Ignite Creation Date:
2024-05-06 @ 12:06 PM
Last Modification Date:
2024-10-26 @ 12:55 PM
Study NCT ID:
NCT03688178
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-07-19
First Post:
2018-09-26
Brief Title:
DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab
Sponsor:
Annick Desjardins MD
Organization:
Duke University
Study Overview
Official Title:
DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-07
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:
DERIVe
Brief Summary:
Patients with newly diagnosed glioblastoma will be consented following tumor resection then undergo leukapheresis for harvest of peripheral blood leukocytes for generation of dendritic cells Subjects will then receive standard of care planned 6 weeks radiation therapy RT and concurrent temozolomide TMZ at a standard targeted dose of 75 mgm2day
The study cycle of TMZ comprises a targeted dose of 150-200mgm2day for 5 days every 4 2 weeks for up to 12 cycles patients with unmethylated MGMT gene promoter will receive only cycle 1 All patients will receive up to a total of 10 DC vaccines called pp65 CMV dendritic cells DC Dendritic Cell DC vaccines 1-3 will be given every two weeks thus delaying the initiation of TMZ cycle 2 for patients receiving TMZ All remaining TMZvaccine cycles will be 4 2 weeks in length
After the first 3 DC vaccines given during Cycle 1 of TMZ the remaining DC vaccine injections are given on Day 21 - 2 days of each TMZ cycle Subjects with unmethylated MGMT will only receive one cycle of adjuvant TMZ however their vaccine schedule will follow the same 4 2 week TMZ cycle schedule
Following RT patients will be randomized into 1 of 3 groups Groups 1 and 2 will be blinded The groups differ in the type of pre-conditioning received prior to DC vaccine 4 additionally Group 3 will be receiving infusions of varlilumab 7 days prior to and with vaccine 1 and 7 days prior to vaccine 3 The pre-conditioning for each group is as follows Group 1 Unpulsed DC pre-conditioning prior to DC vaccine 4 Group 2 Tetanus-diphtheria Td pre-conditioning prior to DC vaccine 4 Group 3 Td pre-conditioning prior to DC vaccine 4 and varlilumab infusion at 7 days prior to each DC vaccine except DC vaccine 2 with Td pre-conditioning prior to vaccine 4
The study cycle of TMZ comprises a targeted dose of 150-200mgm2day for 5 days every 4 2 weeks for up to 12 cycles patients with unmethylated MGMT gene promoter will receive only cycle 1 All patients will receive up to a total of 10 DC vaccines called pp65 CMV dendritic cells DC Dendritic Cell DC vaccines 1-3 will be given every two weeks thus delaying the initiation of TMZ cycle 2 for patients receiving TMZ All remaining TMZvaccine cycles will be 4 2 weeks in length
After the first 3 DC vaccines given during Cycle 1 of TMZ the remaining DC vaccine injections are given on Day 21 - 2 days of each TMZ cycle Subjects with unmethylated MGMT will only receive one cycle of adjuvant TMZ however their vaccine schedule will follow the same 4 2 week TMZ cycle schedule
Following RT patients will be randomized into 1 of 3 groups Groups 1 and 2 will be blinded The groups differ in the type of pre-conditioning received prior to DC vaccine 4 additionally Group 3 will be receiving infusions of varlilumab 7 days prior to and with vaccine 1 and 7 days prior to vaccine 3 The pre-conditioning for each group is as follows Group 1 Unpulsed DC pre-conditioning prior to DC vaccine 4 Group 2 Tetanus-diphtheria Td pre-conditioning prior to DC vaccine 4 Group 3 Td pre-conditioning prior to DC vaccine 4 and varlilumab infusion at 7 days prior to each DC vaccine except DC vaccine 2 with Td pre-conditioning prior to vaccine 4
Detailed Description:
Human cytomegalovirus CMV is a common endemic β-Herpesvirus and over half of adults have been infected with CMV CMV does not usually cause significant clinical disease but can cause health problems for people with weakened immune systems Expression of proteins unique to human CMV has been reported within a large proportion of malignant gliomas MGs including detection of the human CMV immunodominant protein pp65-LAMP pp65-lysosomal-associated membrane protein Human CMV antigens were not detected in surrounding normal brain samples The presence of highly-immunogenic human CMV antigens within MGs affords a unique opportunity to target these tumors immunologically
