Abstract
590
Introduction: CTT1403 is a unique 177Lu-labeled phosphoramidate peptidomimetic that binds irreversibly to prostate specific membrane antigen and contains an albumin binding motif that increases the molecule’s circulation half-life. We report a preliminary investigation of radiation dose estimates in kidneys and an initial assessment of drug pharmacokinetics (PK).
Methods: In this Phase I safety dose escalation study, metastatic castration resistant prostate cancer patients receive up to 2 cycles of CTT1403 (at 0.75-6 GBq doses). This is an interim report from the first set of subjects who received 0.75, 1.5, 2.0 and 3.0 GBq CTT1403. Whole-body planar scintigraphy followed by a single field-of-view SPECT/CT focusing on kidneys was performed for all subjects at 3 or 4 time points (e.g., 2, 24, 48, and 168 hours postinjection). Attenuation, scatter, and resolution recovery corrections were made for all SPECT reconstructions for quantitative analysis. Only the upper energy window (±10% 208 keV) of Lu-177’s gamma emission was used for imaging data collection to avoid significant downscatter photons in the lower energy window (170 keV). Phantom-based calibration scans were performed for two SPECT/CT scanners used prior to the study initiation. Using patient-specific CT datasets as voxelized phantoms for Geant4 Monte Carlo simulation, radiation dosimetry was performed to assess kidney radiation exposure. Blood samples were collected 5-6 times after CTT1403 administration over 14 days, and plasma concentrations of the drug were computed. Drug distribution and elimination half-lives were calculated using biexponential curve fitting.
Results: Quantitative SPECT/CT, combined with the total dose administered, percent of injected activity over time, and Monte Carlo simulation-generated S-values showed that 12 kidneys in the first 6 subjects treated with 0.75 - 3.0 GBq received 0.87±0.41 Gy/GBq (range: 0.38 - 5.4 Gy). PK analysis indicates a biphasic clearance with half-lives of 1.09±0.36 h (range: 0.64 - 1.46 h) for the distribution phase and 27.3±3.7 h (range: 22.4 - 30.1 h) for the elimination phase.
Conclusions: We demonstrated the feasibility of estimating radiation doses in kidneys using quantitative 177Lu-SPECT/CT for CTT1403 therapy. The absorbed dose in kidneys in the first 6 subjects was well below the threshold of 23 Gy, considered the dose limiting exposure level[SY1] [BL2] . The elimination phase half-life of CTT1403 showed prolonged retention in blood plasma for this small molecule peptidomimetic, confirming enhanced circulation time imparted by the albumin binding component. Acknowledgements: The study was supported by the National Institutes of Health under grant R44CA239461, and Cancer Targeted Technology, LLC.