Trial START-001: A phase 1/2 study of STAR0602, a first-in-class, selective T cell receptor (TCR)-targeting, bifunctional antibody-fusion molecule, as monotherapy in patients with antigen-rich tumors post checkpoint inhibitor (CPI) treatment.
Authors: Sullivan Ryan J. , Liu Ke , Redman Jason M. , Tschernia Nicholas , Bayliffe Andrew , Marino Alyssa , Srinivasan Karunya , Katragadda Madan , Moisan Jacques , Chopra Rajesh , Marabelle Aurelien , Kaufman Howard L. , Siu Lillian L. , Su Zhen , Gulley James L. 
Published: June 2023

TPS2671 Background: Many patients do not respond to CPI-based therapies and most responders eventually develop resistance. Thus, the development of more effective therapies for CPI treatment resistance is a significant unmet medical need. STAR0602, a first-in-class, TCR β chain-targeting bifunctional antibody fused to a costimulatory molecule, binds the germline Vβ6/Vβ10 TCRs of human alpha/beta (aβ) T cells, and promotes the selective activation and expansion of CD8+ and CD4+ Vβ6/Vβ10 effector memory T cells by simultaneously engaging direct TCR activation with IL-2 receptor binding and activation in cis. Preclinical studies with STAR0602 and its murine surrogate showed potent single-agent anti-tumor activity in multiple CPI-refractory human organoid and murine syngeneic tumor models, and acceptable tolerability and limited cytokine release in monkeys and mice. Durable anti-tumor responses, with long-term protection from tumor re-challenge, was associated with de novo expansion and tumor infiltration of targeted Vβ T cell subsets with a novel effector memory gene signature and striking increase in TCR repertoire diversity. These data provide strong scientific rationale to investigate the safety and efficacy of STAR0602 in patients with CPI-resistant cancers. Methods: Using a 3+3 trial design, Phase 1 of START-001 is a dose escalation through eight provisional dose levels of STAR0602, administered via an intravenous infusion once every two weeks, to determine a recommended Phase 2 dose (RP2D), based on safety and tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity. Subjects must have one of the following, histologically confirmed solid tumors that are unresectable, locally advanced or metastatic and for which standard curative therapies do not exist or are no longer effective: 1) high mutational burden solid tumors (TMB-H); 2) MSI-H/mismatch repair-deficient (dMMR) cancers; 3) Virally associated tumors including Merkel cell carcinoma, cervical, oropharyngeal, anal, penile, vaginal, and vulval cancers. After an RP2D is selected, Phase 2 (dose expansion at this RP2D) will begin to further investigate the safety and preliminary anti-tumor activity of STAR0602 in 10 provisional cohorts of patients who have the following solid tumors: TMB-H, CPI experienced; TMB-H, no prior CPI experience; MSI-H/dMMR; virally associated tumors; K-RAS wild-type and MSI-L/MMR proficient colorectal cancer (CRC); K-Ras mutant CRC; metastatic triple-negative breast cancer; relapsed and refractory epithelial ovarian cancer; metastatic castration-resistant prostate cancer; primary stage IV or recurrent non-small cell lung cancer. Phase 1 enrollment has begun since January 2023. Clinical trial information: NCT05592626 .