GSL Synthetase Inhibitor or in Combination With Immune Checkpoint Inhibitor in Previously Treated Blood and Solid Tumor

  • End date
    Jun 14, 2025
  • participants needed
  • sponsor
    Chinese PLA General Hospital
Updated on 14 May 2022
solid tumor


Immune checkpoint blockade has made great but unsatisfied success in treating cancers. One important reason is the hijacked HLA (Human Leukocyte Antigen) antigen presentation. Eliglustat could inhibit glycosphingolipids synthesis and restore HLA-I antigen presentation and transform the immunogenicity of tumor cells. Therefore,GSL synthetase inhibitor eliglustat monotherapy or in combination with immune checkpoint inhibitor may explore a new avenue for therapeutic intervention in cancer.


Immune checkpoint blockade has led to great strides in the management of various cancers, however, durable response could be seen in approximately 20% of treated patients with most solid tumors and hematological malignancies. One important reason is that tumor cells often escape from immune surveillance by downregulating one or multiple molecules critical in 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. Therefore, GSL synthetase inhibitor eliglustat monotherapy or in combination with immune checkpoint inhibitor may explore a new avenue for therapeutic intervention in cancer.

The primary objective of this study is to assess the safety and feasibility of GSL synthetase inhibitor eliglustat monotherapy or in combination with immune checkpoint inhibitor in patients with relapsed or refractory hematological malignancies and solid tumors. The secondary objectives include assessing antitumor activity, pharmacokinetics and pharmacodynamics. The exploratory objectives are to evaluate the pathological, immunological or clinical predictive biomarkers for efficacy and toxicity, transformation of tumor microenvironment and dynamic changes of immune cells in peripheral blood.

Condition Solid Tumor, Hematologic Malignancy
Treatment PD-1 Inhibitor, Immune checkpoint inhibitor, Eliglustat, Eliglustat
Clinical Study IdentifierNCT04944888
SponsorChinese PLA General Hospital
Last Modified on14 May 2022


Yes No Not Sure

Inclusion Criteria

Age from 16 to 75 years with estimated life expectancy >3 months
Histopathological confirmed advanced or metastatic systematically pretreated solid tumors and relapsed/refractory hematological malignancies
Have at least one measurable target lesion for solid tumors
Fresh solid tumor samples or formalin-fixed paraffin embedded tumor archival samples within 3 months are necessary; Fresh tumor samples are preferred. Subjects are willing to accept tumor re-biopsy in the process of this study
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
Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 2 at the time of enrollment
Have adequate organ function, which should be confirmed within 2 weeks prior to the first dose of study drugs
Previous treatment with anti-PD-1/PD-L1 antibodies or cytotoxic T lymphocyte associated antigen 4 (CTLA-4) inhibitors are allowed
Ability to understand and sign a written informed consent document
Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and up to 90 days after the last dose of the drug

Exclusion Criteria

Active, known or suspected autoimmune diseases
Patients are unwilling to comply with the requirements of the protocol
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
The patient has documented prior esophageal varices or liver infarction or current liver enzymes (alanine transaminase, aspartate aminotransferase) or total bilirubin >3 times the upper limit of normal
History of severe hypersensitive reactions to other monoclonal antibodies
The patient is known to have any of the following: cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, current treatment with Class IA or Class III antiarrhythmic medicinal products, interstitial lung disease of any grade or severely impaired pulmonary function
History of allergy or intolerance to study drug components
Uncontrolled intercurrent illness, including ongoing or active systemic infection or psychiatric illness/social situations and any other illness that would limit compliance with study requirements and jeopardize the safety of the patient
Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
The patients is taking a CYP2D6 inhibitor and/or concomitantly with a strong or moderate CYP3A inhibitor
History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)
Patients are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment
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
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)]
Vaccination within 30 days of study enrollment
Active bleeding or known hemorrhagic tendency
Subjects with unhealed surgical wounds for more than 30 days
Being participating any other trials or withdraw within 4 weeks
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