NCT06558773

GSL Synthetase Inhibitor Plus Immune Checkpoint Inhibitor and/or Regorafenib in Previously Treated pMMR/MSS CRC.

GSL Synthetase Inhibitor in Combination With Immune Checkpoint Inhibitor and/or Regorafenib for Patients With Advanced/Metastatic pMMR/MSS Colorectal Cancer:an Open-Label, Randomized,Phase II Study

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 120 (estimated)
• Sponsor: Chinese PLA General Hospital · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

In this single-center,open-label, randomized, phase II study, the efficacy and feasibility of GSL synthetase inhibitor in combination with immune checkpoint inhibitor and/or regorafenib therapeutic regimen will be evaluated in patients with advanced/metastatic proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC).In this clinical trial, a total of 120 eligible patients were stratified randomly (with/without liver metastases) assigned to the 3 arms in a 1:1:1 ratio: comparator group-arm A (Regorafenib+Immune checkpoint inhibitor) ,experimental group-arm B (Eliglustat+Immune checkpoint inhibitor) and experimental group-arm C (Eliglustat+Immune checkpoint inhibitor+Regorafenib).It aims to: 1).assess the antitumor effects of GSL synthetase inhibitor in combination with immune checkpoint inhibitor and/or regorafenib;2).evaluate the immunological or clinical predictive biomarkers for efficacy and toxicity; 3).detect the transformation of tumor microenvironment (TME) and dynamic changes of immune cells in peripheral blood after the treatment with GSL synthetase inhibitor in combination with immune checkpoint inhibitor and/or regorafenib.

Detailed description

Immunotherapy has achieved significant therapeutic effect in DNA mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer(mCRC). Distinct from those with dMMR/MSI-H mCRC, isolated immunotherapy has proven to be almost ineffective for patients with pMMR/MSS type mCRC,which indicating a worse prognosis. Previous work has established that the TME is distinct between MSI-H and MSS CRC. Therapeutic combinations of targeted therapy and immunotherapy,such as regorafenib combined with programmed death 1(PD-1) monoclonal antibody ,which can alter the TME and successfully promote favorable immune modulation has attracted extensive attention.Based on the small sample clinical trial results of other regorafenib combined with anti-PD-1 monoclonal antibody , the overall ORR is between 0% and 33.3%, the ORR for non-liver metastases is between 20% and 50%, and the ORR for liver metastases is between 0% and 15%,demonstrating limited clinical benefit. Besides TME,another important reason is that tumor cells often escape from immune surveillance by downregulating one or multiple molecules critical in human leukocyte antigen (HLA ) antigen presentation. As a consequence, options that could restore HLA antigen presentation may augment immune checkpoint inhibitor-mediated immune responses. Abnormal expression of glycosphingolipid (GSL) synthetase is a basic and specific characteristic of most tumors and tumor microenvironment, such as Globo H Ceramide, which is overexpressed in multiple epithelial-derived tumors. Several studies also reported that GSL synthetase was overexpressed in chemotherapy-resistant tumors. Eliglustat is an orally GlcCer synthase inhibitor, which is approved for treating Type-1 Gaucher disease. However, one most recent study reveals that it could inhibit glycosphingolipids synthesis and restore HLA antigen presentation, and transforming the immunogenicity of tumor cells.The investigators has demonstrated the excellent safety and efficacy of the combination of Eliglustat and immune checkpoint inhibitor in advanced/ metastatic solid tumors and r/r hematological malignancies,especially in pMMR/MSS mCRC (even with liver metastases). Based on the above reasons, we designed this open-label, randomized,phase II study to observe the efficacy and feasibility of the GSL synthetase inhibitor in combination with immune checkpoint Inhibitor and/or regorafenib for patients with advanced/metastatic pMMR/MSS CRC and strive to provide a high-level evidence-based basis for combination therapy regimen for these patients. A total of 120 advanced/metastatic pMMR/MSS CRC patients were stratified randomly (with/without liver metastases) assigned to the 3 arms in a 1:1:1 ratio: comparator group-Arm A (Regorafenib+Immune checkpoint inhibitor),experimental group-Arm B(Eliglustat+Immune checkpoint inhibitor) and experimental group-Arm C (Eliglustat+Immune checkpoint inhibitor+Regorafenib).The primary objective of this study is to assess the efficacy and feasibility of the above two experimental groups.The exploratory objectives are to evaluate the immunological or clinical predictive biomarkers for efficacy and toxicity, transformation of tumor microenvironment and dynamic changes of immune cells in peripheral blood.

Conditions

• Colorectal Cancer

Interventions

Type	Name	Description
DRUG	Regorafenib+Immune checkpoint inhibitor	Regorafenib orally 80mg daily .Dose escalation to120mg daily was allowed if well tolerated. Immune checkpoint inhibitor (physician decided) .
DRUG	Eliglustat+Immune checkpoint inhibitor	Eliglustat 84mg will be administered twice daily in the first 14 days and the following every other week. Immune checkpoint inhibitor (physician decided) .
DRUG	Eliglustat+Immune checkpoint inhibitor +Regorafenib	Eliglustat 84mg will be administered twice daily in the first 14 days and the following every other week. Immune checkpoint inhibitor (physician decided) . Regorafenib orally 80mg daily .Dose escalation to 120mg daily was allowed if well tolerated.

Timeline

• Start date: 2026-03-01
• Primary completion: 2027-03-01
• Completion: 2029-03-31
• First posted: 2024-08-19
• Last updated: 2026-02-11

Locations

1 site across 1 country: China