Clinical Trials /

Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed WHO Grade IV Unmethylated Glioma

NCT03927222

Description:

This single-arm phase II study will assess the impact of tetanus pre-conditioning and adjuvant Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) on overall survival of patients newly diagnosed with World Health Organization (WHO) Grade IV glioblastoma who have undergone definitive tumor resection, are cytomegalvirus (CMV) positive and unmethylated, and completed standard temozolomide (TMZ) and radiation treatment. After completion of the standard of care radiotherapy with concurrent TMZ, patients will receive 1 cycle of dose-intensified TMZ followed by pp65-loaded dendritic cell (DC) vaccination beginning on day 23.

Related Conditions:
  • Diffuse Midline Glioma, H3 K27M-Mutant
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed WHO Grade IV Unmethylated Glioma
  • Official Title: I-ATTAC: Improved Anti-Tumor Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed WHO Grade IV Unmethylated Glioma

Clinical Trial IDs

  • ORG STUDY ID: Pro00090683
  • NCT ID: NCT03927222

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
Human CMV pp65-LAMP mRNA-pulsed autologous DCs containing GM CSFCMV-specific dendritic cell vaccine, DCsDC vaccination with Td preconditioning and GM CSF
TemozolomideTemodar, TMZ, TemodalDC vaccination with Td preconditioning and GM CSF
Tetanus-Diphtheria Toxoid (Td)Td pre-conditioning, Td toxoidDC vaccination with Td preconditioning and GM CSF
GM-CSFLEUKINE®, SargramostimDC vaccination with Td preconditioning and GM CSF
111-Indium-labeling of Cells for in vivo Trafficking StudiesDC vaccination with Td preconditioning and GM CSF

Purpose

This is a single-arm phase II study for newly-diagnosed WHO Grade IV glioblastoma patients who have undergone definitive tumor resection, are unmethylated, and completed standard chemoradiation treatment. After completion of the standard of care radiotherapy with concurrent temozolomide (TMZ), patients will receive 1 cycle of dose-intensified TMZ followed by serial vaccines of cytomegalovirus pp65-loaded dendritic cells (DCs) beginning on day 23 with tetanus and GM-CSF vaccine site pre-conditioning. All enrolled patients will undergo a leukapheresis after tumor resection for the generation of DCs. All patients will receive up to a total of 10 DC vaccines every 28 days (± 2 days) given bilaterally at the groin site.

Detailed Description

      Approximately 64 patients with resected, newly-diagnosed WHO Grade IV glioma in which the
      Methylguanine Methyltransferase (MGMT) is not methylated will be accrued to this study before
      standard of care radiation therapy (RT) and concurrent TMZ, with the goal of treating 48
      patients with dose-intensified temozolomide and pp65 loaded dendritic cell vaccine after
      completion of standard RT and TMZ.

      All enrolled patients will undergo a leukapheresis for the generation of DCs. Patients will
      then receive approximately 6 weeks of the standard of care radiation therapy (RT) and
      concurrent TMZ at a standard targeted dose of 75 mg/m2/day. For patients whose initial
      leukapheresis yields less than 3 vaccines, repeat leukapheresis may be obtained. At the
      post-RT clinic visit, a single post-RT cycle of dose-intensified TMZ (100 mg/m2/day for 21
      days) will be given. On day 23 (± 2 days) of the cycle, patients will receive the first of 3
      pp65 DC vaccines every 2 weeks. All patients will receive up to a total of 10 DC vaccines,
      with vaccines administered every 28 days (± 2 days) after the third vaccine, given
      bilaterally at the groin site unless progression occurs with no further cycles of TMZ. DC
      vaccines will be given intradermally (i.d.) and divided equally to both inguinal regions.
      Before the first DC vaccination, patients will receive 0.5 mL of Td (tetanus and diphtheria
      toxoids adsorbed) intramuscularly into the deltoid muscle to ensure adequate immunity to the
      tetanus antigen. Patients will undergo leukapheresis again for immunologic monitoring with a
      specific assessment of baseline antigen-specific cellular and humoral immune responses if
      needed for further DC generations 4 (± 2) weeks after vaccine #3. Prior to pp65 DC
      vaccination #4,(3±1) weeks after leukapheresis 2 the vaccine site will receive a
      pre-conditioning intradermal injection of Td. Up to 16 patients will receive 111-Indium
      labeled DCs at the 4th vaccine followed by SPECT/CT imaging immediately, and at 1 and 2 days
      after injections.
    

