Abstract CT251: LuMIERE: A phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of 177Lu-FAP-2286 in patients with advanced or metastatic solid tumors

Abstract Background: Fibroblast activation protein (FAP) is a membrane-bound protease that is highly expressed on the surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers. With limited expression observed in normal tissues, FAP is a promising therapeutic and imaging target for delivery of radionuclides to cancer tissues. FAP-2286, a low-molecular-weight cyclic peptide that potently and selectively binds to FAP, is attached to a linker and tetraazacyclododecane tetraacetic acid (DOTA) cage that can be used to conjugate radionuclides such as lutetium-177 (177Lu) or gallium-68 (68Ga) for therapeutic or imaging applications, respectively. 177Lu-FAP-2286 has demonstrated antitumor activity in preclinical studies. The LuMIERE study (NCT04939610) is the first phase 1/2 clinical trial of an FAP-targeted radionuclide therapy evaluating 177Lu-FAP-2286 in patients with FAP-expressing solid tumors that are identified with the imaging agent 68Ga-FAP-2286. Methods: Eligible adult patients with advanced or metastatic solid tumors and measurable disease (per RECIST v1.1) will be selected for treatment with 177Lu-FAP-2286 on the basis of FAP expression using 68Ga-FAP-2286. In phase 1, tumors must be refractory to or have progressed following prior treatment, with no satisfactory alternative treatment options. Phase 1 includes dose escalation of 177Lu-FAP-2286, starting at 3.7 GBq to a maximum of 9.25 GBq. Patients may receive up to 6 cycles of 177Lu-FAP-2286 administered on day 1 of each 6-week cycle. Three to 12 patients will be treated at each dose level in the dose-escalation portion. Tolerability will be assessed across multiple doses for determination of a recommended phase 2 dose (RP2D), which may be further evaluated in a phase 1 dose-expansion portion. FDG-PET/CT scans will be collected prior to treatment, and patients will be imaged by planar and SPECT/CT scans at multiple time points to calculate organ and tumor dosimetry to determine absorbed radiation dose. Disease status will be assessed per RECIST v1.1 every 6 weeks. The primary objective of phase 1 is to evaluate the safety of 177Lu-FAP-2286 and determine the RP2D. Secondary objectives include the assessment of radiation dosimetry, pharmacokinetics, and preliminary efficacy of 177Lu-FAP-2286 and the evaluation of safety and tumor uptake of 68Ga-FAP-2286. Phase 2 will evaluate the efficacy, safety, and dosimetry of 177Lu-FAP-2286 in patients with select FAP-expressing solid tumors. Citation Format: Jonathan McConathy, Mallika Dhawan, Ajit H. Goenka, Emerson A. Lim, Yusuf Menda, Beth Chasen, Moh'd Khushman, Akiva Mintz, Yousef Zakharia, John J. Sunderland, Owen Bowles, Jim Xiao, Andrew D. Simmons, Kenton Wride, Aaron Enke, Thomas A. Hope. LuMIERE: A phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of 177Lu-FAP-2286 in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT251.