Childhood Glioblastoma Clinical Trial
Official title:
Autologous Dendritic Cells and Metronomic Cyclophosphamide in Combination With Checkpoint Blockade for Relapsed High-Grade Gliomas in Children and Adolescents
This phase I/II trials evaluates the feasibility, safety and efficacy of an individualized cancer vaccine, based on autologous, tumor-lysate loaded dendritic cells in children and adolescents with relapsed high-grade gliomas. In addition, regulatory T cells are depleted by a short cycle of metronomic cyclophosphamide upfront of the vaccine in order to facilitate induction of immune responses. Therapeutic DC vaccines are followed by four cycles of Nivo/Ipi double checkpoint blockade and a Nivolumab monotherapy maintenance in order to optimize the induced T-cell response.
| Status | Recruiting |
| Enrollment | 25 |
| Est. completion date | January 31, 2025 |
| Est. primary completion date | January 31, 2025 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 3 Years to 21 Years |
| Eligibility | Inclusion Criteria: 1. Diagnosis of relapsed high-grade malignant glioma confirmed by central neuropathological and neuroradiological review (last magnetic resonance imaging diagnosis not older than 4 weeks) - including glioblastoma multiforme (WHO IV), anaplastic astrocytoma World Health Organization (WHO III), anaplastic oligodendroglioma (WHO III), anaplastic oligoastrocytoma (WHO III), anaplastic pilocytic astrocytoma (WHO III), anaplastic ganglioglioma (WHO III), anaplastic pleomorphic xanthoastrocytoma (analogous to WHO III), giant cell glioblastoma (WHO IV), and gliosarcoma (WHO IV) relapsed after first-line therapy. 2. Patients aged 3 years and older but under 21 years at time of relapse diagnosis 3. Written informed consent of the patient (mandatory from 14 years of age) or the parents (mandatory till 18 years of age). 4. Prospect of resection of relapse tumour by neurosurgery (total, subtotal or partial) Exclusion Criteria: 1. Known hypersensitivity or contraindication to cyclophosphamide 2. Known hypersensitivity or contraindications to Nivolumab or Ipilimumab. 3. Other malignancies, either simultaneous or within the last 2 years 4. Active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. 5. Pregnancy and / or lactation 6. Patients who are sexually active refusing to use effective contraception (oral contraception, intrauterine devices, barrier method of contraception in conjunction with spermicidal jelly or surgical sterile) 7. Current or recent (within 4 weeks prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial 8. Severe concomitant diseases (e.g. immune deficiency syndrome) 9. Severe psychological disease or neurological damage without possibility to communicate 10. Clinical signs of intracranial pressure 11. Intracerebral hemorrhage, gliomatosis 12. No severe blood count abnormalities: leukocytes < 2.000/µl, Hb <10 g/dl, thrombocytes < 100.000/µl 13. No severe liver enzyme elevation (> 2-3x fold of normal) 14. Ongoing reirradiation or chemotherapy (within the last 4 weeks) (irradiation of formerly non-involved fields is allowed, but not part of this study) 15. Estimated life expectancy of less than 2 months 16. Preexisting severe cardiac disease 17. Presence of unresectable spinal metastases 18. Karnofsky index < 50% 19. Active infection within the last 2 weeks 20. Previous infection with Human Immunodeficiency, Hepatitis C, Human T-Lymphocyte 1/2, Hepatitis B Virus, Lues, protozoan parasites, or other chronic bacterial infections. 21. With regard to prevention of variant Creutzfeldt-Jakob disease the following patients have to be excluded. 22. Patients receiving systemic immunosuppressive or immunoactivating substances. |
| Country | Name | City | State |
|---|---|---|---|
| Germany | University Children's Hospital | Würzburg | Bavaria |
| Lead Sponsor | Collaborator |
|---|---|
| Wuerzburg University Hospital |
Germany,
Eyrich M, Schreiber SC, Rachor J, Krauss J, Pauwels F, Hain J, Wolfl M, Lutz MB, de Vleeschouwer S, Schlegel PG, Van Gool SW. Development and validation of a fully GMP-compliant production process of autologous, tumor-lysate-pulsed dendritic cells. Cytoth — View Citation
Lohr M, Freitag B, Technau A, Krauss J, Monoranu CM, Rachor J, Lutz MB, Hagemann C, Kessler AF, Linsenmann T, Wolfl M, Ernestus RI, Engelhardt S, Gelbrich G, Schlegel PG, Eyrich M. High-grade glioma associated immunosuppression does not prevent immune res — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 6 month overall survival | overall survival 6 months after diagnosis of relapse | 6 months | |
| Secondary | overall survival | overall survival | 12-24 months | |
| Secondary | progression-free survival | progression-free survival | 12-24 months | |
| Secondary | toxicity metronomic cyclophosphamide | frequency of adverse events associated with metronomic cyclophosphamide | 12-24 months | |
| Secondary | toxicitiy vaccine | frequency of adverse events associated with the vaccine | 12-24 months | |
| Secondary | toxicity checkpoint blockade | frequency of AEs/SAEs associated with Nivolumab and/or Ipilimumab | 12-24 months | |
| Secondary | Treg frequency | frequency of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide in % of CD3+ | 12-24 months | |
| Secondary | Treg numbers | absolute numbers of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide per µl blood | 12-24 months | |
| Secondary | T-cell response | Interferon-gamma Cytotoxic T cell (CTL) assay | 12-24 months | |
| Secondary | serum cytokine levels | Tru Culture cytokine array | 12-24 months | |
| Secondary | correlation with histopathological tumor characteristics | correlation of outcome/immune response with histopathology etc. | 12-24 months |