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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Autologous Dendritic Cells and Metronomic Cyclophosphamide in Combination With Checkpoint Blockade for Relapsed High-Grade Gliomas in Children and Adolescents

Conditions
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Childhood Glioblastoma

Intervention / Treatment
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* Drug: depletion of regulatory T cells
* Procedure: reoperation
* Biological: cancer vaccine
* Biological: checkpoint blockade


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Patients aged 3 years and older but under 21 years at time of relapse diagnosis Written informed consent of the patient (mandatory from 14 years of age) or the parents (mandatory till 18 years of age). Prospect of resection of relapse tumour by neurosurgery (total, subtotal or partial) Exclusion Criteria: Known hypersensitivity or contraindication to cyclophosphamide Known hypersensitivity or contraindications to Nivolumab or Ipilimumab. Other malignancies, either simultaneous or within the last 2 years 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. Pregnancy and / or lactation 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) Current or recent (within 4 weeks prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial Severe concomitant diseases (e.g. immune deficiency syndrome) Severe psychological disease or neurological damage without possibility to communicate Clinical signs of intracranial pressure Intracerebral hemorrhage, gliomatosis No severe blood count abnormalities: leukocytes < 2.000/µl, Hb <10 g/dl, thrombocytes < 100.000/µl No severe liver enzyme elevation (> 2-3x fold of normal) Ongoing reirradiation or chemotherapy (within the last 4 weeks) (irradiation of formerly non-involved fields is allowed, but not part of this study) Estimated life expectancy of less than 2 months Preexisting severe cardiac disease Presence of unresectable spinal metastases Karnofsky index < 50% Active infection within the last 2 weeks Previous infection with Human Immunodeficiency, Hepatitis C, Human T-Lymphocyte 1/2, Hepatitis B Virus, Lues, protozoan parasites, or other chronic bacterial infections. With regard to prevention of variant Creutzfeldt-Jakob disease the following patients have to be excluded. Patients receiving systemic immunosuppressive or immunoactivating substances.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active vaccination arm<br>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<br>* oral metronomic cyclophosphamide<br>Procedure: reoperation<br>* resection of relapsed tumor in order to improve clinical condition of the patient and to acquire tumor tissue for vaccine generation<br>Biological: cancer vaccine<br>* 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<br>Biological: checkpoint blockade<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 month overall survival | overall survival 6 months after diagnosis of relapse | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival | overall survival | 12-24 months | 
| progression-free survival | progression-free survival | 12-24 months | 
| toxicity metronomic cyclophosphamide | frequency of adverse events associated with metronomic cyclophosphamide | 12-24 months | 
| toxicitiy vaccine | frequency of adverse events associated with the vaccine | 12-24 months | 
| toxicity checkpoint blockade | frequency of AEs/SAEs associated with Nivolumab and/or Ipilimumab | 12-24 months | 
| Treg frequency | frequency of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide in % of CD3+ | 12-24 months | 
| Treg numbers | absolute numbers of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide per µl blood | 12-24 months | 
| T-cell response | Interferon-gamma Cytotoxic T cell (CTL) assay | 12-24 months | 
| serum cytokine levels | Tru Culture cytokine array | 12-24 months | 
| correlation with histopathological tumor characteristics | correlation of outcome/immune response with histopathology etc. | 12-24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer vaccine, high-grade glioma, immunomodulation, checkpoint blockade