Ignite Creation Date:
2024-10-26 @ 3:38 PM
Last Modification Date:
2024-10-26 @ 3:38 PM
Study NCT ID:
NCT06558773
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-08-13
Brief Title:
GSL Synthetase Inhibitor Plus Immune Checkpoint Inhibitor andor Regorafenib in Previously Treated pMMRMSS CRC
Sponsor:
None
Organization:
None
Study Overview
Official Title:
GSL Synthetase Inhibitor in Combination With Immune Checkpoint Inhibitor andor Regorafenib for Patients With AdvancedMetastatic pMMRMSS Colorectal Canceran Open-Label RandomizedPhase II Study
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
In this single-centeropen-label randomized phase II study the efficacy and feasibility of GSL synthetase inhibitor in combination with immune checkpoint inhibitor andor regorafenib therapeutic regimen will be evaluated in patients with advancedmetastatic proficient mismatch repairmicrosatellite stable pMMRMSS colorectal cancer CRCIn this clinical trial a total of 120 eligible patients were stratified randomly withwithout liver metastases assigned to the 3 arms in a 111 ratio experimental group-arm AEliglustatImmune checkpoint inhibitorRegorafenibexperimental group-arm BEliglustatImmune checkpoint inhibitor and comparator group-arm CRegorafenibImmune checkpoint inhibitorIt aims to 1assess the antitumor effects of GSL synthetase inhibitor in combination with immune checkpoint inhibitor andor regorafenib2evaluate the immunological or clinical predictive biomarkers for efficacy and toxicity 3detect 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 andor regorafenib
Detailed Description:
Immunotherapy has achieved significant therapeutic effect in DNA mismatch repair-deficient or microsatellite instability-high dMMRMSI-H metastatic colorectal cancermCRC Distinct from those with dMMRMSI-H mCRC isolated immunotherapy has proven to be almost ineffective for patients with pMMRMSS type mCRCwhich indicating a worse prognosis
Previous work has established that the TME is distinct between MSI-H and MSS CRC Therapeutic combinations of targeted therapy and immunotherapysuch as regorafenib combined with programmed death 1PD-1 monoclonal antibody which can alter the TME and successfully promote favorable immune modulation has attracted extensive attentionBased on the small sample clinical trial results of other regorafenib combined with anti-PD-1 monoclonal antibody the overall ORR is between 0 and 333 the ORR for non-liver metastases is between 20 and 50 and the ORR for liver metastases is between 0 and 15demonstrating limited clinical benefit
Besides TMEanother important reason is that tumor cells often escape from immune surveillance by downregulating one or multiple molecules critical in human leukocyte antigen 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 cellsThe investigators has demonstrated the excellent safety and efficacy of the combination of Eliglustat and immune checkpoint inhibitor in advanced metastatic solid tumors and rr hematological malignanciesespecially in pMMRMSS mCRC even with liver metastases
Based on the above reasons we designed this open-label randomizedphase II study to observe the efficacy and feasibility of the GSL synthetase inhibitor in combination with immune checkpoint Inhibitor andor regorafenib for patients with advancedmetastatic pMMRMSS CRC and strive to provide a high-level evidence-based basis for combination therapy regimen for these patients A total of 120 advancedmetastatic pMMRMSS CRC patients were stratified randomly withwithout liver metastases assigned to the 3 arms in a 111 ratio experimental group-Arm AEliglustatImmune checkpoint inhibitorRegorafenibexperimental group-Arm BEliglustatImmune checkpoint inhibitor and comparator group-Arm CRegorafenibImmune checkpoint inhibitorThe primary objective of this study is to assess the efficacy and feasibility of the above two experimental groupsThe exploratory objectives are to evaluate the immunological or clinical predictive biomarkers for efficacy and toxicity transformation of tumor microenvironment and dynamic changes of immune cells in peripheral blood
Previous work has established that the TME is distinct between MSI-H and MSS CRC Therapeutic combinations of targeted therapy and immunotherapysuch as regorafenib combined with programmed death 1PD-1 monoclonal antibody which can alter the TME and successfully promote favorable immune modulation has attracted extensive attentionBased on the small sample clinical trial results of other regorafenib combined with anti-PD-1 monoclonal antibody the overall ORR is between 0 and 333 the ORR for non-liver metastases is between 20 and 50 and the ORR for liver metastases is between 0 and 15demonstrating limited clinical benefit
Besides TMEanother important reason is that tumor cells often escape from immune surveillance by downregulating one or multiple molecules critical in human leukocyte antigen 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 cellsThe investigators has demonstrated the excellent safety and efficacy of the combination of Eliglustat and immune checkpoint inhibitor in advanced metastatic solid tumors and rr hematological malignanciesespecially in pMMRMSS mCRC even with liver metastases
Based on the above reasons we designed this open-label randomizedphase II study to observe the efficacy and feasibility of the GSL synthetase inhibitor in combination with immune checkpoint Inhibitor andor regorafenib for patients with advancedmetastatic pMMRMSS CRC and strive to provide a high-level evidence-based basis for combination therapy regimen for these patients A total of 120 advancedmetastatic pMMRMSS CRC patients were stratified randomly withwithout liver metastases assigned to the 3 arms in a 111 ratio experimental group-Arm AEliglustatImmune checkpoint inhibitorRegorafenibexperimental group-Arm BEliglustatImmune checkpoint inhibitor and comparator group-Arm CRegorafenibImmune checkpoint inhibitorThe primary objective of this study is to assess the efficacy and feasibility of the above two experimental groupsThe exploratory objectives are to evaluate the immunological or clinical predictive biomarkers for efficacy and toxicity transformation of tumor microenvironment and dynamic changes of immune cells in peripheral blood
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None