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

Phase 1

Recruiting

• Conditions: Childhood Glioblastoma
• Interventions: Drug: depletion of regulatory T cells; Procedure: reoperation; Biological: cancer vaccine; Biological: checkpoint blockade

• Registration Number: NCT03879512
• Lead Sponsor: 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.

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.

Study Timeline

• Study Start: 2018-02-07
• Study First Submitted: 2019-03-12
• Study First Submitted QC: 2019-03-14
• Study First Posted: 2019-03-18
• Status Verified: 2023-12
• Last Update Submitted: 2023-12-11
• Last Update Posted: 2023-12-12
• Primary Completion: 2025-01-31
• Study Completion: 2025-01-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 25

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Active vaccination arm	depletion of regulatory T cells	All patients receive depletion of regulatory T cells, reoperation, followed by a personalized cancer vaccine and double checkpoint blockade.
Active vaccination arm	reoperation	All patients receive depletion of regulatory T cells, reoperation, followed by a personalized cancer vaccine and double checkpoint blockade.
Active vaccination arm	cancer vaccine	All patients receive depletion of regulatory T cells, reoperation, followed by a personalized cancer vaccine and double checkpoint blockade.
Active vaccination arm	checkpoint blockade	All patients receive depletion of regulatory T cells, reoperation, followed by a personalized cancer vaccine and double checkpoint blockade.

Primary Outcome Measures

Name	Time	Method
6 month overall survival	6 months	overall survival 6 months after diagnosis of relapse

Secondary Outcome Measures

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

Trial Locations

Locations (1)

University Children's Hospital; 🇩🇪 Würzburg, Bavaria, Germany