Abstract LB278: Application of phase 1 and pre-clinical data to assist in determining the optimal dosage regimen for cancer drugs using the principles of Project Optimus
Authors: Young David , Bigora Sian , Franks Peter , Nyberg Mary , Madden Yvonne 
Published: April 2024

Abstract
Background: In 2022 and 2023 FDA introduced the Project Optimus initiative and the Draft Guidance “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases.” The FDA’s desire is to move away from the maximum tolerated dose (MTD) approach in the development of all oncology drugs and to determine and justify the optimal dosage regimen (ODR), requiring one to evaluate the exposure-response relationship for both the safety and efficacy of oncology drugs. This approach has made the oncology drug developer re-examine their previous beliefs and reconsider the design of the clinical and pre-clinical studies. Processa has begun to implement the ODR evaluation in Phase 1 and pre-clinical studies and will be providing examples as well as how the findings may potentially affect the design of Phase 2/3 trials.
Methods/Results: For Next Generation Irinotecan (NGC-Iri), the toxicity and tumor growth inhibition after NGC-Iri administration (as well as tissue distribution of NGC-Iri) were compared to irinotecan in xenograft transplanted mice. Tumor growth inhibition remained constant at 100% for an NGC-Iri dose at the MTD and at 50% of the MTD. However, tumor growth inhibition after irinotecan administration decreased from 100% at the MTD to approximately 64% at 50% of the MTD. The differences seen in the tumor inhibition when NGC-Iri and irinotecan were administered illustrate that the exposure-efficacy profile of NGC-Iri follows a different pattern than the exposure-safety profile and is different from the irinotecan exposure-efficacy profile even though the active molecule is the same. The dose of NGC-Iri can be decreased to improve safety while not significantly sacrificing efficacy, different than what was seen with irinotecan. In a second example, we are evaluating the PK-safety relationship of a different Next Generation drug in our ongoing Phase 1 trial. We have recently found that the exposure-safety relationship is different for our NGC drug than for the approved drug with the same cancer-killing metabolite(s). Based on the difference in exposure-response in the Phase 1 study, we are designing the Phase 2 trial to determine the potential ODR.
Conclusion: Both preclinical and Phase 1 oncology trials can be designed to better understand the exposure-response relationships for safety and efficacy which will then help the drug developer in designing the Phase 2 and 3 trials for eventual FDA approval of the ODR.
Citation Format: David Young, Sian Bigora, Peter Franks, Mary Nyberg, Yvonne Madden. Application of phase 1 and pre-clinical data to assist in determining the optimal dosage regimen for cancer drugs using the principles of Project Optimus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB278.