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Childhood GlioblastomaPhase 1/2NCT03879512

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

A Phase 1/2 study testing depletion of regulatory T cells, reoperation and cancer vaccine in people with Childhood Glioblastoma, run by Wuerzburg University Hospital at 1 site in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 3 to 21 years
Conditions the study is for
Childhood Glioblastoma
What is being tested?
depletion of regulatory T cells, reoperation and cancer vaccine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
24 participants
Where
1 siteGermany
Study dates
7 Feb 2018to 31 Jul 2024
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 3 to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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)

Who cannot join

  • 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)
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  • 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.

Trial locations and contacts

1 site in 1 country.

Germany1 site

  • University Children's Hospital

    Würzburg, Bavaria, D-97080

Other trials in Germany

About this study

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

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.

Read the 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.

Being tested
depletion of regulatory T cells, reoperation, cancer vaccine, checkpoint blockade
Keywords
cancer vaccine, high-grade glioma, immunomodulation, checkpoint blockade
Medical subject headings
Astrocytoma, Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • depletion of regulatory T cellsDrug

    oral metronomic cyclophosphamide

  • reoperationProcedure or surgery

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

  • cancer vaccineBiological

    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 blockadeBiological

    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.

Study groups in NCT03879512
Study groupRoleWhat they receive
Active vaccination armExperimentalAll patients receive depletion of regulatory T cells, reoperation, followed by a personalized cancer vaccine and double checkpoint blockade.
Receives: Drug: depletion of regulatory T cells; Procedure: reoperation; Biological: cancer vaccine; Biological: checkpoint blockade

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 6 month overall survival

    overall survival 6 months after diagnosis of relapse

    Measured: 6 months

Secondary outcomes (10)

  1. overall survival

    overall survival

    Measured: 12-24 months

  2. progression-free survival

    progression-free survival

    Measured: 12-24 months

  3. toxicity metronomic cyclophosphamide

    frequency of adverse events associated with metronomic cyclophosphamide

    Measured: 12-24 months

  4. toxicitiy vaccine

    frequency of adverse events associated with the vaccine

    Measured: 12-24 months

  5. toxicity checkpoint blockade

    frequency of AEs/SAEs associated with Nivolumab and/or Ipilimumab

    Measured: 12-24 months

  6. Treg frequency

    frequency of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide in % of CD3+

    Measured: 12-24 months

  7. Treg numbers

    absolute numbers of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide per µl blood

    Measured: 12-24 months

  8. T-cell response

    Interferon-gamma Cytotoxic T cell (CTL) assay

    Measured: 12-24 months

  9. serum cytokine levels

    Tru Culture cytokine array

    Measured: 12-24 months

  10. correlation with histopathological tumor characteristics

    correlation of outcome/immune response with histopathology etc.

    Measured: 12-24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Mar 2019
  2. Study start7 Feb 2018
  3. Primary completion31 Jul 2024
  4. Study completion31 Jul 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
24 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03879512
Sponsor's protocol ID
HIT-HGG Rez Immunovac
Status last verified
Dec 2023
First submitted
12 Mar 2019
Last updated
19 Sep 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Lohr M, Freitag B, Technau A, Krauss J, Monoranu CM, Rachor J, Lutz MB, Hagemann C, Kessler AF, Linsenmann T, Wolfl M, Ernestus RI, Engelhardt S, Gelbrich G, Schlegel PG, Eyrich M. High-grade glioma associated immunosuppression does not prevent immune responses induced by therapeutic vaccines in combination with Treg depletion. Cancer Immunol Immunother. 2018 Oct;67(10):1545-1558. doi: 10.1007/s00262-018-2214-0. Epub 2018 Jul 27.

    PubMed 30054667

  • Eyrich M, Schreiber SC, Rachor J, Krauss J, Pauwels F, Hain J, Wolfl M, Lutz MB, de Vleeschouwer S, Schlegel PG, Van Gool SW. Development and validation of a fully GMP-compliant production process of autologous, tumor-lysate-pulsed dendritic cells. Cytotherapy. 2014 Jul;16(7):946-64. doi: 10.1016/j.jcyt.2014.02.017. Epub 2014 May 13.

    PubMed 24831836

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing depletion of regulatory T cells, reoperation and cancer vaccine in people with Childhood Glioblastoma, run by Wuerzburg University Hospital at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

6 month overall survival (time frame: 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03879512, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2024.

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