Clinical Trials /

DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab

NCT03688178

Description:

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 mg/m2/day. The study cycle of TMZ comprises a targeted dose of 150-200mg/m2/day 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 20 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 TMZ/vaccine 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. DCs in vaccine #4 will be labeled with a radioactive substance called 111Indium before injection to allow the study team to track migration using SPECT scans taken at 24 and 48 hours following DC Vaccine #4.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab
  • Official Title: DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab

Clinical Trial IDs

  • ORG STUDY ID: Pro00082570
  • NCT ID: NCT03688178

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
Human CMV pp65-LAMP mRNA-pulsed autologous DCsGr1: DC vaccine (DC pre-conditioning)
TemozolomideTemodar, TMZ, TemodalGr1: DC vaccine (DC pre-conditioning)
Varlilumabanti-CD27Gr3:DC Vaccine+varlilumab(Td pre-conditioning)
TdTetanus-diphtheria (Td) toxoid, Td pre-conditioningGr2: DC Vaccine (Td pre-conditioning)
111In-labeled DCsGr1: DC vaccine (DC pre-conditioning)
Unpulsed DCsUnpulsed DCs pre-conditioningGr1: DC vaccine (DC pre-conditioning)
HIV-Gag mRNA-pulsed autologous DCsGr1: DC vaccine (DC pre-conditioning)

Purpose

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 mg/m2/day. The study cycle of TMZ comprises a targeted dose of 150-200mg/m2/day 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 20 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 TMZ/vaccine 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. DCs in vaccine #4 will be labeled with a radioactive substance called 111Indium before injection to allow the study team to track migration using SPECT scans taken at 24 and 48 hours following DC 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.

      The in vivo distribution of DCs will be evaluated in Vaccine #4 using 111Indium
      (111In)-labeled pp65-LAMP mRNA loaded mature DCs. 111In-labeled DCs have been used
      extensively for evaluation of adoptively transferred tumor infiltrating lymphocytes, natural
      killer cells, granulocytes, dendritic cells, and whole blood leukocytes, for in vivo
      localization studies in humans. Subjects will undergo SPECT/CT imaging immediately after
      Vaccine #4 and then at 1 and 2 days after injection.

      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.

      To examine the impact of Varlilumab on T cell responses to naïve antigen, pp65-loaded DC
      Vaccine #1 will also include separate DCs loaded with the full mRNA of HIV Gag protein;
      responses to HIV-Gag are uncommon and can serve as a naïve antigen in our HIV negative
      patient population. It has been shown that removal of regulatory T cells (TRegs) can enhance
      polyfunctional T-cell responses to HIV Gag. We hypothesize that TReg inhibition through
      Varlilumab may increase polyfunctional immune responses to CMV.
    

