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JOURNAL ONKOLOGIE – STUDIE

Autologous Dendritic Cells, Metronomic Cyclophosphamide and Checkpoint Blockade in Children With Relapsed HGG

Rekrutierend

NCT-Nummer:
NCT03879512

Studienbeginn:
Februar 2018

Letztes Update:
17.09.2020

Wirkstoff:
depletion of regulatory T cells, cancer vaccine, checkpoint blockade

Indikation (Clinical Trials):
Glioblastoma

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Wuerzburg University Hospital

Collaborator:
-

Studienleiter

Kramm Christof, MD
Study Chair
Children's Hospital, University Medical Center Göttingen

Kontakt

Studienlocations (1 von 1)

University Children's Hospital
D-97080 Würzburg
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Matthias Eyrich, MD
Phone: +49-931-201-27728
E-Mail: eyrich_m@ukw.de

Paul G Schlegel, MD
Phone: +49-931-201-27915
E-Mail: schlegel_p@ukw.de
» Ansprechpartner anzeigen

Studien-Informationen

Detailed Description:

Relapsed high-grade gliomas (in the following addressed as high-grade gliomas = HGG) in children and adolescents represent a very bad prognosis group for which a recommended standard salvage therapy is currently not available.

Combination of Dendritic Cell (DC) vaccination, metronomic cyclophosphamide, and checkpoint blockade will be investigated in the present trial as a new treatment strategy for these patients: metronomic cyclophosphamide has been shown to significantly reduce numbers of regulatory T cells (Treg) without inducing general leukopenia. DCs might induce tumour-directed immune responses thereby facilitating long-term remissions. Efficacy of primed T-cell responses by the vaccine will potentially be enhanced by the application of checkpoint inhibitors Nivolumab (antiPD-L1) and Ipilimumab (antiCTLA4) in the post-vaccine phase and during maintenance.

Cyclophosphamide is an established drug used as an anti-cancer or immunosuppressive substance since decades, with extensive experience when used in low, non-myeloablative dosages. DCs represent an innovative new strategy in cellular immunotherapy. DCs in cancer patients have been used in a number of smaller studies, and in some of these trials, promising results could be obtained. Several studies showed a trend towards a prolonged overall survival with a few long-term survivors which is otherwise extremely rare in this high-risk population. Results seemed to be more favourable in pediatric than in adult patients. Checkpoint inhibitors (antiPD-L1 and/or antiCTLA4) have been shown to exhibit synergistic effects with vaccines in preclinical models, and prelimnary data of several early stage trials have shown promising results. Therefore, our study aims to improve the efficacy of a DC-based therapeutic vaccine by optimizing the conditions upfront of the vaccine (Treg depletion) and improving T-cell responses by checkpoint blockade after the vaccine in the effector phase.

In conclusion, this study will exploit the optimal efficacy of a therapeutic vaccine in children and adolescents with relapsed HGG.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. 6 month overall survival (Time Frame - 6 months):
overall survival 6 months after diagnosis of relapse



Secondary outcome:

1. overall survival (Time Frame - 12-24 months):
overall survival

2. progression-free survival (Time Frame - 12-24 months):
progression-free survival

3. toxicity metronomic cyclophosphamide (Time Frame - 12-24 months):
frequency of adverse events associated with metronomic cyclophosphamide

4. toxicitiy vaccine (Time Frame - 12-24 months):
frequency of adverse events associated with the vaccine

5. toxicity checkpoint blockade (Time Frame - 12-24 months):
frequency of AEs/SAEs associated with Nivolumab and/or Ipilimumab

6. Treg frequency (Time Frame - 12-24 months):
frequency of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide in % of CD3+

7. Treg numbers (Time Frame - 12-24 months):
absolute numbers of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide per µl blood

8. T-cell response (Time Frame - 12-24 months):
Interferon-gamma Cytotoxic T cell (CTL) assay

9. serum cytokine levels (Time Frame - 12-24 months):
Tru Culture cytokine array

10. correlation with histopathological tumor characteristics (Time Frame - 12-24 months):
correlation of outcome/immune response with histopathology etc.

Geprüfte Regime

  • depletion of regulatory T cells:
    oral metronomic cyclophosphamide
  • reoperation:
    resection of relapsed tumor in order to improve clinical condition of the patient and to acquire tumor tissue for vaccine generation
  • cancer vaccine:
    4 weekly intradermal injections of lysate-loaded dendritic cells, followed by 3 monthly boost vaccines with tumor lysate and further boost vaccines every three months
  • checkpoint blockade:
    Immediately one week after the DC-induction vaccines, patients will receive four applications of Nivolumab/Ipilimumab double checkpoint blockade in threeweekly intervals, followed by Nivolumab monotherapy every month for a total duration of one year.

Quelle: ClinicalTrials.gov


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