Until the late 1990s, most oncology therapies were non-specific, killing fast-dividing cancer cells, as well as normal fast-dividing cells, such as skin cells, myeloid cells (erythrocytes, neutrophils), and lymphocytes. Due to the non-specific nature of how these early drugs worked, the doses of these agents needed to be as high as the patient could tolerate to maximize their effectiveness. This often resulted in the maximum tolerated dose (MTD) being selected as the clinical dose since the goal of these agents was to kill as many cancer cells as possible. Under this paradigm, it made little sense to study doses lower than the MTD since they would almost certainly be less effective.

Advances in our understanding of the biochemistry of cancer, as well as the complex array of signaling pathways that regulate cell growth, have led to targeted oncology agents, which may block signaling proteins that regulate cell growth, angiogenesis, or apoptosis, as well as therapies that may activate the immune system toward tumor cells.[1] Because these agents are so specific, the difference between an effective dose and a toxic one is often much wider than with non-specific therapies. Choosing the MTD as the clinical dose for targeted therapies will usually result in a dose that is too high, as the MTD will likely be well beyond the plateau for the drug’s beneficial effects. In fact, a number of targeted oncology agents have had their doses lowered post-approval, with significant improvements in their safety profile and with no decrease in efficacy.[2]

Balancing efficacy and safety: How Project Optimus is shaping cancer drug dosage strategies

Recognizing that the science of oncology drug development needed to change due to the selectivity of these newer agents, the FDA established the Oncology Center of Excellence (OCE) in 2017. OCE’s Project Optimus is an ongoing collaboration with pharmaceutical companies, academia, and professional societies in order “to move forward with a dose-finding and dose optimization paradigm across oncology that emphasizes selection of a dose or doses that maximizes not only the efficacy of a drug but the safety and tolerability as well.” [3]

Conducting a successful oncology development program under Project Optimus requires increased emphasis on determining the optimal dose range for your asset. Rather than a singular focus on the MTD, oncology drug development under Project Optimus requires one to develop an approach based on all available data. This includes safety (i.e., all adverse events, not just dose-limiting toxicities), response rate, biomarker responses, and pharmacokinetics.

Factors that will increase your chance for Project Optimus success

Phase 1 study design

The classic 3+3 design is ill-suited for determining an optimal dose, as it will almost certainly lead to choosing a dose that is too high. This design has been superseded by a number of both algorithmic and model-based escalation designs, all of which outperform the classic 3+3 design and greatly improve the chances of choosing a safe dose for further development. Many of these new designs can generalize monotherapy dose escalation into combination escalation and can accommodate late-occurring toxicities, intermediate doses, and backfilling of cohorts.

Exposure response

Developing a rigorous exposure-response model early in development is crucial in determining the optimal dose range to study in Phase 2. Using the objective response rate (ORR) is one obvious choice for the response. Still, other markers, such as ctDNA, and markers of pharmacologic target engagement, are very helpful in determining the optimal dose range for your compound, especially when coupled with an analysis of safety.

Safety

While identifying dose-limiting toxicities is essential, characterizing the long-term safety profile of your product is also critical, as newer oncology agents may be administered for months or years. For products administered chronically, even low-grade toxicity may result in patient non-adherence and dose reductions, both of which may result in the progression of the patient’s disease.[2] It is also important to remember that patients in the typical first-in-human oncology trial have often failed one or more previous therapies and may have different tolerances for adverse events than newly diagnosed patients.[4]  This increases the complexity of the assessment of safety for newer agents.

Early efficacy

A critical decision point in the early development of oncology products is to find early proof-of-concept signals to justify further development costs or attract potential development partners. Historically, this has been explored using a single-arm dose expansion cohort, where the ORR achieved has been compared to standard of care or competitor products. In some cases of overwhelming efficacy signals in small populations, the expansion cohort study has been further enlarged to accommodate an accelerated approval. Options for these designs have been enriched by using Bayesian methods for decision-making and early-phase basket studies where more than one cancer sub-type can be explored simultaneously.

Phase 2

A randomized Phase 2 dose-ranging study will almost certainly be required before advancing your compound to registration trials. Doses chosen for Phase 2 should be based on target engagement, observed efficacy, adverse event profile, and exposure. The doses chosen should have minimal overlap in total and peak exposure. Simulation studies to support the choice of doses to be studied in Phase 2 are essential. The low dose should be the minimum dose thought to be efficacious based on all safety, efficacy, and PK/PD data. The high dose is chosen to determine if increased drug exposure results in a better response. It is important to note that these studies are not usually powered to detect statistically significant differences between doses; instead, the goal in Phase 2 is to get a sense of the exposure-response relationship for the compound[5] and provide the basis for proof-of-concept decision-making. Choosing an adaptative design that allows for dropping a dose at this stage of development may save significant time.

Final takeaways

The evolution of oncology drug development, particularly with the advent of targeted therapies, has necessitated a shift in how we approach dosing strategies, and the FDA’s Project Optimus has emphasized a more nuanced and data-driven approach to dose optimization. By moving away from the traditional MTD model, we can better balance efficacy and safety, ultimately improving patient outcomes.

Interested in learning more? Watch Michael Fossler and James Matcham in their on demand Cytel webinar, “Project Optimus: Dose Escalation and Stratification Designs in Early Oncology Development”

CLICK HERE TO WATCH

References:

[1] American Cancer Society. (2014). History of cancer treatments: Targeted therapy. https://www.cancer.org/cancer/understanding-cancer/history-of-cancer/cancer-treatment-targeted-therapy.html

[2] Shah, M., Rahman, A., Theoret, M.R., & Pazdur, R. (2021). The Drug-dosing conundrum in oncology — When less is more. The New England Journal of Medicine, 385(16), 1445–1447. https://doi.org/10.1056/NEJMp2109826

[3] U.S. Food and Drug Administration. (2024). Project Optimus. https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus

[4] Gao, W., Liu, J., Shtylla, B., Venkatakrishnan, K., Yin, D., Shah, M., Nicholas, T., & Cao, Y. (2023). Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development. CPT Pharmacometrics & Systems Pharmacology, 13(5), 1–9. https://doi.org/10.1002/psp4.13079

[5] Murphy, R., Halford, S., & Symeonides, S.N. (2023). Project Optimus, an FDA initiative: Considerations for cancer drug development internationally, from an academic perspective. Frontiers in Oncology, 13, 1144056. https://doi.org/10.3389/fonc.2023.1144056

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