Impact of Pre-Administration of Anti-IGF-1R Antibody FPI 1175 on the Dosimetry, Tumor Uptake, and Pharmacokinetics of the IGF-1R Targeted Theranostic Imaging Agent [111In] FPI 1547 in Patients with Solid Tumors

Introduction: [¹¹¹In]‑FPI‑1547 is an In‑111 labeled antibody (Ab) targeting the insulin-like growth factor 1 receptor (IGF-1R). [¹¹¹In]‑FPI‑1547, the imaging biomarker analogue of the therapeutic Ac‑225 labeled Ab, is being used for patient selection and quantification of IGF-1R expression in a Phase 1 study of [²²⁵Ac]‑FPI‑1434. The objective of this study is to identify the maximum tolerated dose and optimal dosing regimen of [²²⁵Ac]‑FPI‑1434 in patients with IGF-1R avid tumors assessed by imaging. Concurrent with the dose escalation portion of the Phase 1 study, an exploratory sub-study was conducted to assess the impact of pre-dosing with the parent Ab (cold Ab, FPI‑1175, formerly AVE1642) on biodistribution, pharmacokinetics (PK), and dosimetry of [¹¹¹In]-FPI-1547.

Methods: Each patient in the cold Ab sub-study (CASS) underwent two [¹¹¹In]‑FPI‑1547 imaging evaluations, with and without pre-administration of FPI‑1175, such that each patient served as their own control to evaluate the extent of any changes in biodistribution and organ dosimetry. In each imaging evaluation, the absorbed radiation dose to major organs and tumor lesions was estimated after intravenous administration of 185 MBq of [¹¹¹In]‑FPI‑1547 with or without pre-dosing of 0.5 or 1.5 mg/kg FPI‑1175. Serial anterior/posterior scintigraphic images were obtained over 6 to8 days and count data were used to estimate absorbed dose to normal organs/tissues and tumor lesions per the MIRD schema. Plasma PK of [¹¹¹In]‑FPI‑1547 were determined by radioanalysis of samples collected. The impact of FPI‑1175 pre-administration on normal organ and lesion dosimetry for the corresponding ²²⁵Ac form was assessed by evaluating the changes in biodistribution, residence time, and absorbed dose estimates with and without FPI‑1175 in normal organs relative to changes in tumor lesions.

Results: A total of five patients completed the CASS, of which two were randomized to 0.5 mg/kg and three to 1.5 mg/kg FPI‑1175. Normal organ/tissue dosimetry was available for four patients and lesion dosimetry data for five patients. In general, a favorable dosimetry shift was noted with the addition of FPI‑1175 relative to [¹¹¹In]‑FPI‑1547 alone, with improved lesion-to-normal organ ratio of radiation absorbed dose estimates in most patients who received FPI‑1175 pre-administration. Results at 0.5 mg/kg were generally more favorable versus 1.5 mg/kg FPI‑1175. With the addition of FPI‑1175, sites of improved lesion uptake were noted independent of anatomic location (including bone, mediastinum, lung, liver, and lymph nodes). Pre-administration of FPI‑1175 significantly increased [¹¹¹In]‑FPI‑1547 plasma exposure (AUC) without any changes in the [¹¹¹In]‑FPI‑1547 safety profile. No grade ≥3 toxicity with or without pre-dosing with FPI‑1175 were observed. The PK profile of [¹¹¹In]‑FPI‑1547 with the added FPI‑1175 was consistent with previously reported PK of the parental Ab FPI‑1175.

Conclusions: This prospective analysis of FPI-1175 administration prior to [¹¹¹In]-FPI-1547 did not identify any significant change in the safety profile of [¹¹¹In]-FPI-1547, demonstrated a favorable gain in tumor lesion uptake versus normal tissue and supports assessment of pre-administration of FPI-1175 prior to [²²⁵Ac]-FPI-1434. Additional data on lesion uptake and PK parameters in the different dose cohorts will be presented. Exploration of the potential value of adding FPI-1175 to [²²⁵Ac]-FPI-1434 dosing regimen have been incorporated into the ongoing Phase 1 study (NCT03746431).

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