Nivolumab With DC Vaccines for Recurrent Brain Tumors
Condition: Malignant Glioma; Astrocytoma; Glioblastoma
MeSH terms: Glioblastoma; Astrocytoma; Glioma
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      This two-arm randomized trial will evaluate the safety of nivolumab in combination with DC
      vaccinations for the treatment of bevacizumab-naïve subjects with first or second recurrent,
      resectable World Health Organization (WHO) Grade III and IV malignant gliomas (MGs). Up to 66
      patients will be enrolled and treated with the goal of accruing 30 patients (15 per arm) that
      will receive nivolumab and at least 3 vaccines. After enrollment, leukapheresis will be done
      for generation of DC vaccines and immunologic monitoring. All subjects will undergo standard
      of care tetanus booster vaccination with 0.5 mL of Td (tetanus and diphtheria toxoids
      adsorbed) intramuscularly (I.M.) into the deltoid muscle to ensure adequate immunity to the
      tetanus antigen. Subjects will initially return every 2 weeks and receive approximately 3
      infusions of nivolumab 3 mg/kg IV while the DC vaccines are being prepared from the initial
      leukapheresis and will then be randomized 1:1 to one of 2 arms (Group I: nivolumab only
      pre-surgery; Group II: nivolumab with DC vaccines pre-surgery). Patients who are unable to
      tolerate nivolumab will be withdrawn from the study and replaced. Patients whose DCs or
      Peripheral Blood Lymphocytes (PBLs) fail to meet release criteria will continue to receive
      nivolumab only and will not undergo repeat leukapheresis. For patients whose leukapheresis
      yields less than 4 vaccines, a repeat leukapheresis may be obtained a minimum of 2 weeks from
      the previous leukapheresis (and may be repeated as needed) if stable. Peripheral blood will
      be drawn for immune monitoring prior to treatment with the 4th cycle of nivolumab (first
      post-randomization infusion of nivolumab).

      Group I Treatment Plan (Nivolumab Only Pre-Surgery) After randomization, patients in Group I
      will receive nivolumab 3 mg/kg IV every 2 weeks x approximately 8 weeks. The subject will
      then undergo surgical resection of tumor within approximately 1-3 weeks. Approximately 2-4
      weeks later, leukapheresis is repeated for generation of DC vaccines and immunologic
      monitoring. Approximately 1 day to 2 weeks after leukapheresis, the subject will resume
      nivolumab 3mg/kg IV every two weeks with DC vaccine administration intradermally (i.d.) for a
      total of 3 vaccines. At the time of the third DC vaccine, patients will receive vaccine site
      pre-conditioning. A single dose of Td toxoid (1 flocculation unit (Lf) in 0.4 milliliters
      (mL) of saline) will be administered to a single side of the groin i.d. (as described above
      for all vaccine administrations 12-24 hours prior to the third DC vaccine, which is always
      given bilaterally at the groin site. At the vaccine #3 visit, prior to vaccine # 3
      administration, erythema and induration measurements will be taken of pre-conditioning site.
      Group I subjects will then receive monthly DC vaccine administrations intradermally for 5
      months or until progression (whichever comes first).Total vaccines to be administered will be
      8 post-surgery unless subject is removed. Nivolumab will continue until progression. At the
      clinic visit following the last vaccine (#8), subjects will have peripheral blood drawn for
      immune monitoring prior to infusion of nivolumab.

      Group II Treatment Plan (Nivolumab with DC Vaccines Pre-Surgery) After randomization,
      patients in Group II will receive the fourth cycle of nivolumab then receive nivolumab 3
      mg/kg IV along with DC vaccines intradermally every 2 weeks x approximately 6 weeks for a
      total of 3 vaccines. At the time of the third DC vaccine, patients will receive vaccine site
      pre-conditioning. A single dose of Td toxoid (1 Lf in 0.4 mL of saline) will be administered
      to a single side of the groin i.d. 12-24 hours before the third DC vaccine, which is always
      given bilaterally at the groin site. At the vaccine #3 visit, prior to vaccine #3
      administration, erythema and induration measurements will be taken of pre-conditioning
      site.The subject will then undergo surgical resection of tumor within approximately 1-3
      weeks. Approximately 2-4 weeks later, leukapheresis is repeated for generation of DC vaccines
      and immunologic monitoring. Approximately 1 day to 2 weeks after leukapheresis, the subject
      will resume nivolumab 3mg/kg IV every two weeks. When DC vaccines have completed processing
      and are available for administration, monthly DC vaccine administrations as described above
      will be administered for 5 months or until progression (whichever comes first). Total
      vaccines to be administered will be 8 (3 pre- and 5 post-surgery) unless subject is removed.
      Nivolumab will continue until progression. At the clinic visit following the last vaccine
      (#8), subjects will have peripheral blood drawn for immune monitoring prior to infusion of
      nivolumab.
    

Intervention name(s): nivolumab; DC
Intervention type(s): Drug; Biological
Intervention description(s): 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.
Other intervention name(s): BMS-936558; MDX1106; DC vaccine; pp65 DC vaccine; Human CMV pp65-LAMP mRNA-pulsed autologous DCs; CMV pp65 DCs
Intervention MeSH terms: Nivolumab; Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment