DC Migration Study for Newly-Diagnosed GBM
Condition: Glioblastoma; Astrocytoma, Grade IV; Giant Cell Glioblastoma; Glioblastoma Multiforme
MeSH terms: Glioblastoma; Astrocytoma
Study type: Interventional
Phase: Phase 2

Summary: 
      This randomized phase II study will assess the impact of pre-conditioning on migration and
      survival among newly diagnosed glioblastoma (GBM) patients who have undergone definitive
      resection and completed standard temozolomide (TMZ) and radiation treatment, as well as the
      impact of tetanus pre-conditioning and basiliximab together on survival. After completing
      standard of care radiotherapy with concurrent TMZ, patients will be randomized to 1 of 3
      treatment arms: 1). receive cytomegalovirus (CMV)-specific dendritic cell (DC) vaccines with
      unpulsed (not loaded) DC pre-conditioning prior to the 4th vaccine; 2). receive CMV-specific
      DC vaccines with Tetanus-Diphtheria Toxoid (Td) pre-conditioning prior to the 4th vaccine;
      3). receive basiliximab infusions prior to the 1st and 2nd DC vaccines along with Td
      pre-conditioning prior to the 4th vaccine. A permuted block randomization algorithm using a
      1:1:1 allocation ratio will be used to assign patients to a treatment arm. Randomization will
      be stratified by CMV status (positive, negative), with the assignment to arms I and II being
      double-blinded. Effective March 2017, randomization to Group III has been terminated.
    

Detailed description: 
      A maximum of 100 patients with resected, newly-diagnosed World Health Organization (WHO)
      Grade IV GBM will be enrolled in this study with the expectation that approximately 79
      patients will be randomized to subsequent treatment after completion of radiation treatment
      with concurrent temozolomide. Effective March 2017, randomization to Group III has been
      terminated. All consented patients will undergo a leukapheresis after resection for harvest
      of Peripheral Blood Lymphocytes (PBLs) for generation of DCs. Patients will then receive
      Radiation Therapy (RT) and concurrent TMZ at a standard targeted dose of 75 mg/m^2/d.
      Patients should start RT within approximately 6 weeks of surgery. Patients who experience
      progressive disease during radiation, are dependent on steroid supplements above physiologic
      levels at time of first vaccination, are unable to tolerate TMZ, or whose DCs or PBLs fail to
      meet release criteria will be withdrawn from the study and replaced and will not undergo
      repeat leukapheresis. For patients whose initial leukapheresis yields less than 3 vaccines,
      repeat leukapheresis may be obtained a minimum of 2 weeks from the previous leukapheresis
      (and may be repeated as needed) if pre-pheresis blood work is within the Apheresis Center's
      parameters and as long as this does not cause a significant delay in treatment for the
      patient.

      After RT and concurrent TMZ, patients will then be randomized and begin the initial cycle of
      TMZ at a standard targeted dose of 150-200mg/m^2/d for 5 days at the discretion of the
      treating oncologist 4 (± 2) weeks after completing RT. The study cycle of TMZ comprises a
      targeted dose of 150-200mg/m^2/d for 5 days every 5 (± 1) weeks. All patients will receive up
      to a total of 10 DC vaccines given bilaterally at the groin site unless progression occurs.
      DC vaccines will be given intradermally (i.d.) and divided equally to both inguinal regions.
      DC vaccines #1-3 will be given every two weeks, thus delaying the initiation of TMZ cycle 2.
      Patients will then be vaccinated in conjunction with subsequent TMZ cycles every 5 (± 1)
      weeks for a total of 6 to 12 cycles after RT at the discretion of the treating oncologist.
      DCs will be given on day 21 ± 2 days of each TMZ cycle. DC vaccinations will continue during
      TMZ cycles up to a total of 10 unless progression occurs.

      Before the first DC vaccination, all patients will receive immunization with 0.5 mL of Td
      intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen.
      Those assigned to Group III will receive basiliximab 20 mg infusions 1 week before the 1st
      and 1 week before the 2nd vaccine. At the time of the fourth DC vaccine, patients will
      receive pre-conditioning per the assigned group (Group I-unpulsed DCs i.d.; Group II- Td
      i.d.; Group III-Td i.d.). A single dose of Td toxoid (1 flocculation unit, in 0.3 milliliters
      (mLs) of saline for a total volume of 0.4 mLs) or 0.4 mLs of 1 x 10^6 autologous unpulsed DCs
      in saline will be administered to a single side of the groin, and 0.4 mLs of saline
      administered to the contralateral side 12-24 hours prior to the fourth DC vaccine, which is
      always given bilaterally at the groin site. Patients in Groups I and II will then receive
      111In-labeled DCs to compare the effects of different skin preparations on DC migration
      followed by Single-Photon Emission Computed Tomography and Computed Tomography (SPECT/CT)
      imaging immediately and at 1 and 2 days after injection. Group III will not undergo migration
      studies. Groups I and II will be double blinded. Group III will not be blinded.

      All patients will undergo leukapheresis again for immunologic monitoring with specific
      assessment of baseline antigen-specific cellular and humoral immune responses and further DC
      generations 4 (± 2) weeks after vaccine #3. Patients will be imaged bimonthly without
      receiving any other prescribed anti-tumor therapy. Patients will undergo an additional
      leukapheresis for generation of DCs if needed to continue vaccinations.

      As part of standard care for these patients, upon tumor progression, participants may undergo
      stereotactic biopsy or resection. As this is not a research procedure consent will be
      obtained separately. However, if tissue is obtained, it will be used to confirm tumor
      progression histologically and to assess immunologic cell infiltration and pp65 antigen
      escape at the tumor site.
    

Intervention name(s): Unpulsed DCs; Td; Human CMV pp65-LAMP mRNA-pulsed autologous DCs; 111In-labeled DCs; Temozolomide; Saline; Basiliximab
Intervention type(s): Biological; Biological; Biological; Biological; Drug; Drug; Drug
Intervention description(s): Patients in Group I will receive 1 x 10^6 autologous unpulsed DCs in saline administered to a single side of the groin intradermally 1 day before the fourth vaccine.; Patients in Groups II and III will receive a single dose of Td toxoid (1 flocculation unit, Lf, in 0.4 mLs) administered to a single side of the groin given intradermally 1 day before the fourth vaccine.; 2x10^7 human CMV pp65-LAMP mRNA-pulsed autologous DCs are given intradermally and bilaterally at the groin site (divided equally to both inguinal regions). Patients will receive up to a total of 10 DC vaccines.; 111In-labeled DCs are 2 x 10^7 pp65-LAMP mRNA loaded mature DCs will be labeled with 111In (50 μCi / 5 x 10^7 DCs) and given i.d. as fourth vaccine for Groups I and II only.; Temozolomide is a standard chemotherapy given to all enrolled patients at a targeted dose of 150-200mg/m2/d for 5 days every 5 (± 1) weeks for a total of 6 to 12 cycles at the discretion of the treating oncologist.; 0.4mL of saline given in the opposite groin 1 day before the fourth vaccine in all groups; Group III will receive basiliximab infusions (20 mg I.V) 1 week before the first vaccine and 1 week before the second vaccine.
Other intervention name(s): Unpulsed DCs pre-conditioning; Td toxoid; Td pre-conditioning; CMV-specific dendritic cell vaccine; DCs; Temodar; TMZ
Intervention MeSH terms: Temozolomide; Basiliximab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment