Phase 1 first-in-human trial of AG01, a recombinant humanized monoclonal antibody to progranulin/glycoprotein 88 (GP88) to determine the safety, tolerability, pharmacokinetics, and preliminary antitumor activity in subjects with advanced solid tumor malignancies.

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TPS2669 Background: Progranulin also called GP88/PGRN plays a major role as an autocrine growth & survival factor associated with resistance to standard of care (SOC) targeted and chemo therapies in several cancers including breast cancer (BC) & non-small cell lung carcinoma (NSCLC): 1) GP88 is expressed in 80% breast invasive ductal carcinomas & is negative in normal mammary tissue; 2) GP88 tumor expression is a prognostic indicator of recurrence & survival in BC, NSCLC & prostate cancer patients (pts) 4) Elevated serum GP88 levels are present in several cancers including metastatic breast cancer (MBC), lung & prostate cancer pts compared to healthy subjects; 5) Elevated/rising GP88 serum levels in MBC pts are associated with disease progression & inferior survival. These results make GP88 an ideal therapeutic & diagnostic target in solid tumors. An anti-human PGRN/GP88 monoclonal antibody inhibiting PGRN/GP88 action was developed & expressed in CHO cells. Pharmacology, GMP manufacturing, formulation, stability studies & GLP toxicology studies in non-human primates were done. The IND application cleared by the US FDA led to the FIH AG01 study in adults with advanced solid tumors lacking effective therapies. Methods: A Phase 1 FIH dose-escalation study was designed in pts with advanced solid tumor malignancies, the study is approved by the University of Maryland IRB. AG01 monoclonal antibody is administered intravenously (IV) over 90 minutes every 14 days +/- 1 day; DLT observation period is the 1st cycle=28days, with AGO1 Dose levels of,1mg/kg, 2mg/kg, 4mg/kg, 6mg/kg, 8 mg/kg. Initially accelerated titration design (1pt/dose level) was followed by 3+3 design). Eligibility criteria include pathologically confirmed diagnosis of advanced/relapsed/refractory solid tumor malignancy; failed >=1 SOC therapy or not a candidate/declines SOC therapy, ECOG <=2, adequate organ/bone marrow function, at least 1 RECIST 1.1 measurable and/or evaluable lesion. Tumor imaging-every 2 cycles (8 weeks) is used for response assessment. Primary objective is to determine the maximum tolerated dose MTD and/or maximum administered dose MAD of AG01 in the target population. Secondary objectives are to determine the RP2D, safety, tolerability, PKs, immunogenicity (ADA) & the preliminary anti-tumor activity of AG01 in pts with advanced solid tumors. Exploratory objectives will determine PGRN/GP88 expression in tumor tissue & PGRN/ GP88 blood levels (A&G’s IHC & ELISA test). The study is ongoing; & pts are currently enrolled. A parallel prospective study investigates the association of serum GP88 in MBC pts with response to SOC therapy and progression of disease based on RECIST 1.1 criteria. These studies are supported by NCI grants R44CA224718 and CA210817. Clinical trial information: NCT05627960 .

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