Phase I study of AMG 509, a STEAP1 x CD3 T-cell recruiting XmAb 2+1 immune therapy, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kelly William Kevin , Pook David William , Appleman Leonard Joseph , Waterhouse David Michael , Horvath Lisa , Edenfield William Jeffery , Matsubara Nobuaki , Danila Daniel Costin , Aggarwal Rahul Raj , Petrylak Daniel Peter , Sartor A. Oliver , Sumey Christopher Joseph , Adra Nabil , Armstrong Andrew J. , Cheng Fu-Chih , Stieglmaier Julia , Kouros-Mehr Hosein , Dorff Tanya B. 
Published: March 2021

TPS183 Background: Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen that is highly expressed in prostate cancer. AMG 509 is a potent bispecific XmAb 2+1 immune therapy designed to direct T effector cells to STEAP1-expressing cells. AMG 509 contains two identical humanized anti-STEAP1 Fab domains that bind STEAP1-expressing cells, an anti-CD3 scFv domain that binds T cells, and an Fc domain, engineered to lack effector function, that extends serum half-life. In preclinical studies, AMG 509 induced potent and specific T-cell-mediated lysis of STEAP1-expressing cancer models. Methods: This open-label, phase 1, first-in-human study will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 509 in patients with relapsed/refractory mCRPC. The dose exploration phase (n=40) will estimate the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) using a Bayesian logistic regression model. The dose expansion phase (n=30) will confirm safety, PK, and pharmacodynamics at the MTD or RP2D and collect further safety, efficacy, and biomarker data. Efficacy will be assessed by prostate-specific antigen response, circulating tumor cell response, and objective tumor response per RECIST 1.1 with Prostate Cancer Working Group 3 modifications. Key inclusion criteria: men ≥18 years with histologically/cytologically confirmed mCRPC who are refractory to novel hormonal therapy (e.g., abiraterone and/or enzalutamide) and have failed 1–2 taxane regimens or are medically unsuitable for or have refused taxanes; ongoing castration with total serum testosterone ≤50 ng/dL; evidence of progressive disease; ECOG performance status 0–1; life expectancy ≥3 months; and adequate hematologic, renal, hepatic, and cardiac function. In the dose exploration phase, novel antiandrogen therapy must have been given in the metastatic setting. Key exclusion criteria: pure small cell or neuroendocrine carcinoma of the prostate; untreated CNS metastases or leptomeningeal disease; any anticancer therapy or immunotherapy, radiation therapy, or major surgery <4 weeks from first dose; history of or current autoimmune disease or any disease requiring immunosuppressive therapy (≤10 mg/d prednisone permitted); prior STEAP1-targeted therapy; infection requiring IV antimicrobials <7 days from first dose. The study opened in January 2020 and is recruiting patients. ClinicalTrials.gov: NCT04221542. 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT04221542.