3571 Background: Transforming growth factor β (TGF-β) plays a dynamic role in cancer biology. It acts as a tumor suppressor in early stages of tumor development. Certain tumor types, such as colorectal cancer (CRC), exploit this signaling route to induce pathways that promote tumor growth, enhancing the tumor's aggressiveness. CRC of the mesenchymal subtype exhibits prominent TGF-β activation, contributing to drug resistance, including to 5-fluorouracil (5-FU)-based chemotherapy. This subtype is found in most CRC patients with peritoneal metastases. Therefore, combining TGF-β inhibition with chemotherapy could be a beneficial approach to overcome resistance. Methods: This two-center, open-label, non-randomized proof-of-principle phase II study with a safety lead-in involved combining TGF-β inhibitor galunisertib (150 mg twice daily) with capecitabine (1000 mg/m 2 twice daily) for 14 days in a 28-day cycle. Adult patients with histologically or cytologically proven CRC and confirmed peritoneal metastases were eligible for inclusion if they were in a good clinical condition, had exhausted all their treatment options, and had no gastrointestinal impaired function. In the safety lead-in phase, six patients were evaluated for safety and tolerability, as assessed by the incidence of dose limiting toxicities (DLTs) and adverse events. Phase II followed a Simon two stage design with progression to the second stage when ≥2 objective tumor responses out of 15 patients were reached. Secondary objectives included pharmacokinetics (PK) and pharmacodynamics (e.g. TGF-β expression, immunohistochemical staining for phosphorylated SMAD2/3). Results: As of January 23 2026, inclusion was closed, after 22 patients were recruited. 54% of patients were female, with a median age of 60 years (38-77). No DLTs were observed in 21 DLT-evaluable patients. Only grade 1/2 treatment-related adverse events occurred. The most common events were nausea (23%), hypophosphatemia (18%), and fatigue (18%). No objective responses were observed. Four of 20 patients evaluable for efficacy showed stable disease with a median duration of 4 months. PK analysis of patients in the safety lead-in showed high interpatient variability for galunisertib, capecitabine and 5-FU (CV% AUC (0-12) : between 54%-70%). Galunisertib did not show drug accumulation over time (AUC (0-inf) on cycle 1 day 1 and AUC (0-12) on cycle 1 day 14 were 7.6 and 6.6 µg*h/mL, respectively). The PK of capecitabine and 5-FU were similar to those described in the literature. Pharmacodynamic analyses are ongoing. Conclusions: The combination of galunisertib and capecitabine did not result in objective responses or long term stable disease in chemotherapy-resistant CRC patients with peritoneal metastases. The treatment was well tolerated and PK results for both compounds were similar to those described in the literature. Clinical trial information: NCT05700656 .
Kanhailal et al. (Wed,) studied this question.