Dendritic Cell Cancer Vaccine for High-grade Glioma
Condition: Glioblastoma Multiforme
MeSH terms: Glioblastoma
Study type: Interventional
Phase: Phase 2

Summary: 
      A randomised, open-label, 2-arm, multi-centre, phase II clinical study with one group
      receiving standard therapy with Temozolomide, radiotherapy, and Trivax; and a control group
      receiving standard therapy with Temozolomide and radiotherapy only; after tumour resection of
      at least 70% in both groups. The hypothesis is based on the assumption that time to
      progression will be doubled in the treatment group.
    

Detailed description: 
      Vaccination represents a success story in modern medicine and its principles have been found
      to be valid in different species, at least in the case of infectious diseases. As of today,
      there is little reason to believe that this would not be true in the case of tumours. It is
      now generally acknowledged that human tumours carry a mutational antigenic (non-self)
      repertoire of immunogenic potential that may be a suitable target for antitumour immune
      therapy. During the last years accumulating evidence from mouse experiments indicates that
      one can immunise prophylactically against cancers as effectively as against an infectious
      agent. However, in contrast to most experimental mouse tumour models, human tumours have in
      general been within their host for a long time and thus had the opportunity to influence
      their microenvironment and the larger immunological environment. Antigens capable of
      mediating specific rejection were found in human as well as in mouse tumours.

      Many of the clinical trials using dendritic cell (DC) -based cancer vaccination techniques
      were designed for the treatment of melanoma. Other important diseases in which DC-based
      cancer vaccination was studied include prostate cancer, B cell lymphoma, renal cell
      carcinoma, glioma and glioblastoma, breast and ovarian cancer, gastrointestinal cancer, and
      selected solid paediatric tumours. In most of these trials some in vivo and/or in vitro
      evidence for the generation of anti-tumour immunity was found and even complete or partial
      remission of the tumour was observed in selected cases. The first phase III trial
      demonstrating the efficacy of DC cancer vaccination for the treatment of prostate cancer was
      reported recently (www.dendreon.com). Also patients suffering from glioblastoma multiforme
      appear to benefit from DC cancer immune therapy. The side effects observed in DC cancer
      vaccinations were usually described to be mild and not limiting the application.

      We developed a DC cancer vaccine technology, Trivax, advancing the design of DC cancer immune
      therapy in one critical aspect. It is the first such vaccine that is enable for releasing the
      immune modulatory cytokine interleukin (IL) -12. Trivax is comprised of IL-12 secreting DCs
      and a mixture of protein tumour antigens derived from the individual patient's tumour cells.
      No synthetic tumour antigen component is involved. Both components of Trivax are derived from
      the individual patient and are used for the treatment of only this patient. Trivax therefore
      represents a fully individualised somatic cell therapy medicine. Trimed's early clinical
      evaluations in patients suffering from kidney cancer, prostate cancer, bone tumours, and
      malignancies of childhood have confirmed the safety and the feasibility of the Trivax
      technology.

      Glioblastoma multiforme (GBM) (ICD-O M9440/3) is the most malignant astrocytic tumour,
      composed of poorly differentiated neoplastic astrocytes. Histopathological features include
      cellular polymorphism, nuclear atypia, brisk mitotic activity, vascular thrombosis,
      micro-vascular proliferation and necrosis. GBM typically affects patients of various age
      beginning in childhood and up to high age. It is preferentially located in the cerebral
      hemispheres. GBM may develop from diffuse astrocytomas WHO grade II or anaplastic
      astrocytomas (secondary GBM), but more frequently, they manifest after a short clinical
      history de novo, without evidence of a less malignant precursor lesion (primary GBM). In
      spite of modern oncological treatment, the prognosis of GBM remains dismal, with a median
      survival of little over 1 year.

      GBM-Vax is a randomised, open-label, 2-arm, multi-centre, phase II clinical study with both
      groups undergoing surgery and receiving standard therapy with Temozolomide and radiotherapy;
      and the treatment group that in addition to the standard therapy receives cancer immune
      therapy with Trivax. Our aim is to extend therapy options presently including surgery,
      irradiation and Temozolomide with DC cancer vaccination to improve the poor prognosis of
      patients with GBM.

      Primary objective

      • Progression free survival measured as percentage of non-progressive patients with newly
      diagnosed GBM 12 months after a post-operative MRI scan treated according to the current
      standard (surgical resection, irradiation, oral chemo-therapy with Temozolomide), and Trivax,
      an autologous DC cancer vaccine charged with autologous tumour protein, as add-on therapy
      (group A), in comparison to patients receiving standard treatment without Trivax (group B).

      Secondary objectives

        -  Progression free survival measured as percentage of non-progressive patients with newly
           diagnosed GBM 18 and 24 months after a post-operative MRI scan receiving standard
           treatment and Trivax as add-on therapy (group A), in comparison to patients receiving
           standard treatment without Trivax (group B).

        -  Extension of overall survival of patients with newly diagnosed GBM receiving standard
           treatment and Trivax as add-on therapy, in comparison to patients receiving standard
           treatment without Trivax.

        -  Quality of life in patients treated with Trivax as an add-on therapy using ECOG (Eastern
           Cooperative Oncology Group) performance status compared to qual-ity of life of patients
           receiving standard therapy (for study patients older 18 years).

      Number of subjects In total, 56 patients will be enrolled in the study. The study consists of
      2 arms and at least 28 patients should be randomly assigned to one of the two arms. It is
      expected to recruit the study patients within a period of one year. Randomisation is based on
      stratification according to study sites at a 1:1 ratio. Patients younger than 18 years will
      not be randomised but will all receive add-on therapy with Trivax. We feel that it would be
      not just to expect from children to understand and accept that there is a new treatment
      available but only every second patient will receive it. Obviously, patients younger than 18
      years will not be analysed together with adult patients in the context of the study; and
      paediatric patients will not count towards the recruiting number of 2 x 28. Thus, the results
      obtained in paediatric GBM patients will not influence the outcome of the study in patients
      older than 18 years.
    

Intervention name(s): Trivax, Temozolomide, Surgery, Radiotherapy; Temozolomide, Surgery, Radiotherapy
Intervention type(s): Drug; Drug
Intervention description(s): Trivax: 5 x 10e6 dendritic cells, intranodal in 500 µl NaCl, weeks 7, 8, 9, 10, 12, 16, 20, 24, 28, 32
Irradiation: 2 Gy per fraction once daily, five days per week (Mo-Fr), weeks 1, 2, 3, 4, 5, 6, total dose 60 Gy
Temozolomide concomitant to radiotherapy: 75 mg/m²/day, 5 days per week (Mo-Fr), weeks 1, 2, 3, 4, 5, 6.
Break: weeks 7, 8, 9, 10.
Temozolomide adjuvant: 150 mg/m²/day, five days per week (Mo-Fr), week 11; 200 mg/m²/day, five days per week (Mo-Fr), weeks 15, 19, 23, 27, 31.; Irradiation: 2 Gy per fraction once daily, five days per week (Mo-Fr), weeks 1, 2, 3, 4, 5, 6, total dose 60 Gy
Temozolomide concomitant to radiotherapy: 75 mg/m²/day, 5 days per week (Mo-Fr), weeks 1, 2, 3, 4, 5, 6
Break: weeks 7, 8, 9, 10
Temozolomide adjuvant: 150 mg/m²/day, five days per week (Mo-Fr), week 11; 200 mg/m²/day, five days per week (Mo-Fr), weeks 15, 19, 23, 27, 31
Intervention MeSH terms: Temozolomide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Dendritic cell; Cancer vaccine; Anti-tumor immune therapy; Interleukine-12; Individualised autologous therapy; Brain cancer; Temozolomide; Radiotherapy; Irradiation; High-grade glioma; Advanced therapy medicinal product ATMP; Somatic cell therapy; Leukocyte apheresis; Neurosurgery; Neurooncology; Neurology; Immunology; Tumor immunology; Transfusion medicine; Monocyte; Killer cell; Cytotoxic T-cell; Cytotoxic T-lymphocyte