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
Chinese PLA General Hospital
120 participants
Mar 1, 2026
INTERVENTIONAL
Conditions
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.
Eligibility
Inclusion Criteria12
- Age ≥18 years old and ≤75 years old.
- Histologically confirmed diagnosis of unresectable locally advanced, recurrent or metastatic colorectal cance have failed at least two lines of prior treatment.
- Tumor tissues were identified as pMMR by immunohistochemistry (IHC) method or MSS by polymerase chain reaction (PCR).
- CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs).
- Eastern Cooperative Oncology Group (ECOG) performance status score≤2 and Estimated life expectancy of more than 3 months.
- At least one measurable lesion at baseline according to RECIST version 1.1.
- 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.
- 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.
- 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.
- Previous treatment with anti-PD-1/PD-L1 antibodies or cytotoxic T lymphocyte associated antigen 4 (CTLA-4) inhibitors are allowed.
- 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.
- Ability to understand and sign a written informed consent document.
Exclusion Criteria18
- Participants with dMMR /MSI-H colorectal cancer.
- CYP2D6 ultra-rapid metabolizers (URMs).
- Active, known or suspected autoimmune diseases.
- The patients is taking a CYP2D6 inhibitor and/or concomitantly with a strong or moderate CYP3A inhibitor.
- Subjects are being treated with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
- History of severe hypersensitive reactions to other monoclonal antibodies.
- History of allergy or intolerance to study drug components.
- 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.
- 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.
- Known positive test result for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
- 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 \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].
- Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
- Vaccination within 30 days of study enrollment.
- Active bleeding or known hemorrhagic tendency.Any life Threatening bleeding within 3 months prior to the enrollment.
- Uncontrolled hypertension (systolic pressure \>150 mm Hg or diastolic pressure \> 100 mm Hg on repeated measurement) despite optimal medical management.
- 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
- Being participating any other trials or withdraw within 4 weeks.
- Researchers believe that other reasons are not suitable for clinical trials.
Interventions
Regorafenib orally 80mg daily .Dose escalation to120mg daily was allowed if well tolerated. Immune checkpoint inhibitor (physician decided) .
Eliglustat 84mg will be administered twice daily in the first 14 days and the following every other week. Immune checkpoint inhibitor (physician decided) .
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.
Locations(1)
View Full Details on ClinicalTrials.gov
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NCT06558773