Introduction

In a groundbreaking development, ST316, a unique antagonist targeting the interaction between β-catenin and its co-activator BCL9, has shown encouraging results in the ongoing Phase 1 dose-escalation ST316-101 study (NCT05848739). This new treatment is specifically aimed at addressing Wnt/β-catenin pathway-driven malignancies, marking a significant step forward in cancer therapy.

Trial Overview

As of September 24, 2024, the clinical trial has treated 23 patients suffering from various cancers, including colorectal cancer (CRC; n = 14), non-small cell lung cancer (NSCLC; n = 4), pancreatic ductal adenocarcinoma (n = 2), and rare cases of breast and ovarian cancer (n = 1 each). Patients received ST316 intravenously at varying doses from 0.5 mg/kg to 12 mg/kg on a weekly basis, and the results have been very promising.

Safety and Efficacy

The treatment has been found to be safe and well-tolerated, with no significant toxicities reported. Out of the 23 patients, 17 experienced treatment-related adverse events, mostly of low grade, with only two instances categorized as grade 3, both of which resolved effectively. Notably, several patients demonstrated a prolonged stable disease state, suggesting early evidence of antitumor activity.

Tumor Engagement and Immunological Impact

Excitingly, in 4 out of 7 patients evaluated, the treatment confirmed tumor uptake and engagement of the target, indicated by a shift in the localization of β-catenin from the nucleus to the cytoplasm or membrane after administration. Furthermore, ST316 also significantly decreased levels of immunosuppressive polymorphonuclear myeloid-derived suppressor cells in patients with elevated baseline levels, which may enhance the effectiveness of the immune response against tumors.

Expert Insights

Dr. Abi Vainstein-Haras, Chief Medical Officer at Sapience, expressed optimism regarding the trial's findings. "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," she stated. "The tolerability and biomarker data encourage us as we move forward with our ongoing phase 2 dose expansion study, where we are evaluating ST316 in various combinations and treatment lines for colorectal cancer."

Eligibility and Objectives

The Phase 1 study primarily focused on patients with advanced solid tumors likely harboring abnormalities in the Wnt/β-catenin signaling pathway. Experts are meticulously assessing the safety, pharmacokinetics, and preliminary activity of ST316 to recommend an appropriate dosing for Phase 2 trials.

Eligibility criteria for participants include adults aged 18 and older, with a performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) scale. Patients must have locally advanced or metastatic tumors and may have undergone up to three prior lines of systemic therapy for metastatic disease. They are also required to provide biopsies before and during treatment to monitor the treatment’s effect on tumor biology.

The primary objective of the trial is to evaluate the occurrence of treatment-related adverse events, while secondary objectives include overall survival rates, duration of response, and progression-free survival among participants.

About ST316

ST316 stands out as a first-in-class antagonist specifically designed to selectively inhibit the Wnt/β-catenin signaling pathway, which has been implicated in numerous cancers. Unlike earlier agents targeting this pathway, ST316 offers a novel approach that avoids associated toxicities, representing a significant advancement in the treatment landscape.

Currently, ST316 is being explored in the phase 2 studies for colorectal cancer in combination with existing treatments. Furthermore, ST316 received orphan drug designation from the FDA for treating familial adenomatous polyposis, highlighting its potential in rare genetic disorders linked to cancer.

As research progresses, the field of cancer therapy may soon witness a transformative change with ST316 paving the way for more effective, targeted treatment options for patients with challenging malignancies.