Cytomegalovirus (CMV) RNA-Pulsed Dendritic Cells for Pediatric Patients and Young Adults With WHO Grade IV Glioma, Recurrent Malignant Glioma, or Recurrent Medulloblastoma
Condition: Glioblastoma; Malignant Glioma; Medulloblastoma Recurrent; Pediatric Glioblastoma Multiforme; Pediatric Brain Tumor, Recurrent; Pediatric Brain Tumor
MeSH terms: Glioblastoma; Glioma; Brain Neoplasms; Medulloblastoma; Recurrence
Intervention: CMV-DCs with GM-CSF; Td (tetanus toxoid)
Intervention description: CMV-DCs are autologous dendritic cells derived from PBMCs loaded with RNA encoding the human CMV matrix protein pp65 as a fusion protein with the full-length LAMP protein (pp65-flLAMP) plus GM-CSF.; Patients will receive preconditioning with Td in the right groin, and approximately 6-24 hours later, they will receive their first CMV-DC vaccination. Patients will also receive Td preconditioning approximately 6-24 hours prior to their 4th vaccine and subsequent vaccines, if any.
Intervention MeSH terms: Molgramostim; Sargramostim
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 0 Years
Maximum age: 35 Years
Healthy volunteers: No
Keywords: glioblastoma; medulloblastoma; glioma; pediatric; recurrent; newly diagnosed; Pro00092868; Landi

Summary:

      The purpose of this study is to determine the feasibility and safety of administering CMV
      RNA-pulsed dendritic cells (DCs), also known as CMV-DCs, to children and young adults up to
      35 years old with nWHO Grade IV glioma, recurrent malignant glioma, or recurrent
      medulloblastoma. Evidence for efficacy will also be sought. This will be a phase 1 study
      evaluating CMV-DC administration with tetanus toxoid (Td) preconditioning and Granulocyte
      Macrophage-Colony Stimulating Factor (GM-CSF) adjuvant in children and young adults up to 35
      years old with WHO grade IV glioma, recurrent malignant glioma, or recurrent medulloblastoma.
      This safety study will enroll a maximum of 10 patients.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age requirements:

               1. ≤ 35 years for patients with grade IV glioma or recurrent World Health
                  Organization (WHO) grade IV glioma

               2. 3-35 years old for patients with recurrent medulloblastoma

          2. Newly diagnosed or recurrent WHO grade IV glioma, recurrent WHO grade III glioma, or
             recurrent medulloblastoma (multifocal/disseminated disease is eligible, at the
             discretion of the PI)

          3. Patients with WHO grade IV glioma who received surgery and radiation are eligible even
             without recurrence or progression

          4. Patients must have recovered from all previous treatments including chemotherapy,
             radiation therapy, surgery, and other immunotherapies, etc.

             a. If the patient was receiving bevacizumab at the time of enrollment, the treating
             oncologist has the discretion of administering and adjusting bevacizumab 10 mg/kg
             every 14 days. The rationale for continuing patients on bevacizumab is to prevent
             rebound cerebral edema commonly seen after stopping this agent.

          5. Laboratory Studies:

               1. Platelets ≥ 100,000 cells/mm3

               2. Creatinine ≤ 1.2 x upper limit of normal (ULN)

               3. Total bilirubin, Aspartate Aminotransferase (AST), Alanine Aminotransferase
                  (ALT), alkaline phosphatase ≤ 2.5 x ULN

               4. Neutrophil count ≥ 1000 cells/mm3

               5. Hemoglobin ≥ 9 g/dl prior to biopsy (can be transfused)

          6. Able to undergo brain MRI with and without contrast

          7. Karnofsky Performance Status (KPS) ≥ 70 or Lansky Performance Status (LPS) ≥ 70

          8. A signed informed consent form approved by the Institutional Review Board (IRB) will
             be required for patient enrollment into the study. Patients (if 18 years old or older)
             or their parent(s) or guardian(s) (if younger than 18 years old) must be able to read
             and understand the informed consent document and must sign the informed consent
             indicating that they are aware of the investigational nature of this study.

          9. For females of childbearing potential, negative serum pregnancy test within 48 hours
             of leukapheresis

         10. Females of childbearing potential must be willing to use acceptable contraceptive
             method to avoid pregnancy throughout the study and for at least 24 weeks after the
             last dose of study drug

         11. Males with female partners of childbearing potential must agree to practice adequate
             contraceptive methods throughout the study and should avoid conceiving children for 24
             weeks following the last dose of study drug

         12. Newly diagnosed WHO grade IV glioma patients only: must be expected to complete
             standard of care radiation (minimum ~54 Gray)

        Exclusion Criteria:

          1. Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease
             free for ≥ 3 years. (For example, carcinoma in situ of the breast, oral cavity, and
             cervix are all permissible)

          2. Disease outside of the central nervous system (CNS)

          3. Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C seropositive

          4. Known active infection requiring intravenous (IV) antibiotics or active
             immunosuppressive disease

          5. Severe, active co-morbidity, defined as follows:

               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
                  initiation of Radiation Therapy (XRT)/Temozolomide (TMZ)

               4. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness
                  requiring hospitalization or precluding study therapy at initiation of XRT/TMZ
                  for newly diagnosed patients or at initiation of dose-intensified (DI) TMZ for
                  recurrent patients

               5. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

               6. Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease
                  Control and Prevention (CDC) definition. The need to exclude patients with AIDS
                  from this protocol is necessary because the treatments involved in this protocol
                  may be significantly immunosuppressive

               7. Patients with autoimmune disease requiring medical management with
                  immunosuppressant(s)

               8. Major medical illnesses or psychiatric impairments that, in the investigator's
                  opinion, will prevent administration or completion of protocol therapy

               9. Active connective tissue disorders such as lupus or scleroderma that, in the
                  investigator's opinion, place the patient at high risk for radiation toxicity

          6. Pregnant or lactating women

          7. Prior allergy to TMZ, GM-CSF, gadolinium (Gd), or Td

          8. Prior history of brachial neuritis or Guillain-Barré syndrome

          9. Patients treated on any other therapeutic clinical protocols within 30 days prior to
             study entry

         10. Patients receiving > 0.1mg/kg or 4mg/day dexamethasone or equivalent

        10. For recurrent patients only: Patients who have not recovered from the toxic effects of
        prior chemo- and/or radiation therapy. Guidelines for this recovery period are dependent
        upon the specific therapeutic agent being used:

          1. Patients who have received chemotherapy or bevacizumab ≤ 4 weeks [except for
             nitrosourea (6 weeks) or metronomic dosed chemotherapy such as daily etoposide or
             cyclophosphamide (1 week)] prior to starting the study drug unless patients have
             recovered from the side effects of such therapy. If the patient was receiving
             bevacizumab at the time of enrollment, the treating oncologist has the discretion of
             administering and adjusting bevacizumab 10 mg/kg every 14 days.

          2. Patients who have received immunotherapy ≤ 4 weeks prior to starting the study drug
             unless patients have recovered from the side effects of such therapy