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Adjuvant Dendritic Cell Immunotherapy for Pediatric Patients With High-grade Glioma or Diffuse Intrinsic Pontine Glioma (ADDICT-pedGLIO)

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ClinicalTrials.gov Identifier: NCT04911621
Recruitment Status : Recruiting
First Posted : June 3, 2021
Last Update Posted : September 20, 2021
Sponsor:
Collaborators:
Kom Op Tegen Kanker
Stichting Semmy
Olivia Hendrickx research Fund vzw
Information provided by (Responsible Party):
University Hospital, Antwerp

Brief Summary:

Childhood aggressive gliomas are rare brain tumors with very poor prognosis. Due to the tumor's location and infiltrative nature, surgical removal is not always possible, and even when resection is performed and combined with chemo- and/or radiotherapy, tumor cells frequently persist, eventually giving rise to tumor recurrence. A promising strategy to eradicate persisting tumor cells is vaccination with dendritic cells (DC). DC are immune cells that play an important role in organizing the body's defense against cancer. The goal of DC vaccination is to activate these natural anti-tumor defense mechanisms to delay or prevent tumor progression or recurrence. Previous clinical studies have demonstrated that DC vaccination is well-tolerated, safe and capable of eliciting tumorspecific immunity.

A clinical study including 10 pediatric patients (aged ≥ 12 months and < 18 years at the time of signing the informed consent) with brain (stem) tumors is initiated at the Antwerp University Hospital to investigate intradermal vaccination with WT1 mRNA-loaded autologous monocyte-derived DCs, either combined with first-line chemoradiation treatment or administered as adjuvant therapy following previous therapies. The general objective of this phase I/II clinical study is (1) to demonstrate that WT1-targeted DC vaccine production and administration in pediatric patients with HGG and DIPG, either combined with first-line chemoradiation treatment or administered as adjuvant therapy following previous therapies, is feasible and safe, (2) to study vaccine-induced immune responses, (3) to document patients' quality of life and clinical outcome for comparison with current patients' outcome allowing indication of the added value.


Condition or disease Intervention/treatment Phase
High Grade Glioma Diffuse Intrinsic Pontine Glioma Biological: Dendritic cell vaccination + temozolomide-based chemoradiation Biological: Dendritic cell vaccination +- conventional next-line treatment Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Both newly diagnosed patients and patients who previously underwent anti-glioma treatment are eligible for the study, provided they comply with all in- and exclusion criteria. The study hence consists of two strata, newly diagnosed patients are included in stratum A, while pre-treated patients are included in stratum B.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Adjuvant Dendritic Cell Immunotherapy Complementing Conventional Therapy for Pediatric Patients With High-grade Glioma and Diffuse Intrinsic Pontine Glioma
Estimated Study Start Date : September 10, 2021
Estimated Primary Completion Date : June 1, 2027
Estimated Study Completion Date : June 1, 2027


Arm Intervention/treatment
Experimental: Stratum A (newly diagnosed)
Dendritic cell vaccination plus temozolomide-based chemoradiotherapy
Biological: Dendritic cell vaccination + temozolomide-based chemoradiation
  1. Leukocyte apheresis (before chemoradiation): for dendritic cell (DC) vaccine production.
  2. Chemoradiation (1st part standard treatment, initiated as soon as the patient's hematological blood values are adequate after apheresis, but no later than 6 weeks after surgery or confirmed diagnosis): 1.8 Gy once daily 5 days/week for 6 weeks with 90 mg/m² temozolomide daily from the first until the last day of radiotherapy.
  3. Induction immunotherapy: intradermal vaccination with autologous Wilms' tumor-1 (WT1) mRNA-loaded DCs weekly (-1 day, +2 days) for 3 weeks, starting ≥ 1 week after radiotherapy.
  4. Chemo-immunotherapy: 150-200 mg/m²/d temozolomide days 1-5 every 28 days +/- 3 days (max. 6 months, 2nd part standart treatment) starting ≥3 days after the third vaccine of the induction immunotherapy + DC vaccination on day 21±3 days of every 28-day cycle.

Experimental: Stratum B (prior treatment)
Dendritic cell vaccination plus optional conventional anti-glioma treatment (in line with standard-of-care practice, at the investigator's discretion)
Biological: Dendritic cell vaccination +- conventional next-line treatment
  1. Leukocyte apheresis (upon recovery of hematological blood values following previous anti-glioma treatments and ≥ 4 weeks after the last dose of any investigational agent): for DC vaccine production.
  2. Induction immunotherapy: intradermal vaccination with autologous WT1 mRNA-loaded DCs weekly (-1 day, +2 days) for 3 weeks, starting ≥ 4 weeks after apheresis.
  3. Booster immunotherapy: 6 DC booster vaccinations administered at regular intervals (+- 4 weeks), starting ≥ 3 weeks after the last induction vaccine.
  4. (Optional) Concomitant conventional anti-glioma treatment: The decision to continue or re-initiate conventional anti-glioma treatment, and, if applicable, its dose and scheme, are at the Investigator's discretion and will depend on the patient's previous treatment scheme and condition.




