Nivolumab With DC Vaccines for Recurrent Brain Tumors
Condition: Malignant Glioma; Astrocytoma; Glioblastoma
MeSH terms: Glioblastoma; Astrocytoma; Glioma
Intervention: nivolumab; DC
Intervention description: Nivolumab is a fully human monoclonal antibody that targets the programmed death-1 (PD-1) cluster of differentiation 279 cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes. Binding of PD-1 to its ligands, programmed death-ligands 1 and 2, results in the down-regulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes immune responses and antigen-specific T cell responses to both foreign antigens as well as self-antigens. Nivolumab is expressed in Chinese hamster ovary cells and is produced using standard mammalian cell cultivation and chromatographic purification technologies. The clinical study product is a sterile solution for parenteral administration.; DCs are potent immunostimulatory cells that continuously sample the antigenic environment of the host and specifically activate cluster of differentiation 4 positive (CD4+) and cluster of differentiation 8 positive (CD8+) T-cells and B-cells. They are at the crossroads of many of the elegant networks of the immune system, and DCs represent the most promising contemporary biologic entity for realizing the promise of immunotherapy. Potent immune responses and encouraging clinical results have been seen in Phase I and II human clinical trials in systemic cancers. Numerous animal studies and the investigator's institution's humans studies have demonstrated potent antitumor responses using DC-based immunotherapy against MGs.
Intervention MeSH terms: Nivolumab; Vaccines
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      Patients will be randomized to one of two treatment arms - Group I and Group II. Group I will
      receive nivolumab monotherapy until surgical resection, and Group II will receive nivolumab
      alone and with DC vaccine therapy until surgical resection. During surgical resection blood
      and tumor samples will be assessed and compared. Following surgery, both groups will continue
      to receive DC vaccines (total of 8) and nivolumab therapy until confirmed progression.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age 18-80 years of age

          -  First or second recurrence of MG (WHO Grade III or IV glioma or astrocytoma) in
             surgically accessible areas with prior histologic diagnosis of MG

          -  Bevacizumab-naïve - no prior exposure to Bevacizumab

          -  Karnofsky Performance Status (KPS) of ≥ 70%

          -  Radiation Therapy (RT) with ≥ 45 Gray (Gy) tumor dose, completed ≥ 8 weeks prior to
             study entry

          -  Laboratory values must meet the following criteria:

               1. White Blood Count (WBC) ≥ 2000/microliters (uL)

               2. Neutrophils ≥ 1500/uL

               3. Platelets ≥ 100x103/uL

               4. Hemoglobin ≥ 9.0 g/dL

               5. Serum creatinine ≤ 1.5x the upper limit of normal (ULN) or creatinine clearance
                  (CrCl)≥ 40 mL/min (using the Cockcroft-Gault formula) c. Female CrCl = (140 - age
                  in years) x weight in kg x 0.85 /72 x serum creatinine in mg/dL d. Male CrCl =
                  (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL

               6. Aspartate Aminotransferase (AST) ≤ 3x ULN

               7. Alanine Aminotransferase (ALT) ≤ 3x ULN

               8. Bilirubin≤ 1.5x ULN (except subjects with Gilbert Syndrome, who can have total
                  bilirubin < 3.0 mg/dL)

               9. Subjects must have resting baseline O2 saturation by pulse oximetry of ≥ 92% at
                  rest.

          -  Patients of child bearing potential or with partners of child-bearing potential must
             practice recommended contraceptive methods to prevent pregnancy during treatment and
             for 5 months after the last dose of nivolumab for women, 7 months after the last dose
             of nivolumab for men, and for 6 months after the last dose of bevacizumab for subjects
             receiving bevacizumab.

        Exclusion Criteria:

          -  Contrast-enhancing tumor component crossing the midline, multi-focal tumor, or tumor
             dissemination (subependymal or leptomeningeal)

          -  Clinically significant increased intracranial pressure (e.g., impending herniation),
             uncontrolled seizures, or requirement for immediate palliative treatment

          -  Pregnant or need to breast feed during the study period (Negative human chorionic
             gonadotropin (β-HCG) test required), or unable to maintain use of contraception while
             on study and for 31 weeks after the last dose of nivolumab

          -  Active infection requiring treatment or an unexplained febrile (> 101.5o F) illness

          -  Known immunosuppressive disease, autoimmune disease or human immunodeficiency virus
             infection, Hepatitis B or Hepatitis C

          -  Known allergy or hypersensitivity to tetanus, or any other tetanus or diphtheria
             toxoid-containing vaccine, or any component of this vaccine (i.e., aluminum phosphate,
             formaldehyde)

          -  Known severe (Grade 3 or 4) infusion-related allergy or hypersensitivity to any
             monoclonal antibody

          -  Previous radiation therapy with anything other than standard radiation therapy (such
             as previous stereotactic radiosurgery) or previous treatment with an immune checkpoint
             inhibitor (i.e., nivolumab, pembrolizumab, ipilimumab)

          -  Unstable or severe intercurrent medical conditions such as severe heart (New York
             Association Class 3 or 4) or lung (FEV1 < 50%) disease, uncontrolled diabetes mellitus

          -  Corticosteroid use > 4 mg/day at time of consent

          -  Prior inguinal lymph node dissection.