TPS3172 Background: Parathyroid hormone-related protein (PTHrP) is a hormone frequently overexpressed in tumors such as pancreatic ductal adenocarcinoma (PDAC), lung, and head and neck cancers. In some cases, this overexpression can lead to hypercalcemia in patients with malignancies. PTHrP is a ligand of G-protein–coupled receptor (GPCR) known as parathyroid hormone type 1 receptor (PTH1R), thereby activating multiple downstream signaling pathways. Despite the significant role of GPCRs in cancer biology, therapeutic options targeting these receptors in oncology remain limited. BGM-2121 is a potent, first-in-class, humanized IgG1 monoclonal antibody targeting the N-terminal region of PTHrP, aiming to inhibit the PTHrP/PTH1R pathway. Preclinical studies exhibit high affinity and specificity for PTHrP, demonstrating robust antitumor activity in pancreatic cancer xenograft models, and significantly prolonging survival. In lung squamous cell carcinoma models, BGM-2121 was found to prevent and reverse hypercalcemia and cancer-associated weight loss, which are the key features of humoral hypercalcemia of malignancy and cachexia. Methods: BGM-2121-001 (NCT07346846) is a first-in-human, open-label, phase 1 trial designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor, anti-cachexia, and anti-hypercalcemia activity in adults with advanced solid tumors. Eligible participants are adults with histologically or radiographically confirmed advanced solid tumors who are refractory to, intolerant of, or without available standard therapies. Tumor types of primary interest include pancreatic, esophageal, head and neck, and non–small cell lung cancers, particularly sub-type of squamous cell carcinoma. Participants must have ECOG performance status ≤2 and adequate organ function. Key exclusions include active central nervous system metastases, significant cardiovascular disease, uncontrolled infections, recent anticancer therapy, prior allogeneic transplantation, active viral hepatitis or HIV infection. BGM-2121 is administered intravenously every 2 weeks in sequential dose-escalation cohorts (160, 320, 480, 800, and 1200 mg) using a standard 3+3 design. Dose-limiting toxicities are assessed during the first 28 days, and the maximum tolerated dose is defined as the highest dose at which ≤1 of 6 patients experiences a dose-limiting toxicity. Dose modifications are determined by the Safety Review Committee. Treatment continues until disease progression, unacceptable toxicity, or loss of clinical benefit. Clinical trial information: NCT07346846 .
Ou et al. (Thu,) studied this question.