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

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Eliglustat+Immune checkpoint inhibitor; Drug: Regorafenib+Immune checkpoint inhibitor; Drug: Eliglustat+Immune checkpoint inhibitor +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.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Weidong Han, Ph.D; Phone Number: 010-66937231; Email: hanwdrsw@sina.com
• Study Contact Backup: Name: Yang Liu, M.D; Phone Number: : 010-66939460; Email: liuyang301blood@163.com

Study Locations

• China
  • Biotherapeutic Department of Chinsese PLA Gereral Hospital
    • Beijing, Biotherapeutic Department of Chinsese PLA Gereral Hospital, China
      • Recruiting
      • China
      • Contact: Yang Liu, M.D; Phone Number: 010-66939460; Email: liuyang301blood@163.com
      • Contact: Weidong Han, Ph.D; Phone Number: 010-66937231; Email: hanwdrsw@sina.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years old and ≤75 years old.
2. Histologically confirmed diagnosis of unresectable locally advanced, recurrent or metastatic colorectal cance have failed at least two lines of prior treatment.
3. Tumor tissues were identified as pMMR by immunohistochemistry (IHC) method or MSS by polymerase chain reaction (PCR).
4. CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs).
5. Eastern Cooperative Oncology Group (ECOG) performance status score≤2 and Estimated life expectancy of more than 3 months.
6. At least one measurable lesion at baseline according to RECIST version 1.1.
7. Fresh solid tumor samples or formalin-fixed paraffin embedded tumor archival samples within 6 months are necessary; Fresh tumor samples are preferred. Subjects are willing to accept tumor rebiopsy in the process of this study.
8. Have adequate organ function as assessed by the laboratory required by protocol, which should be confirmed within 2 weeks prior to the first dose of study drugs.
9. Previous treatment must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to <= grade 1 toxicity.
10. Previous treatment with anti-PD-1/PD-L1 antibodies or cytotoxic T lymphocyte associated antigen 4 (CTLA-4) inhibitors are allowed.
11. Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year.
12. Ability to understand and sign a written informed consent document.

Exclusion Criteria:

1. Participants with dMMR /MSI-H colorectal cancer.
2. CYP2D6 ultra-rapid metabolizers (URMs).
3. Active, known or suspected autoimmune diseases.
4. The patients is taking a CYP2D6 inhibitor and/or concomitantly with a strong or moderate CYP3A inhibitor.
5. Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
6. History of severe hypersensitive reactions to other monoclonal antibodies.
7. History of allergy or intolerance to study drug components.
8. Known brain metastases or active central nervous system (CNS). Subjects with CNS metastases who were treated with radiotherapy for at least 3 months prior to enrollment, have no central nervous symptoms and are off corticosteroids, are eligible for enrollment, but require a brain MRI screening.
9. Uncontrolled intercurrent illness, including ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations and any other illness that would limit compliance with study requirements and jeopardize the safety of the patient.
10. Known positive test result for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
11. Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
12. Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
13. Vaccination within 30 days of study enrollment.
14. Active bleeding or known hemorrhagic tendency.Any life Threatening bleeding within 3 months prior to the enrollment.
15. Uncontrolled hypertension (systolic pressure >150 mm Hg or diastolic pressure > 100 mm Hg on repeated measurement) despite optimal medical management.
16. Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy test performed within 7 days before the enrollment, and a negative result must be documented
17. Being participating any other trials or withdraw within 4 weeks.
18. Researchers believe that other reasons are not suitable for clinical trials.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm B:Eliglustat+Immune checkpoint inhibitor; Eliglustat 84mg will be administered twice daily in patients who are CYP2D6 extensive metabolizers (EMs), or intermediate metabolizers (IMs), in the first 14 days and the following every other week until 24 weeks. For patients who still benefit from the trial, eliglustat 84mg will be administered twice daily every other week to 96 weeks. Immune checkpoint inhibitor (physician decided) will be administered intravenously on day 5 every 3 weeks. For patients who still benefit from the trial, immune checkpoint inhibitor will be administered every 3 week to 96 weeks.	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) .; Other Names: Eliglustat(Cerdelga)
Active Comparator: Arm A:Regorafenib+Immune checkpoint inhibitor; Regorafenib orally 80mg daily for 21 days (3 weeks on, 1 week off, 4 weeks as a cycle).Dose escalation to 120mg daily was allowed if well tolerated. until:unacceptable toxicity occurred or disease progression. Immune checkpoint inhibitor (physician decided) will be administered intravenously on day 5 every 3 weeks. For patients who still benefit from the trial, immune checkpoint inhibitor will be administered every 3 week to 96 weeks.	Drug: Regorafenib+Immune checkpoint inhibitor; Regorafenib orally 80mg daily .Dose escalation to120mg daily was allowed if well tolerated. Immune checkpoint inhibitor (physician decided) .; Other Names: Regorafenib(Stivarga)
Experimental: Arm C:Eliglustat+Immune checkpoint inhibitor+Regorafenib; Eliglustat 84mg will be administered twice daily in patients who are CYP2D6 extensive metabolizers (EMs), or intermediate metabolizers (IMs), in the first 14 days and the following every other week until 24 weeks. For patients who still benefit from the trial, eliglustat 84mg will be administered twice daily every other week to 96 weeks. Immune checkpoint inhibitor (physician decided) will be administered intravenously on day 5 every 3 weeks. For patients who still benefit from the trial, immune checkpoint inhibitor will be administered every 3 week to 96 weeks. Regorafenib orally 80mg daily for 21 days (3 weeks on, 1 week off, 4 weeks as a cycle).Dose escalation to 120mg daily was allowed if well tolerated. until:unacceptable toxicity occurred or disease progression.	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.; Other Names: Regorafenib(Stivarga); Eliglustat(Cerdelga)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Objective response rate includes complete response and partial response defined by investigators according to RECIST 1.1or iRECIST criteria.	Up to 120 days after the last dose of study drugs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	Time from the date of first administration of the study drug to disease progression or death from any cause (any earliest date).	Up to 2 years
Overall Survival (OS)	Time from the date of first administration of the study drug to the date of death.	Up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunological response (cytokines, lymphocyte phenotype)	The concentration of cytokines (mainly include interleukin-2(IL-2), interleukin-6(IL-6),tumor necrosis factor α (TNF-α), the unit is picograms per milliliter) in tumor beds and peripheral blood and the changes of lymphocyte phenotype ( mainly include the number and percentage of cluster of differentiation 4(CD4+) and CD8+ T cells) following the treatment, will be assessed by quantitative polymerase chain reaction (qPCR) and flow cytometer.	Up to 120 days after the last dose of study drugs]
Biomarkers predictive of response and toxicity	Biomarkers from tumor cells, lymphocytes and tumor microenvironment will be assessed for their potential in predicting clinical response and toxicity.All participants with treatment-related adverse events (AE) as assessed by National Cancer Institute Common Terminology Criteria for Adverse Event, Version 5.0(CTC AE 5.0).	Up to 120 days after the last dose of study drugs]

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital
• Investigators: Principal Investigator: Weidong Han, Ph.D, Biotherapeutic Department, Chinese PLA General Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 31, 2029

Study Registration Dates

• First Submitted: August 13, 2024
• First Submitted That Met QC Criteria: August 15, 2024
• First Posted (Actual): August 19, 2024

Study Record Updates

• Last Update Posted (Actual): February 11, 2026
• Last Update Submitted That Met QC Criteria: February 9, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Immune checkpoint inhibitor; regorafenib; GSL synthetase inhibitor
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; eliglustat
• Other Study ID Numbers: CHN-PLAGH-BT-088

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No