ST316 Shows Promise in Phase 1 Trial for Wnt/β-Catenin-Driven Cancers

Colorectal cancer image: © mi_viri - stock.adobe.com

ST316, a first-in-class antagonist of the interaction between β-catenin and its co-activator BCL9, has demonstrated promising results in the phase 1 dose-escalation ST316-101 study (NCT05848739) for the treatment of patients with Wnt/β-catenin pathway-driven cancers.¹ 

In the study, ST316 was shown to be safe and welltolerated at all tested doses, with no significant toxicities reported. As of September 24, 2024, 23 patients with colorectal cancer (CRC; n = 14), non–small cell lung cancer (NSCLC; n = 4), pancreatic ductal adenocarcinoma (n = 2), or breast and ovarian cancer (n = 1 each), were treated in 6 cohorts who received ST316 intravenously at doses ranging from 0.5 mg/kg to 12 mg/kg once weekly.² 

Treatment-related AEs were observed in 17 patients and were mostly low grade, except for 2 AEs that were grade 3 and resolved. The agent also prolonged stable disease in several patients, consistent with early signals of antitumor activity.¹

In 4 of the 7 patients assessed, tumor uptake and target engagement were confirmed, as shown by a shift in β-catenin localization from the nucleus to the cytoplasm/membrane following treatment. ST316 also significantly reduced the expression of immunosuppressive polymorphonuclear myeloid-derived suppressor cells in all phase 1 patients with elevated baseline levels.

"With signals of antitumor activity, strong pharmacodynamic data, and a clean safety profile, we are pleased that the ST316 phase 1 dose escalation study demonstrated clinical proof-of-concept as a single agent, in a patient population in which single agent response is limited," Abi Vainstein-Haras, MD, Sapience's chief medical officer, said in a press release. "ST316's tolerability as a single agent, together with the biomarker data from its phase 1 study, are encouraging for its continued development in our ongoing phase 2 dose expansion study, which is evaluating ST316 across multiple combinations and lines of treatment in colorectal cancer."

The phase 1, first-in-human, dose-escalation and -expansion study enrolled patients with advanced solid tumors likely to harbor abnormalities in the Wnt/β-catenin pathway. Experts are evaluating the safety, pharmacokinetics (PK), biomarker and preliminary activity of ST316, and to recommend a phase 2 dose.³

The phase 1 dose-escalation portion of the study examined ST316 at various dose levels in patients with select advanced solid tumors that are known to harbor abnormalities of the Wnt/β-catenin signaling pathway, including CRC.

Eligible patients must be 18 years of age or older with an ECOG performance status of 0 to 1. The study is enrolling individuals with locally advanced or metastatic inoperable tumors, with specific tumor types varying by phase.

For the dose-escalation phase, eligible tumor types include CRC, hepatocellular carcinoma, triple-negative breast cancer, NSCLC, ovarian cancer, melanoma, cholangiocarcinoma, and synovial sarcoma. The expansion phase focuses exclusively on CRC, though additional indications and combinations may be added with updated criteria. Patients may have received up to 3 prior lines of systemic therapy for metastatic disease and must be refractory, intolerant, or have refused available standard-of-care options.

Further, patients must agree to provide a newly obtained biopsy of an accessible lesion prior to treatment initiation and undergo a repeat biopsy during treatment, unless inaccessible, in which case archival tumor tissue is acceptable. Lesions must not be previously irradiated, except for new or progressing lesions within a radiation field. Patients must be deemed by the investigator as unlikely to derive clinical benefit from or ineligible for standard therapies, or have failed or not tolerated prior anticancer treatments.

The primary end point is to evaluate the number of patients with treatment-related adverse events as assessed by CTCAE v5.0. Secondary end points include duration of response, PK, overall survival, progression-free survival, and objective response rate.

About ST316

ST316 is a first-in-class antagonist of β-catenin and its co-activator, BCL9, that is designed to selectively shut down the Wnt/β-catenin signaling pathway. Preclinical studies have shown that ST316 synergizes with checkpoint inhibition. By selectively modulating the Wnt/β-catenin pathway downstream, ST316 avoids the toxicities associated with earlier Wnt-targeting agents.¹ 

ST316 is currently being tested in the phase 2 portion of this study for patients with CRC when given in combination with relevant standards of care and in multiple lines of treatment.

Previously, the FDA granted orphan drug designation to ST316 for the treatment of familial adenomatous polyposis.

REFERENCES:

1. Sapience Therapeutics presents ST316 phase 1 dose escalation data at the 2025 American Society of Clinical Oncology (ASCO) gastrointestinal (GI) Cancers Symposium. News release. Sapience Therapeutics, Inc. January 27, 2025. Accessed March 14, 2025. https://tinyurl.com/mptymk7n

2. El-Khoueiry A, Lakhani N, Henry J, et al. Safety and biomarker assessment of ST316, a novel peptide antagonist of ß-catenin, in patients with advanced solid tumors. J Clin Oncol. 2025;43(suppl 4):286. doi:10.1200/JCO.2025.43.4_suppl.286

3. A phase 1-2 of ST316 with selected advanced unresectable and metastatic solid tumors. ClinicalTrials.gov. Accessed Updated February 17, 2025. March 14, 2025. https://clinicaltrials.gov/study/NCT05848739