Autologous Dendritic Cells, Metronomic Cyclophosphamide and Checkpoint Blockade in Children With Relapsed HGG
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03879512|
Recruitment Status : Recruiting
First Posted : March 18, 2019
Last Update Posted : September 17, 2020
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|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||25 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
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
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.
- 6 month overall survival [ Time Frame: 6 months ]overall survival 6 months after diagnosis of relapse
- overall survival [ Time Frame: 12-24 months ]overall survival
- progression-free survival [ Time Frame: 12-24 months ]progression-free survival
- toxicity metronomic cyclophosphamide [ Time Frame: 12-24 months ]frequency of adverse events associated with metronomic cyclophosphamide
- toxicitiy vaccine [ Time Frame: 12-24 months ]frequency of adverse events associated with the vaccine
- toxicity checkpoint blockade [ Time Frame: 12-24 months ]frequency of AEs/SAEs associated with Nivolumab and/or Ipilimumab
- Treg frequency [ Time Frame: 12-24 months ]frequency of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide in % of CD3+
- Treg numbers [ Time Frame: 12-24 months ]absolute numbers of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide per µl blood
- T-cell response [ Time Frame: 12-24 months ]Interferon-gamma Cytotoxic T cell (CTL) assay
- serum cytokine levels [ Time Frame: 12-24 months ]Tru Culture cytokine array
- correlation with histopathological tumor characteristics [ Time Frame: 12-24 months ]correlation of outcome/immune response with histopathology etc.
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
|Contact: Matthias Eyrich, MD||+49-931-201 ext firstname.lastname@example.org|
|Contact: Paul G Schlegel, MD||+49-931-201 ext email@example.com|
|Study Chair:||Kramm Christof, MD||Children's Hospital, University Medical Center Göttingen|