2070 Background: Proliferative, pro-angiogenesis, and pro-inflammatory actions mediated by L-thyroxine in glioblastoma (GBM) are initiated at cell surface thyrointegrin αvβ3 receptors for thyroid hormone, located on the extracellular domain of αvβ3 integrin. Thyrointegrin αvβ3 receptors are over-expressed in cancer and rapidly dividing endothelial cells. fb-PMT (NP751) is a macromolecule in which fluorobenzyl is conjugated to monodisperse polyethylene glycol via mono-triazole tetraiodo thyroacetic acid, with high affinity and specificity for thyrointegrin αvβ3 receptors. In pre-clinical murine xenograft models, fb-PMT resulted in a dose-dependent suppression of GBM tumor growth and viability, and histopathological analysis revealed loss of the vascularity along with extensive tumor necrosis and apoptosis. Genomic micro-array studies suggested multiple growth pathways in GBM are modulated by fb-PMT. Based on this promising pre-clinical data, we conducted a first-in-human Phase 1 study of fb-PMT in patients with recurrent GBM. Methods: Patients with first or second recurrence of GBM were enrolled to receive fb-PMT via subcutaneous injection once daily for 28-day cycles, following a 3+3 design. Predefined dose levels were 0.08, 0.24, 0.48, 0.96, and 1.44 mg/kg/day, respectively. The study objectives were to evaluate the safety and tolerability of daily administration of fb-PMT, and establish the recommended phase 2 dose (RP2D) of fb-PMT. Exploratory objectives included pharmacokinetic profiling of fb-PMT, expression of αvβ3 integrin, fb-PMT, and other proteins in available tumor samples, and estimating preliminary efficacy of fb-PMT. Results: As of January 2026, accrual has been completed, with 22 patients enrolled and 20 patients completing at least one treatment cycle. Treatment with fb-PMT was well tolerated across the 5 dose levels examined. No serious adverse events (SAEs) related to fb-PMT and no dose-limiting toxicities occurred; the RP2D is 0.96 mg/kg/day. PK analysis demonstrated a dose-dependent increase in systemic drug exposure with escalating doses. Immunohistochemical evaluation of integrin αvβ3 expression in available tumor samples detected target expression, with variable levels of integrin αvβ3 expression and predominant localization to tumor-associated vasculature and regions of necrosis and hemorrhage. Preliminary efficacy evaluation is ongoing, with two patients in Cohort 4 (0.96 mg/kg/day) having partial response and remaining on study (cycle 35+ and cycle 26+, respectively). Conclusions: This Phase 1 study demonstrated that treatment of recurrent glioblastoma with fb-PMT was safe and well tolerated, with a predictable pharmacokinetic profile. Two patients remain on therapy beyond 24 months. Future studies are planned. Clinical trial information: NCT05226494 .
Blondin et al. (Wed,) studied this question.