Preclinical Project Optimus dose escalation of SN-38 pro-drug PCS11T.

e15023 Background: FDA’s Project Optimus initiative on optimizing the dose of drugs used for the treatment of cancer emphasizes the need to justify the dosage regimen for approval based on a safety-efficacy evaluation of more than one dose. FDA suggests evaluating the efficacy-safety in at least 2-3 doses rather than just using efficacy from the Maximum Tolerated Dose (MTD) as has been the approach for many years. Processa is evaluating the safety and efficacy of the SN-38 pro-drug, PCS11T (11T), compared to FDA approved irinotecan (Iri) and irinotecan liposome injection (Oni). 11T is designed to preferentially generate an intra-membrane SN-38 pro-drug depot site in cancer cells. The enhanced permeability and retention effect allows the drug to accumulate in the tumor more than normal cells, potentially resulting in greater cancer cell death and less SN-38 side effects. To better understand the dose-efficacy/safety relationships and potential optimal dosage regimen (ODR) for 11T, a Project Optimus dose evaluation and optimization preclinical study was conducted to evaluate the safety-efficacy benefits of 11T vs Iri. Methods: Preclinical studies were conducted in the SW620 colorectal cancer xenograft mouse model to evaluate the efficacy and safety profiles of different doses of 11T and Iri. A dose-response study following the principles of Project Optimus was conducted to evaluate the efficacy, as measured by the tumor growth inhibition (TGI) based on the tumor volume and change in tumor volume, and the safety of 11T and Iri at the MTD, 50% of MTDs, and 25% of MTDs. To compare the cancer targeting potential of 11T, the tissue distribution of SN-38 in tumor, plasma, and muscle was also determined using the SN-38 AUC after 11T and Iri administration. A second study comparing the tissue distribution of Oni to Iri was also conducted. Studies comparing 11T directly to Oni were not conducted given the lack of 11T drug supply. Results: 100% TGI of 11T occurred at the MTD, 50% MTD and 25% MTD while the TGI decreased from 85% to 64% to 53% for Iri at MTD, 50% MTD and 25% MTD. The tumor to muscle SN-38 AUC ratio for 11T was approximately 200 while the ratios for Iri and Oni were less than 15. The tumor to plasma ratio for 11T was approximately 10 while the ratios for Iri and Oni were less than 7. Conclusions: 11T efficacy of 100% TGI was maintained from MTD to 25% MTD while the adverse events (AEs) continually decreased suggesting that the ODR is not the MTD but likely lower than the MTD. This differs from Iri where both efficacy and AEs decrease with decreasing dose making the MTD a potential ODR. The difference in the dose-efficacy vs dose-safety relationships may be because 11T selectively enhances tumor permeability and prolongs SN-38 tumor exposure. These data suggest that 11T could potentially provide greater efficacy with less adverse events in patients who now receive the FDA approved drugs.