Trial Arms

NameTypeDescriptionInterventions
DC vaccination with Td preconditioning and GM CSFExperimentalThis single-arm phase II study will assess the impact of tetanus pre-conditioning and adjuvant GM-CSF on overall survival of newly diagnosed GBM patients who have undergone definitive resection, are unmethylated, and completed standard temozolomide and radiation treatment. All enrolled patients will undergo a leukapheresis for the generation of DCs. Patients will then receive approximately 6 weeks of standard of care radiation therapy (RT) and concurrent TMZ. A single post-RT cycle of dose intensified TMZ (100 mg/m2/day for 21 days) will then be given. On day 23 (± 2 days) of the cycle, patients will receive the first of 3 pp65 DC vaccines every 2 weeks. All patients will receive up to a total of 10 DC vaccines
  • Human CMV pp65-LAMP mRNA-pulsed autologous DCs containing GM CSF
  • Temozolomide
  • Tetanus-Diphtheria Toxoid (Td)
  • GM-CSF
  • 111-Indium-labeling of Cells for in vivo Trafficking Studies

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18 years

          -  World Health Organization (WHO) Grade IV Glioma with definitive resection prior to the
             consent, with a residual radiographic contrast-enhancing disease on the postoperative
             computed tomography (CT) or Magnetic Resonance Imaging (MRI) of <1 cm in maximal
             diameter in any axial plane.

          -  MRI post-RT does not show progressive disease at the time of enrollment

          -  Enough tumor tissue available for determination of MGMT gene promoter status (must be
             unmethylated)

          -  CMV Seropositive

          -  KPS of > 80%

          -  Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,500 cells/µl, platelets ≥
             125,000 cells/µl.

          -  Serum creatinine ≤ 1.5 mg/dl, serum glutamic-oxaloacetic transaminase (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 breastfeeding. 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 procedure (leukapheresis).

          -  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 breastfeeding.

          -  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-
             diethylenetriamine penta-acetic acid (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.

          -  Prior chemotherapy or radiosensitizers (including Gliadel wafers) for cancers of the
             head and neck region, other than TMZ prescribed during radiation for GBM (prior
             chemotherapy for a different cancer is allowable)

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

               1. Unstable angina and/or congestive heart failure requiring hospitalization;

               2. Transmural myocardial infarction within the last 6 months;

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

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

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

               6. Known Human Immunodeficiency Virus (HIV) and Hepatitis C positive status;

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

               8. 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 the 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 the 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 of subjects receiving Td pre-conditioning with GM-CSF
Time Frame:5 years
Safety Issue:
Description:Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up has OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.

Secondary Outcome Measures

Measure:Migration and Survival from vaccine 4
Time Frame:5 years
Safety Issue:
Description:The Cox proportional hazards model will assess the impact of migration on survival after vaccine #4. Migration is defined as the maximum percentage of 111In-labeled DCs reaching inguinal nodes during the 48 hours after the 4th vaccination. The hazard ratio associated with a 1-unit change in migration will be estimated with 95% confidence intervals.CSF to site-draining inguinal lymph nodes after Td pre-conditioning and survival after vaccine # 4.
Measure:Chemokine (C-C motif) ligand 3 (CCL3) and Survival from vaccine 4
Time Frame:5 years
Safety Issue:
Description:The Cox proportional hazards model will assess the impact of CCL3 on survival post-vaccine 4. The hazard ratio associate with a 1-unit increase in CCL3 will be estimated with 95% confidence intervals
Measure:Polyfunctionality and Survival from vaccine 4
Time Frame:5 years
Safety Issue:
Description:Cox proportional hazards model will assess the association between fold change increase between baseline and the leukapheresis 2 in the frequency of pp65 antigen-specific CD8+ T cells producing three or more cytokines (IFNγ, CCL3, IL-2, TNFα, CD107a), and survival post-vaccine 4. The hazard ratio associate with a 1-unit fold change in polyfunctionality will be estimated with 95% confidence intervals.
Measure:Maximum peak increase from vaccine 1 in percent Regulatory T cells (TReg) of CD4+ T cells
Time Frame:1 year
Safety Issue:
Description:The mean difference in TRegs between vaccine 1 and the maximum measured level post-vaccine 1 will be reported.
Measure:Proportion of patients with unacceptable toxicity
Time Frame:1 year
Safety Issue:
Description:The proportion of patients experiencing an unacceptable toxicity will be reported. An unacceptable toxicity is defined as any grade 3 or greater toxicity that is possibly, probably, or definitely attributed to the pre-conditioning agent Td or pp65 DC vaccine that does not resolve to baseline within 3 weeks; any Grade 3 hypersensitivity reactions or autoimmune toxicity requiring steroids or hormone replacement; , and is not due to progressive disease, or any life-threatening event not attributable to concomitant medication, co-morbid event, or disease progression. Toxicities will be graded according to the National Cancer Institute Common Toxicity Criteria of Adverse Events (NCI CTCAE) version 5 criteria.

Details

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

Trial Keywords

  • Glioblastoma
  • Dendritic cells
  • Temozolomide
  • Tetanus
  • David Ashley
  • Immunotherapy
  • Vaccine

Last Updated

October 2, 2019