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Trial record 87 of 2040 for:    cancer vaccine

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

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ClinicalTrials.gov Identifier: NCT03879512
Recruitment Status : Recruiting
First Posted : March 18, 2019
Last Update Posted : September 17, 2020
Sponsor:
Information provided by (Responsible Party):
Wuerzburg University Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Childhood Glioblastoma Drug: depletion of regulatory T cells Procedure: reoperation Biological: cancer vaccine Biological: checkpoint blockade Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Autologous Dendritic Cells and Metronomic Cyclophosphamide in Combination With Checkpoint Blockade for Relapsed High-Grade Gliomas in Children and Adolescents
Actual Study Start Date : February 7, 2018
Estimated Primary Completion Date : April 30, 2024
Estimated Study Completion Date : April 30, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Active vaccination arm
All patients receive depletion of regulatory T cells, reoperation, followed by a personalized cancer vaccine and double checkpoint blockade.
Drug: depletion of regulatory T cells
oral metronomic cyclophosphamide

Procedure: reoperation
resection of relapsed tumor in order to improve clinical condition of the patient and to acquire tumor tissue for vaccine generation

Biological: 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

Biological: 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.




Primary Outcome Measures :
  1. 6 month overall survival [ Time Frame: 6 months ]
    overall survival 6 months after diagnosis of relapse


Secondary Outcome Measures :
  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.



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Ages Eligible for Study:   3 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03879512


Contacts
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Contact: Matthias Eyrich, MD +49-931-201 ext 27728 eyrich_m@ukw.de
Contact: Paul G Schlegel, MD +49-931-201 ext 27915 schlegel_p@ukw.de

Locations
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Germany
University Children's Hospital Recruiting
Würzburg, Bavaria, Germany, D-97080
Contact: Matthias Eyrich, MD    +49-931-201-27728    eyrich_m@ukw.de   
Contact: Paul G Schlegel, MD    +49-931-201-27915    schlegel_p@ukw.de   
Sponsors and Collaborators
Wuerzburg University Hospital
Investigators
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Study Chair: Kramm Christof, MD Children's Hospital, University Medical Center Göttingen
Additional Information:
Publications of Results:
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Responsible Party: Wuerzburg University Hospital
ClinicalTrials.gov Identifier: NCT03879512    
Other Study ID Numbers: HIT-HGG Rez Immunovac
First Posted: March 18, 2019    Key Record Dates
Last Update Posted: September 17, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Wuerzburg University Hospital:
cancer vaccine
high-grade glioma
immunomodulation
checkpoint blockade
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue