Abstract OT3-13-01: First in Human Study of AG01 a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88)

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Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats in the granulin-epithelin family. PGRN/GP88 is an autocrine biological driver of tumorigenesis, survival & drug resistance in several cancers including breast, ovarian, multiple myeloma, prostate cancers, non-small cell lung carcinoma (NSCLCA) & digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level in metastatic breast, lung & prostate cancer patients is associated with poor outcomes such as progression & shortened survival. An anti-human PGRN/GP88 monoclonal antibody inhibiting PGRN/GP88 action has been developed & expressed as recombinant antibody in CHO cells. Activities including pharmacology, manufacturing, formulation & GLP toxicology studies have been carried out. The IND application has been cleared by the Food and Drug Administration to proceed with the first-in-human AG01 clinical study in adult patients ((pts) with advanced solid tumors. We present an ongoing First in Human Phase 1A (dose escalation,1+(3+3) & IB (expansion cohorts) study of AG01 in pts advanced solid tumor malignancies (1A) with 4 expansion cohorts (1B) in pts with advanced Triple Negative Breast Cancer (TNBC), Hormone Resistant ER+/Her2- BC, advanced NSCLC & mesothelioma. Study Design: This is an open-label, dose escalation study of AG01 antibody administered intravenously (IV) over 90 minutes every 14 days +/- 1 day (1A), followed by 4 predefined expansion cohorts, which will be treated at the RP2D determined in the phase 1A of this study. In the 1A part, initially accelerated titration design will be utilized to guide dose progression & estimation of the maximum tolerated dose (MTD and/or maximum administered dose (MAD). In the 1A portion of the study pts with advanced relapsed/refractory solid tumor malignancies who failed 1 or more standard of care (SOC) therapies (tx) or for whom no SOC tx exists will be accrued. The primary objective of the 1A part is to determine the MTD and/or MAD of AG01. Secondary objectives are to determine the RP2D, assess the safety/tolerability, the pharmacokinetics (PKs) & immunogenicity of AG01 & the preliminary anti-tumor activity of AG01 via RECIST 1.1. The exploratory objectives are to determine PGRN/GP88 expression in tumor tissue and PGRN/GP88 blood levels using A&G’s ELISA test. In the 1B Cohort Expansion phase, 4 separate cohorts of pts with PGRN/GP88 tissue expression of 1+, 2+, 3+ by IHC will be enrolled. Cohort 1- TNBC: ER and/or PR < 1% by IHC, HER2 < 3+ by IHC and/or FISH negative, pts must have failed 1 or more SOC tx for metastatic BC. Cohort 2- Hormone-resistant BC: ER and/or PR >1%, HER2 < 3+ by IHC and/or FISH negative, failed 1 or more prior hormonal tx (HT) or HT/CD4/6 kinase inhibitor tx or other targeted tx. Cohort 3- NSCLCA: metastatic/recurrent NSCLCA failed 2 or more SOC tx. Cohort 4 -Mesothelioma- failed 1 or more SOC tx for metastatic/recurrent mesothelioma or not a candidate for SOC tx. The primary objective of 1B part is to evaluate the antitumor efficacy of AG01 by overall response rate (ORR) defined as completed response (CR), partial response (PR), stable disease >=24 weeks (SD) (CR+PR+ SD) based on RECIST v1.1 in the 4 cohorts with each cohort assessed separately for response. Secondary objectives are to evaluate progression free survival (PFS), duration of response (DOR) & overall survival (OS) of pts in cohorts 1-4, & to evaluate the ORR, DOR & PFS based on GP88 tissue expression, to further characterize the PKs & the safety/tolerability of AG01. Exploratory objectives in 1B part will assess AG01 effect on circulating PGRN/GP88 levels in plasma or other potential biomarkers in the 4 cohorts. The estimated study sample is approximately 77 pts; 17 pts for the 1A part & 60 pts for 1B part. The study is open to accrual at the UMGCCC. Supported by NCI grants R44CA224718 and R44CA162629 Citation Format: KATHERINE TKACZUK, Paula Rosenblatt, Ranee Mehra, Katherine Scilla, Nancy Tait, Binbin Yue, Ginette Serrero. First in Human Study of AG01 a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-13-01.

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