studies and overall development.
Key takeaway 4: Impact on biomarker and assay development
Project Optimus emphasizes the importance of dose and exposure response, promoting the development of relevant blood or tissue-based biomarkers to inform dose-finding trials. Objective radiographic response (ORR) may not be the most sensitive measure of PD activity, highlighting the need for robust biomarker development.
The final guidance calls for comprehensive PK sampling and analysis plans in each protocol to characterize PK parameters (e.g., linearity, absorption, distribution, elimination) following the first dose and at steady-state. Population PK and modeling are also emphasized, supporting biomarker-guided efficacy endpoints and enrollment criteria to find the right patients at the optimal dose.
Actionable insight: Develop robust blood or tissue-based biomarkers and comprehensive PK sampling plans to inform dose-finding trials, ensuring optimal patient selection and dosing.
Key takeaway 5: Financial implications for the biotech industry
The financial impact of recent trends is significant, especially for small- to midsize biotech companies with limited funding. The increased size, scope, and cost of first-in-human (FIH) studies challenge these companies to balance adequate design and power with available funding. Creative commercial terms, such as milestone-based payments and phased engagements, are becoming crucial to helping these companies advance their assets.
These changes necessitate additional early financing and resources, which may negatively affect the development of innovative cancer treatments.
Actionable insight: Explore creative commercial terms like milestone-based payments and phased engagements to secure early financing and resources, ensuring the advancement of innovative cancer treatments despite financial constraints.
Project Optimus is fundamentally reshaping early-phase oncology drug development by prioritizing dose optimization over traditional maximum tolerated dose strategies. Key takeaways from the BIO 2025 panel highlight the importance of early and frequent FDA engagement, the adoption of model-based trial designs, and the integration of robust PK/PD and biomarker strategies. While these innovations enhance scientific rigor and patient outcomes, they also introduce operational complexity and financial pressure—particularly for small to midsize biotech companies.
These insights underscore the need for innovative approaches and strategic planning to advance effective and safe oncology treatments.
Catalyst Oncology is a full-service, specialty clinical research organization (CRO) built to serve the global biotech industry. Backed by leading retention rates and a culture rooted in its core values, Catalyst Oncology provides customers with teams experienced across all functions, knowledgeable in complex drug classes and study designs, and with data-centric methodologies that help bring next-generation therapies to cancer patients. Connect with Catalyst Oncology on LinkedIn.
