Abstract CT011: First in human study of activin-A inhibitor, STM434, in patients with granulosa cell ovarian cancer and other advanced solid tumors

Abstract

Abstract Background: STM434 is a soluble receptor ligand trap targeting activin A, a protein in the TGF-beta family that plays important roles in growth, differentiation, and cancer cachexia. Activin A overexpression is a common feature in many gynecologic cancers. Granulosa cell tumors also harbor pathognomonic mutations in FOXL2, which specifically promotes dysregulated activin signaling. The role of inhibiting activin A signaling in human cancers has not been previously explored. Methods: Primary endpoint was to establish to maximum tolerated dose of STM434. Dose was initially escalated by accelerated titration and then 3+3 design. Secondary endpoints included safety per CTCAE v4, pharmacokinetics, and response by RECIST v1.1. As Activin A is also implicated in metabolism and muscle function, changes in key metabolic parameters including lean body and fat mass established by DXA scan and 6 minute walk test (6MWT), were serially measured. Results: 32 patients were treated at doses ranging from 0.25 - 8 mg/kg IV every 2-4 weeks. Tumor types included ovarian granulosa cell (n=13), epithelial ovarian (n=7), colon (n=3), pancreatic (n=2), and other solid tumors (n=7). A total of 5 DLTs were observed in 3 pts (all grade 3): hemorrhagic ascites (0.5 mg/kg Q4W) and stomatitis, gastritis, epistaxis, and alkaline phosphatase increase (all 8 mg/kg Q2W). The most common treatment-related AEs were fatigue (n=12), epistaxis (n=11), and gingival bleeding (n=6). Other observed hematologic related-AEs included telangiectasia (n=3), hemorrhagic ascites (n=2), and petechiae (n=2). No treatment-related grade 4 or 5 AEs occurred. STM434 resulted in the expected FSH level decreases in most patients. STM434 also resulted in metabolic parameter changes, including an increase in total lean body mass (1%-20%, 0.5 mg/kg Q2W to 4 mg/kg Q2W cohorts) and 6-minute walk test (25-150 meters in the 0.5 mg/kg Q2W-2 mg/kg Q2W cohort) and decrease in total fat mass (-3% to -18% in the 0.5 mg/kg Q4W- 4 mg/kg Q2W cohorts). One patient with fatty liver on baseline imaging had complete resolution of this finding after 2 cycles of therapy. No responses were observed in the 28 evaluable patients. In granulosa cell patients, the stable disease rate was 9/12 (75%) although the significance of this finding is uncertain. Conclusions: The MTD of STM434 was 4 mg/kg Q2W. STM434 use resulted in mucocutaneous bleeding complications likely related to off-target inhibition of bone morphogenic protein 9 (BMP9). BMP9 bears substantial homology to activin A and inherited inactivation of BMP9 can result in hereditary hemorrhagic telangiectasia which shares a phenotype similar to the AE profile observed here. While no direct antitumor efficacy was documented, potentially clinically meaningful dose-related metabolic effects were observed that support further exploration of Activin A inhibitors that avoid BMP9 blockade in cancer. Citation Format: Jessica J. Tao, Joyce F. Liu, Drew W. Rasco, Willis Navarro, Christopher M. Haqq, David M. Hyman. First in human study of activin-A inhibitor, STM434, in patients with granulosa cell ovarian cancer and other advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT011.