RT Journal Article SR Electronic T1 Preliminary Dosimetry Results from a First-in-Human Phase I Study Evaluating the Efficacy and Safety of [225Ac]-FPI-1434 in Patients with IGF-1R Expressing Solid Tumors JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 74 OP 74 VO 62 IS supplement 1 A1 Juneau, Daniel A1 Saad, Fred A1 Berlin, Alejandro A1 Metser, Ur A1 Puzanov, Igor A1 Lamonica, Dominick A1 Sparks, Richard A1 Burak, Eric A1 Simms, Ryan A1 Rhoden, John A1 Creeden, Lauren A1 Watson, Courtney A1 Armor, Thomas A1 Kazakin, Julia A1 O'Leary, James A1 Beauregard, Jean-Mathieu A1 Chenard-Poirier, Maxime YR 2021 UL http://jnm.snmjournals.org/content/62/supplement_1/74.abstract AB 74Objectives: [225Ac]-FPI-1434 is a radioimmunoconjugate consisting of a humanized monoclonal antibody, a proprietary bifunctional chelate, and the alpha-emitting radionuclide actinium-225 (Ac-225) which binds to the external domain of the insulin-like growth factor type 1 receptor (IGF-1R), a receptor tyrosine kinase expressed by a majority of cancer cells. Internalization of the radioimmunoconjugate causes tumor cell death primarily through double stranded DNA breaks induced by alpha particles emitted from the decay of Ac-225. An indium-111 analog, [111In]-FPI-1547, with the identical antibody and bifunctional chelate is used for patient selection based on quantification of IGF-1R expressing targets and organ-based dosimetry prior to therapy. The aim of this phase 1 study (NCT03746431) is to evaluate the safety and tolerability of [111In]-FPI-1547 and [225Ac]-FPI-1434 in patients with advanced refractory solid tumors and to determine the Recommended Phase 2 Dose (RP2D) of [225Ac]-FPI-1434 in patients with IGF-1R expressing tumors. Patient-specific dosimetry is employed for treatment planning to confirm the protocol-specified administered activity does not exceed radiation absorbed dose limits for selected organs of interest. Methods: The radiation absorbed dose to critical organs was estimated after an IV administration of 185 MBq of [111In]-FPI-1547. Four serial anterior/posterior whole-body scans were obtained over an 8 day period. Count data was extracted from each scan and used in conjunction with CT-based volumes to estimate radiation absorbed dose to normal organs and tissues per the MIRD schema. Radiation absorbed dose estimates for planned therapeutic administrations of [225Ac]-FPI-1434 were performed using OLINDA/EXM software (versions 2.1-2.2) and verified to be within protocol-specified radiation dose limits for the kidneys (18 Gy), liver (31 Gy) and lungs (16.5 Gy). Single therapeutic administrations of [225Ac]-FPI-1434 followed a modified 3+3 dose escalation design in the first three cohorts of 10, 20, and 40 kBq/kg body weight. Multiple administration cohorts of 75 and 100 kBq/kg body weight are ongoing until RP2D is determined. Results: Results are available for 13 patients from the single dose administration portion of the study. All 13 (100%) demonstrated avidity in at least one lesion and all were eligible to receive study drug based on dosimetry. Estimated mean radiation doses (±SD) per unit of administered activity were: kidneys, 988±305 mGy-Eq/MBq; liver, 934±319 mGy-Eq/MBq; lungs, 626±175 mGy-Eq/MBq. Mean total body radiation dose (±SD) was 140±16 mGy-Eq/MBq (range 111-167 mGy-Eq/MBq). Twelve (92%) patients received at least one therapeutic administration of [225Ac]-FPI-1434 ranging from 0.80 to 4.2 MBq. [225Ac]-FPI-1434 demonstrated a manageable safety profile with no drug-related serious adverse events and/or dose limiting toxicity. Conclusion: This prospective treatment planning paradigm for targeted alpha therapy of IGF-1R expressing tumors is an important safety checkpoint to estimate potential risks to tissue distribution in critical organs such as kidneys, liver and lungs. Patient-specific treatment planning provides a means for optimizing therapeutic administration, incorporating individualized biodistribution, biokinetics, and clearance patterns.