Nelmastobart (hSTC810) combined with capecitabine therapy in metastatic colorectal cancer with resistance or intolerance to oxaliplatin and irinotecan-based chemotherapy: A phase 1b clinical trial.

162 Background: Treatment options for patients with metastatic colorectal cancer (mCRC) who experienced disease progression after receiving oxaliplatin and irinotecan-based chemotherapy are limited. Nelmastobart (hSTC810), a humanized anti-BTN1A1 (butyrophilin subfamily 1 member A1) monoclonal antibody of the IgG4 isotype, showed acceptable safety profile and the disease control rate was 39.3% in the first-in-human study, suggesting its potential efficacy. This phase Ib study was designed to evaluate the safety and explore synergistic anti-tumor activity of nelmastobart in combination capecitabine. The study aims to determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination therapy in patients with mCRC who are refractory to standard therapy. Methods: Dose escalation phases were conducted in patients with mCRC who were administered orally twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) and nelmastobart (400mg, 800mg intravenously every 3 weeks). Standard "3 + 3" dose escalation was used to define the MTD. In this phase 1b, 12 participants enrolled between February 5 2024 and June 11 2024 were 18 years of age or older with mCRC previously treated oxaliplatin and irinotecan in the metastatic setting. Results: The first 3 patients at the dose level 0 (nelmastobart 400mg, capecitabine 1,000 mg/m 2 twice daily) and level 1 (nelmastobart increased to 800 mg, capecitabine 1,000mg/m 2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 2 (nelmastobart 400mg, capecitabine 1,250mg/m 2 twice daily), 2 of 3 had DLTs (grade 3 hand-foot syndrome), which were attributed to capecitabine. When dose level 2 was expanded to 3 additional patients, 2 more patients experienced DLTs (grade 3 mucositis and hand-foot syndrome). Consequently, the combination of nelmastobart 800 mg once every three weeks and capecitabine 1,000 mg/m² twice daily (2 weeks on 1 week off) was established as the MTD/RP2D in patients with mCRC. The most common AEs were hand-foot syndrome (n=4), nausea (n=3) and stomatitis (n=2) which were related with capecitabine. Four patients experienced grade 1 fatigue, which was considered to be related to nelmastobart. Two patients (16.7%) out of 12 showed partial response and 8 patients have maintained stable disease for more than 4 months among 9 patients who had a median follow-up of more than 4 months (as of August 30). Conclusions: The combination of hSTC810 and capecitabine is well tolerated at the MTD, without unexpected AEs and shows promising antitumor activity in patients with heavily treated mCRC. The phase 2 study is currently in progress. Clinical trial information: NCT0599054 .