START-001 is Evaluating TCR-Targeted Bifunctional Antibody in Patients With Solid Tumors

The phase 1 START-001 study (NCT05592626) is evaluating STAR0602, a T-cell receptor (TCR)-targeting bifunctional antibody, in patients with solid tumors refractory to checkpoint inhibitors (CPIs).

The study design and progress were presented at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois,by Ryan J. Sullivan, MD, Associate Professor, Medicine, Harvard Medical School and Massachusetts General Hospital.

“Many patients do not respond to CPI-based therapies and most responders eventually develop resistance. Development of more effective therapies for CPI treatment resistance is a significant unmet medical need,” Sullivan and colleagues wrote.

START-001 began enrolling patients in January 2023. STAR0602 is a TCR β chain-targeting bifunctional antibody fused to a costimulatory molecule that binds the germline Vβ6/Vβ10 of T-cells to promote selective activation and expansion of CD8- and CD4+ Vβ6/Vβ10 effector memory T cells by direct TCR engagement and co-stimulation and co-stimulation of IL-2 receptors.The targeted T cell subsets are present in 6-10% of tumor-infiltrating lymphocytes across different solid tumors.

The study is enrolling adult patients with measurable, refractory solid tumors, with at least an ECOG performance status of 2 and a life expectancy of at least 12 weeks. The study is excluding patients with a history of known autoimmune disease except vitiligo, psoriasis or atopic dermatitis, Graves’ disease, hypothyroidism, alopecia, or arthritis; patients receiving treatment with over 10 mg of prednisone or equivalent immuno-suppressive drugs; or clinically significant cardiovascular/vascular disease or gastrointestinal disorders. The study is beginning with a dose-escalation phase evaluating up to 8 dose levels to evaluate safety, tolerability, and the recommended phase 2 dose (RP2D). The study will progress to the phase 2 dose expansion phase that will evaluate the RP2D in cohorts with TMB-H ICI experienced patients, MSI-H ICI experienced patients, patients with virally associated tumors, and TMB-H IVI naïve patients.

“Preclinical studies with STAR0602 and a 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,” Sullivan and colleagues wrote. “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.”

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REFERENCE

Sullivan RJ, Liu K, Redman JM, et al. 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. Presented at: ASCO 2023 Annual Meeting; June 2-6; Chicago, Illinois. Poster #509a