GSL synthetase inhibitor with immunotherapy and/or regorafenib for previously treated pMMR/MSS colorectal cancer

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

This trial will test whether adding a GSL synthetase inhibitor to an immune checkpoint blocker, with or without regorafenib, helps people with previously treated pMMR/MSS metastatic colorectal cancer.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 120 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Chinese PLA General Hospital (other)
• Drugs / interventions: prednisone, chemotherapy, Immunotherapy
• Locations: 1 site (Beijing, Biotherapeutic Department of Chinsese PLA Gereral Hospital)
• Trial ID: NCT06558773 on ClinicalTrials.gov

What this trial studies

This is a single-center, open-label, randomized phase II study enrolling 120 patients with unresectable or metastatic pMMR/MSS colorectal cancer who have failed at least two prior therapies. Participants are randomized 1:1:1 (stratified by liver metastases) to receive regorafenib plus an immune checkpoint inhibitor, eliglustat (a GSL synthetase inhibitor) plus an immune checkpoint inhibitor, or eliglustat plus immune checkpoint inhibitor plus regorafenib. The trial will measure antitumor activity (including response rates) and collect tumor and immune biomarkers and serial biopsies to characterize tumor microenvironment changes and predictors of benefit or toxicity. Safety, feasibility, and exploratory biomarker correlations are key secondary objectives.

Who should consider this trial

Good fit: Adults aged 18–75 with histologically confirmed unresectable locally advanced, recurrent, or metastatic pMMR/MSS colorectal cancer who have failed at least two prior lines of therapy, have ECOG ≤2, measurable disease, available tumor tissue (or agree to rebiopsy), and acceptable organ function are ideal candidates.

Not a fit: Patients with dMMR/MSI-H tumors, severe organ dysfunction, inadequate performance status, inability to tolerate study drugs or required biopsies, or contraindicating CYP-related issues are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If successful, this approach could restore antigen presentation and improve responses to immunotherapy for patients with pMMR/MSS colorectal cancer who currently get little benefit from checkpoint inhibitors alone.

How similar studies have performed: Small prior trials combining regorafenib with PD-1 inhibitors have shown mixed response rates (0–33%) with better outcomes in non-liver metastases, while addition of a GSL synthetase inhibitor is a novel, largely untested approach in this disease.

Eligibility criteria

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.

Where this trial is running

Beijing, Biotherapeutic Department of Chinsese PLA Gereral Hospital

• China — Beijing, Biotherapeutic Department of Chinsese PLA Gereral Hospital, China (RECRUITING)

Study contacts

• Principal investigator: Weidong Han, Ph.D — Biotherapeutic Department, Chinese PLA General Hospital
• Study coordinator: Weidong Han, Ph.D

Conditions: Colorectal Cancer, GSL synthetase inhibitor, Immune checkpoint inhibitor, regorafenib