GSL Synthetase Inhibitor in Combination With Immune Checkpoint Inhibitor in Previously Treated Blood and Solid Tumor
Condition: Solid Tumor; Hematologic Malignancy
MeSH terms: Neoplasms; Hematologic Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      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 in combination with immune checkpoint inhibitor may explore a new avenue for
      therapeutic intervention in cancer.
    

Detailed description: 
      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 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 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.
    

Intervention name(s): Eliglustat; Immune checkpoint inhibitor
Intervention type(s): Drug; Drug
Intervention description(s): Eliglustat will be given to enrolled patients at dose of 84mg daily (dose 1) , and then at dose of 84mg twice daily (dose 2).; immune checkpoint inhibitor (physician decided).
Intervention MeSH terms: Immune Checkpoint Inhibitors; Eliglustat
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: GSL synthetase inhibitor; Immune checkpoint inhibitor; Solid tumor; Hematologic Malignancy