Dose-escalation Study of [225Ac]-FPI-1434 (FPI-1434) in Patients (pts) with IGF-1R Expressing Advanced Solid Tumors: Preliminary Pharmacology and Dosimetry Results

Introduction: Type I Insulin-like Growth Factor Receptor (IGF-1R) overexpression is associated with cancer growth, survival, and metastases. It is overexpressed in several malignancies, including breast, ovarian, prostate, colon, pancreatic cancer, and sarcomas. FPI-1434, a novel, targeted alpha therapeutic (TAT), consists of an anti-IGF-1R humanized monoclonal antibody (mAb, FPI-1157, formerly AVE1642), a proprietary bifunctional chelate, and an α-emitting radionuclide, actinium-225. FPI-1547 is the indium-111 imaging analogue of FPI-1434 and is used for selection of pts with IGF-1R-expressing tumors. TATs induce cell death via double-strand DNA breaks. Tumor cell death may also occur due to TAT-induced radiation crossfire, bystander, and vaccine-like (activation of antigen-specific CD8+ T cells) effects.

Methods: Phase 1 consists of FPI-1434 dose escalation (single- and multi-dose cohorts), an imaging cold Ab sub-study (administration of FPI-1175/ “cold Ab” prior to FPI-1547), and “cold+hot” dose escalation (administration of cold Ab prior to FPI-1547 and FPI-1434). SPECT and whole-body planar imaging with FPI-1547 (185 MBq) is used to assess individual pt dosimetry/safety and eligibility for FPI-1434 treatment defined as tumor-to-background ratio (TBR) ≥2. Other key inclusion criteria include age ≥18 yrs, ECOG PS ≤1, and adequate organ function. Study objectives are to determine MTD/RP2D of FPI-1434 alone and/or “cold+hot” regimen based on safety, tolerability, dosimetry, biodistribution, PK; and to assess preliminary anti-tumor activity. The traditional 3+3 dose escalation is used. DLT observation period is 8 wks in single- and 6 wks in multi-dose escalation cohorts.

Results: As of December 19, 2022, 38 pts with different tumor types were enrolled.23/38 pts satisfied all eligibility criteria, including TBR and were treated with FPI-1434 (dose range 10-75 kBq/kg) ± FPI-1175 (0.5 mg/kg). The FPI-1175 dose was selected based on the results of the cold antibody sub-study in which biodistribution using 0.5 mg/kg versus 1.5 mg/kg FPI‑1175 was evaluated (JNM June 2022, 63 (supplement 2) 2275).

FPI-1434 plasma exposure (area under the curve) generally increased with dose during the dose escalation with considerable inter-individual variability in the "hot-only" cohort. FPI-1175 pre-dosing to FPI-1547/FPI-1434 (“cold+hot” cohort) led to substantial increase in systemic exposure of FPI-1547/FPI-1434 while the PK profile of the FPI-1175 was consistent with the previously reported PK of the parental FPI-1175

Conclusions: Pre-administration of FPI-1175 relative to FPI-1547 alone led to favorable PK and dosimetry shift with improved tumor-to-normal organ ratio of radiation absorbed dose estimates. Evaluation of “cold+hot” therapeutic regimen is ongoing. Safety, biodistribution, dosimetry, PK, and preliminary efficacy analyses of administration of FPI-1434 with or without pre-dosing with FPI-1175 will be presented.