Preclinical Radiation Dose Optimization, Dosimetry And Maximum Tolerated Dose Studies Of Lu-177-Labeled Ctt1403, A Phosphoramidate-Based Psma Inhibitor For Targeted Radionuclide Therapy Of Prostate Cancer.

135 Objectives: Prostate-specific membrane antigen (PSMA) has proven to be an exceptional biomarker for prostate cancer as it is expressed on nearly all prostate cancers, and increased expression correlates with progression to metastatic disease and castration resistance. The performance of PSMA-targeted imaging and therapeutic agents is often limited by unfavorable rapid renal clearance. Previously, we developed a new PSMA targeted radiotherapeutic agent, CTT1403, which contained an albumin binding motif that extends blood circulation time with an irreversible PSMA inhibitor. Building upon the superior therapeutic efficacy of CTT1403 in a PSMA+ PC3-PIP human xenograft model, we performed translational studies on CTT1403 in rodent models, including dose optimization, dosimetry, and maximum tolerated dose (MTD). Methods: For the dose optimization study, tumor-bearing mice in treatment groups were randomly selected to receive 1 to 3 reduced doses of CTT1403 or put into an untreated control group, and tumor growth was monitored for up to 120 days. In the dosimetry study, rats were euthanized at various time points up to 5 weeks post administration of CTT1403 for biodistribution. Their organs as well as excretion were collected and counted in a gamma counter for dosimetry analysis using OLINDA/EXM to estimate the equivalent human doses. In a MTD study, rats were given increasing CTT1403 doses based on weight and closely monitored for up to 7 weeks. Blood samples were collected weekly for complete blood count (CBC) and liver and kidney enzyme analysis. Results: In the dose optimization study, therapeutic responses were observed in mice receiving CTT1403 treatment compared to controls. Half of the mice receiving 2 or 3 doses of CTT1403 survived longer than the duration of the study. Dosimstry data demonstrate the kidney to be the dose limiting organ, with an effective dose of 5.18 mSv/MBq, which corresponds to a limit of 4.4 GBq in humans. In the MTD study, mice receiving a dose equivalent to 10.5 GBq in humans did not have dose-limiting toxicity, which is more than twice what was dose limiting from the dosimetry study. Conclusions: Multiple (2 or 3) lower doses of CTT1403 were found to be effective in the PSMA+ PC3-PIP human xenograft model, extending the potential administration options for CTT1403. Kidney was found to be the dose limiting organ, with an administration limit of 4.4 GBq in humans; this is less than half of the estimated MTD (10.5 Gbq). Overall, the preclinical efficacy and toxicity of CTT1403 suggests this agent would be safe and effective in humans. Research Support: This work was supported by a contract from the National Institutes of Health (HHSN261201500074C) and a grant from the Department of Energy (DE-SC0008833) for partial support of JJG and XL. UPCI shared resources (In Vivo Imaging Facility) were used in this research and supported in part by NCI P30CA047904.