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

NCT06558773 | Recruiting Phase 2

• 1 other identifier: CHN-PLAGH-BT-088
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Colorectal Cancer

Keywords

GSL synthetase inhibitor; Immune checkpoint inhibitor; regorafenib

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Progression Free Survival (PFS)

  Up to 2 years

• Overall Survival (OS)

  Up to 2 years

Other Outcomes (2)

• Immunological response (cytokines, lymphocyte phenotype)

  Up to 120 days after the last dose of study drugs]

• Biomarkers predictive of response and toxicity

  Up to 120 days after the last dose of study drugs]

Study Arms (3)

Arm A:Regorafenib+Immune checkpoint inhibitor

ACTIVE COMPARATOR

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

Arm B:Eliglustat+Immune checkpoint inhibitor

EXPERIMENTAL

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

Arm C:Eliglustat+Immune checkpoint inhibitor+Regorafenib

EXPERIMENTAL

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

Interventions

Eliglustat+Immune checkpoint inhibitor DRUG

Eliglustat 84mg will be administered twice daily in the first 14 days and the following every other week. Immune checkpoint inhibitor (physician decided) .

Also known as: Eliglustat(Cerdelga)

Arm B:Eliglustat+Immune checkpoint inhibitor

Regorafenib+Immune checkpoint inhibitor DRUG

Regorafenib orally 80mg daily .Dose escalation to120mg daily was allowed if well tolerated. Immune checkpoint inhibitor (physician decided) .

Also known as: Regorafenib(Stivarga)

Arm A:Regorafenib+Immune checkpoint inhibitor

Eliglustat+Immune checkpoint inhibitor +Regorafenib DRUG

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.

Also known as: Regorafenib(Stivarga), Eliglustat(Cerdelga)

Arm C:Eliglustat+Immune checkpoint inhibitor+Regorafenib

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Chinese PLA General Hospital: lead

Study Sites (1)

China

Beijing, Biotherapeutic Department of Chinsese PLA Gereral Hospital, China

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

eliglustat

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Weidong Han, Ph.D

  Biotherapeutic Department, Chinese PLA General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Weidong Han, Ph.D

CONTACT

010-66937231; hanwdrsw@sina.com

Yang Liu, M.D

CONTACT

: 010-66939460; liuyang301blood@163.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Biotherapeutic Department

Study Record Dates

• First Submitted: August 13, 2024
• First Posted: August 19, 2024
• Study Start: March 1, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 31, 2029
• Last Updated: February 11, 2026

Record last verified: 2026-02

Locations

CN (1)