Preliminary Dosimetry Results from a First-in-Human Phase I Study Evaluating the Efficacy and Safety of [Ac-225]-FPI-1434 in Patients with IGF-1R Expressing Solid Tumors

74 Objectives: [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.