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.
• 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.