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

NCT03879512 | Completed Phase 1 DMC

• 1 other identifier: HIT-HGG Rez Immunovac
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Childhood Glioblastoma

Keywords

cancer vaccine; high-grade glioma; immunomodulation; checkpoint blockade

Outcome Measures

Primary Outcomes (1)

• 6 month overall survival

  overall survival 6 months after diagnosis of relapse

  6 months

Secondary Outcomes (10)

• overall survival

  12-24 months

• progression-free survival

  12-24 months

• toxicity metronomic cyclophosphamide

  12-24 months

• toxicitiy vaccine

  12-24 months

• toxicity checkpoint blockade

  12-24 months

Study Arms (1)

Active vaccination arm

EXPERIMENTAL

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; Procedure: reoperation; Biological: cancer vaccine; Biological: checkpoint blockade

Interventions

depletion of regulatory T cells DRUG

oral metronomic cyclophosphamide

Active vaccination arm

reoperation PROCEDURE

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

Active vaccination arm

cancer vaccine BIOLOGICAL

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

Active vaccination arm

checkpoint blockade BIOLOGICAL

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.

Active vaccination arm

Eligibility Criteria

• Age: 3 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Wuerzburg University Hospital: lead

Study Sites (1)

University Children's Hospital

Würzburg, Bavaria, D-97080, Germany

Location

Related Publications (2)

• 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.

  PMID: 30054667 RESULT

• 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.

  PMID: 24831836 RESULT

Related Links

• homepage for patient and families

MeSH Terms

Conditions

Astrocytoma; Glioma

Interventions

Reoperation; Cancer Vaccines; Immune Checkpoint Inhibitors

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Surgical Procedures, Operative; Vaccines; Biological Products; Complex Mixtures; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents, Immunological; Antineoplastic Agents; Therapeutic Uses

Study Officials

• Kramm Christof, MD

  Children's Hospital, University Medical Center Göttingen

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 12, 2019
• First Posted: March 18, 2019
• Study Start: February 7, 2018
• Primary Completion: July 31, 2024
• Study Completion: July 31, 2024
• Last Updated: September 19, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)