Dendritic cells DCs are antigen-presenting cells in the immune system DCs are activated then migrate to the lymph nodes to interact with T cells and B cells which initiates the adaptive immune response This study generates autologous DCs from peripheral blood leukocytes obtained from the subject during leukapheresis RNA transfection is the method used in this study for loading antigens onto DCs DCs are pulsed with human CMV pp65-LAMP mRNA
Tetanus-diphtheria Td toxoid is used for active immunization in children and adults against infection with the bacteria Clostridium tetani and Corynebacterium diphtheria It is thought that Td toxoid induces an inflammatory milieu within the intradermal vaccine site thereby promoting the migration of injected tumor-specific DCs Additionally in the context of vaccinating the host with tumor-derived peptides conditioning the vaccine site with Td toxoid has demonstrated enhanced immunogenicity with these peptides Previous trials have suggested that giving the Td prior to immunotherapy may help improve the effectiveness of the DC vaccine by activating the immune response This study will further examine whether Td helps activate the immune response by comparing subjects who receive Td pre-conditioning to subjects who receive autologous unpulsed DCs as pre-conditioning
Varlilumab is a fully human monoclonal antibody mAb that targets CD27 a critical molecule in the activation pathway of lymphocytes Varlilumab is an agonist anti-CD27 mAb that has been shown to activate human T cells in the context of T cell receptor stimulation In pre-clinical models varlilumab has been shown to mediate anti-tumor effects and may be particularly effective in combination with other immunotherapies Anti-CD27 mAb has emerged as a novel costimulatory immune modulator that depletes TRegs without impairing activated effector T cells to improve antitumor immunity We hypothesize that TReg inhibition through Varlilumab may increase polyfunctional immune responses to CMV
Dendritic cells DCs are antigen-presenting cells in the immune system DCs are activated then migrate to the lymph nodes to interact with T cells and B cells which initiates the adaptive immune response This study generates autologous DCs from peripheral blood leukocytes obtained from the subject during leukapheresis RNA transfection is the method used in this study for loading antigens onto DCs DCs are pulsed with human CMV pp65-LAMP mRNA
Tetanus-diphtheria Td toxoid is used for active immunization in children and adults against infection with the bacteria Clostridium tetani and Corynebacterium diphtheria It is thought that Td toxoid induces an inflammatory milieu within the intradermal vaccine site thereby promoting the migration of injected tumor-specific DCs Additionally in the context of vaccinating the host with tumor-derived peptides conditioning the vaccine site with Td toxoid has demonstrated enhanced immunogenicity with these peptides Previous trials have suggested that giving the Td prior to immunotherapy may help improve the effectiveness of the DC vaccine by activating the immune response This study will further examine whether Td helps activate the immune response by comparing subjects who receive Td pre-conditioning to subjects who receive autologous unpulsed DCs as pre-conditioning
Varlilumab is a fully human monoclonal antibody mAb that targets CD27 a critical molecule in the activation pathway of lymphocytes Varlilumab is an agonist anti-CD27 mAb that has been shown to activate human T cells in the context of T cell receptor stimulation In pre-clinical models varlilumab has been shown to mediate anti-tumor effects and may be particularly effective in combination with other immunotherapies Anti-CD27 mAb has emerged as a novel costimulatory immune modulator that depletes TRegs without impairing activated effector T cells to improve antitumor immunity We hypothesize that TReg inhibition through Varlilumab may increase polyfunctional immune responses to CMV
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None