Abstract 4514: The impact of Project Optimus and FDA guidance on study design of early-phase clinical trials

Abstract Methods: All early phase protocols activated at Sarah Cannon Research Institute between 2021-2023 were reviewed (n=286 protocols). Information such as class of therapy, study design, and dose optimization plan (if applicable) were extracted from review of each protocol. Fisher’s exact test was used to compare proportions across categories and a p-value <0.05 was considered statistically significant. Results: 268 unique protocols including 215 first in human trials (80%) were initiated with 179 different sponsors between 2021 and 2023. Trial classification by mechanism of action included 114 targeted therapies (43%), 109 immunotherapies (41%), 29 antibody drug conjugates (11%), 12 Immune effector cellular therapies (4%), and 4 chemotherapies (1%). Most trials employed a Bayesian dose escalation design (53%) versus rule-based (3+3), and this did not vary significantly year-over-year. 32% of trials (N=86) had a dose optimization plan. 47 trials (18%) included a dose optimization plan with randomization while 39 trials (14%) discussed optimization without randomization. The percentage trials with a dose optimization plan increased annually from 2021-2023 (22%, 29%, and 47% respectively; p=0.002). There was an increase in the proportion of trials which included backfill cohorts from 2021 (60%) to 2022-2023 (76%) (p=0.007) in addition to the proportion of protocols which allowed intra-patient dose escalation (45% in 2021 versus 57% in 2022-2023, p<0.001). The number of additional patients required in the trials with a dose optimization plan ranged from 12 - 200 with a median of 40. The inclusion of patient reported outcomes in early phase protocols was low at 12% from 2021-2023 and only 3 protocols (1%) addressed enrollment of underrepresented groups in the protocol. Conclusion: Overall, there has been a trend towards increased implementation of a dose optimization plan within early phase protocols since the announcement of the FDA’s Project Optimus initiative in 2021. Moreover, Bayesian designs, backfill cohorts, and intra-patient dose escalation are common in contemporary dose escalation studies. However, patient-centered outcomes and underrepresented populations are not routinely addressed in these protocols. Updated analysis including early phase clinical trials activated in 2024 is planned. Citation Format: Deepak Bhamidipati, Suzanne Jones, David Spigel, Gerald Falchook, Manish Patel, Howard Burris, Vivek Subbiah. The impact of Project Optimus and FDA guidance on study design of early-phase clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4514.