Trial Arms

NameTypeDescriptionInterventions
Gr1: DC vaccine (DC pre-conditioning)ExperimentalPatients will receive TMZ at a target dose of 150-200 mg/m^2/d for 5 days every 4 (+2) weeks for up to 12 cycles. DC vaccines will be administered in equal amounts to both inguinal regions. DC vaccines #1-3 occur every 2 weeks and all subsequent vaccines (up to 20) occur monthly. Group 1 patients will receive autologous unpulsed DC vaccines administered to a single side of the groin and saline administered to the contralateral side the day prior to the 4th DC vaccine as pre-conditioning. Patients will then receive 111In-labeled DCs as the 4th vaccine to compare the effects of different skin preparations on DC migration followed by SPECT/CT imaging immediately and at 1 and 2 days after injections.
  • Human CMV pp65-LAMP mRNA-pulsed autologous DCs
  • Temozolomide
  • 111In-labeled DCs
  • Unpulsed DCs
  • HIV-Gag mRNA-pulsed autologous DCs
Gr2: DC Vaccine (Td pre-conditioning)ExperimentalPatients will receive TMZ at a target dose of 150-200 mg/m^2/d for 5 days every 4 (+2) weeks for up to 12 cycles. DC vaccines will be administered in equal amounts to both inguinal regions. DC vaccines #1-3 occur every 2 weeks and all subsequent vaccines (up to 20) occur monthly. Group 2 patients will receive a single dose of Td toxoid administered to a single side of the groin and saline administered to the contralateral side the day prior to the 4th DC vaccine, which is always given bilaterally at the groin site. Patients will then receive 111In-labeled DCs as the 4th vaccine to compare the effects of different skin preparations on DC migration followed by SPECT/CT imaging immediately and at 1 and 2 days after injection.
  • Human CMV pp65-LAMP mRNA-pulsed autologous DCs
  • Temozolomide
  • Td
  • 111In-labeled DCs
  • HIV-Gag mRNA-pulsed autologous DCs
Gr3:DC Vaccine+varlilumab(Td pre-conditioning)ExperimentalPatients will receive TMZ at a target dose of 150-200 mg/m^2/d for 5 days every 4 (+2) weeks for up to 12 cycles. DC vaccines will be administered in equal amounts to both inguinal regions. DC vaccines #1-3 occur every 2 weeks and all subsequent vaccines (up to 20) occur monthly. Group 3 patients will receive the first 3 DC vaccines every 2 weeks, same as Groups 1 and 2, but they will also receive varlilumab intraveneously (iv) 7 days before vaccine #1 and again at the same visit as vaccine #1, as well as 7 days before every DC vaccine except vaccine #2. Prior to the 4th vaccine, patients will receive a single dose of Td toxoid administered to a single side of the groin and saline administered to the contralateral side. Patients will then receive 111In-labeled DCs at the 4th vaccine to compare the effects of varlilumab with the different skin preparations on DC migration followed by SPECT/CT imaging immediately and at 1 and 2 days after injection.
  • Human CMV pp65-LAMP mRNA-pulsed autologous DCs
  • Temozolomide
  • Varlilumab
  • Td
  • 111In-labeled DCs
  • HIV-Gag mRNA-pulsed autologous DCs

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥18 years of age.

          -  Glioblastoma with definitive resection prior to enrollment, with residual radiographic
             contrast enhancing disease on the post-operative CT or MRI of <1 cm in maximal
             diameter in any axial plane.

          -  Enough tumor tissue available for determination of MGMT gene promoter status.

          -  CMV Seropositive.

          -  KPS of ≥ 80%

          -  Hemoglobin ≥ 9.0 g/dl, ANC ≥ 1,500 cells/µl, platelets ≥ 100,000 cells/µl.

          -  Serum creatinine ≤ 1.5 mg/dl, serum SGOT and bilirubin ≤ 1.5 times upper limit of
             normal.

          -  Signed informed consent approved by the Institutional Review Board.

          -  Female patients must not be pregnant or breast-feeding. Female patients of
             childbearing potential (defined as < 2 years after last menstruation or not surgically
             sterile) must use a highly effective contraceptive method (allowed methods of birth
             control, [i.e. with a failure rate of < 1% per year] are implants, injectables,
             combined oral contraceptives, intra-uterine device [IUD; only hormonal], sexual
             abstinence or vasectomized partner) during the trial and for a period of > 6 months
             following the last administration of trial drug(s). Female patients with an intact
             uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy
             test within 48 hours prior to first study treatment.

          -  Fertile male patients must agree to use a highly effective contraceptive method
             (allowed methods of birth control [i.e. with a failure rate of < 1% per year] include
             a female partner using implants, injectables, combined oral contraceptives, IUDs [only
             hormonal], sexual abstinence or prior vasectomy) during the trial and for a period of
             > 6 months following the last administration of trial drugs.

        Exclusion Criteria:

          -  Pregnant or breast-feeding.

          -  Women of childbearing potential and men who are sexually active and not willing/able
             to use medically acceptable forms of contraception.

          -  Patients with known potentially anaphylactic allergic reactions to gadolinium-DTPA.

          -  Patients who cannot undergo MRI or SPECT due to obesity or to having certain metal in
             their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal
             prostheses, joints, rods, or plates).

          -  Patients with evidence of tumor in the brainstem, cerebellum, or spinal cord,
             radiological evidence of multifocal disease, or leptomeningeal disease.

          -  Severe, active comorbidity, including any of the following:

               -  Unstable angina and/or congestive heart failure requiring hospitalization;

               -  Transmural myocardial infarction within the last 6 months;

               -  Acute bacterial or fungal infection requiring intravenous antibiotics at the time
                  of study initiation;

               -  Chronic obstructive pulmonary disease exacerbation or other respiratory illness
                  requiring hospitalization or precluding study therapy;

               -  Known hepatic insufficiency resulting in clinical jaundice and/or coagulation
                  defects;

               -  Known HIV and Hepatitis C positive status;

               -  Major medical illnesses or psychiatric impairments that, in the investigator's
                  opinion, will prevent administration or completion of protocol therapy;

               -  Active connective tissue disorders, such as lupus or scleroderma that, in the
                  opinion of the treating physician, may put the patient at high risk for radiation
                  toxicity.

          -  Co-medication that may interfere with study results; e.g. immuno-suppressive agents
             other than corticosteroids.

          -  Prior, unrelated malignancy requiring current active treatment with the exception of
             cervical carcinoma in situ and adequately treated basal cell or squamous cell
             carcinoma of the skin. (Treatment with tamoxifen or aromatase inhibitors or other
             hormonal therapy that may be indicated in prevention of prior cancer disease
             recurrence, are not considered current active treatment.)

          -  Patients are not permitted to have had any other conventional therapeutic intervention
             other than steroids prior to enrollment outside of standard of care chemotherapy and
             radiation therapy. Patients who receive previous inguinal lymph node dissection,
             radiosurgery, brachytherapy, or radiolabeled monoclonal antibodies will be excluded.

          -  Current, recent (within 4 weeks of the administration of this study agent), or planned
             participation in an experimental drug study.

          -  Known history of autoimmune disease (with the exceptions of medically-controlled
             hypothyroidism and Type I Diabetes Mellitus).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Median Overall Survival (OS) of Subjects Receiving Td pre-conditioning
Time Frame:5 years
Safety Issue:
Description:OS is defined as the time in months between randomization and death, or last follow-up if alive (Groups 1 and 2). Kaplan-Meier methods will be used to estimate median OS

Secondary Outcome Measures

Measure:Median Overall Survival (OS) of Subjects Receiving DC vaccines, varlilumab, and Td pre-conditioning
Time Frame:5 years
Safety Issue:
Description:OS is defined as the time in months between randomization and death, or last follow-up if alive (Group 3). Kaplan-Meier methods will be used to estimate median OS
Measure:Median Progression-free Survival (PFS)
Time Frame:5 years
Safety Issue:
Description:PFS is defined as the time between randomization and initial failure (disease progression or death) (all Groups). If the patient remains alive without disease progression, PFS will be censored at the time of last follow-up. Kaplan-Meier methods will be used to estimate median PFS
Measure:Median Percentage of 111In-labeled DCs Reaching Inguinal Nodes
Time Frame:2 days
Safety Issue:
Description:The percentage of 111In-labeled DCs reaching inguinal nodes calculated from the initial signal at the injections site in the groin at 1 and 2 days after the 4th vaccination base upon SPECT/CT. The median percentage at each time point will be presented
Measure:Median Chemokine (C-C motif) ligand 3 (CCL3) Levels in Serum at 24, 48, and 72 hours after Pre-conditioning
Time Frame:2 days
Safety Issue:
Description:CCL3 levels in serum 24, 48, and 72 hours after pre-conditioning by multiplex. The median CCL3 level will be presented

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Gary Archer Ph.D.

Trial Keywords

  • Glioblastoma
  • Dendritic cells
  • Temozolomide
  • Duke University
  • Varlilumab

Last Updated

April 3, 2020