Primary Outcome Measures :
  1. Feasibility of leukapheresis in pediatric patients with HGG and DIPG [ Time Frame: Vaccine production and quality testing (i.e. from leukapheresis until 4 weeks after) ]
    Proportion of patients in the intention-to-treat (ITT) population that had successful leukapheresis

  2. Feasibility of WT1-targeted DC vaccine production [ Time Frame: Vaccine production and quality testing (i.e. from leukapheresis until 4 weeks after) ]
    Proportion of patients in the ITT population that had successful vaccine production (i.e. production of 9 or more vaccine doses meeting quality control requirements)

  3. Feasibility of DC vaccine administration in pediatric patients with HGG and DIPG (administration of 1st vaccine) [ Time Frame: At the administration of the 1st vaccine (i.e. +- 2 months after leukapheresis) ]
    Proportion of efficacy evaluable patients (i.e. having received at least 1 vaccine + no major protocol violation) in the intention-to-treat (ITT) population

  4. Feasibility of DC vaccine administration in pediatric patients with HGG and DIPG according to the study treatment schedule [ Time Frame: Study treatment scheme (i.e. from leukapheresis to administration of the 9th vaccine, +- 34 weeks) ]
    Proportion of patients in the ITT population who completed the study treatment (i.e. from leukapheresis until administration of the 9th vaccine)

  5. Safety of DC vaccine administration in pediatric patients with HGG and DIPG: Related (Severe) Adverse Events ((S)AEs) [ Time Frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later) ]
    Proportion of patients of the safety population that experienced (S)AEs possibly, probably or definitely related to DC vaccination

  6. Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (number) [ Time Frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later) ]
    Number of (S)AEs in the safety population (i.e. having received at least 1 DC vaccine)

  7. Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (grade) [ Time Frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later) ]
    Grade of (S)AEs in the safety population


Secondary Outcome Measures :
  1. Indicators of clinical efficacy: Best overall response (BOR) [ Time Frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later). ]
    BOR will be determined per patient as the best response designation over the study, based on radiologic RANO criteria. The response categories are: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD).

  2. Indicators of clinical efficacy: Progression-free survival (PFS) [ Time Frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later). PFS may be updated after study completion. ]
    PFS is defined as the time (in months) between diagnosis/study entry and the date of progression (recurrence in the case of total resection) or death due to any cause, whichever occurs first.

  3. Indicators of clinical efficacy: Overall survival (OS) [ Time Frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later). OS may be updated after study completion. ]
    OS is defined as the time (in months) between diagnosis/study entry and death due to any cause.

  4. Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: occurrence of WT1-specfic CD8+ T cells [ Time Frame: On the day of the 1st (about 2 months after leukapheresis), 4th (about 3 months after leukapheresis) and 7th DC vaccine (about 6 months after leukapheresis) ]
    Occurrence of WT1-specific CD8+ T cells as assessed by tetramer staining (% positive cells)

  5. Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: occurrence of WT1-specfic CD8+ T cells [ Time Frame: On the day of the 1st (about 2 months after leukapheresis), 4th (about 3 months after leukapheresis) and 7th DC vaccine (about 6 months after leukapheresis) ]
    Occurrence of WT1-specific CD8+ T cells as assessed by TCR sequencing

  6. Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: Functional WT1-specific T cell responses [ Time Frame: On the day of the 1st (about 2 months after leukapheresis), 4th (about 3 months after leukapheresis) and 7th DC vaccine (about 6 months after leukapheresis) ]
    Functional WT1-specific T cell responses as assessed by multiparametric flow cytometry following antigen-specific stimulation (% positive cells)

  7. Evaluation of changes in quality of life: How patients experience different phases of the study treatment schedule [ Time Frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later) ]
    PedsQL Generic core scale and PedsQL Cancer Module. Higher scores indicate better health-related quality of life/lower problems.

  8. Evaluation of changes in quality of life: How patient- and proxy-reported disease-related symptoms evolve over time during the study [ Time Frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later) ]
    PedsQL Cancer Module. Higher scores indicate lower problems.

  9. Evaluation of changes in quality of life: How patient- and proxy-reported general quality of life evolves over time during the study [ Time Frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later) ]
    PedsQL Generic core scale. Higher scores indicate better health-related quality of life.


Other Outcome Measures:
  1. Biomarker identification [ Time Frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later) ]
    By means of associative analyses with clinical response and outcome, biomarkers will be identified among immunological parameters and tumor characteristics (if homogeneity of population allows).

  2. Evaluation of changes in executive function [ Time Frame: at baseline, upon completion of the study treatment scheme (i.e. after the 9th DC vaccine), at progression (if applicable) and 90 days after the final DC vaccine ]
    By means of BRIEF (Behavior Rating Inventory of Executive Function) questionnaires, completed before and after the study treatment scheme, it will be assessed how the patient's executive function changes from baseline. Higher T scores mean worse outcome.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Months to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of

    • High grade glioma (WHO grade III or IV), histologically verified
    • Diffuse Intrinsic Pontine Glioma, verified by radiologic criteria (magnetic resonance imaging (MRI)) or by histology. A biopsy is not required but recommended.
  • Aged ≥ 12 months and < 18 years at the time of signing the informed consent
  • Body weight ≥ 10 kg
  • Lansky score (for patients < 16 years) or Karnofsky score (for patients ≥ 16 years) of ≥ 50
  • Reasonable life expectancy ≥ 8 weeks, as estimated by the treating physician
  • Adequate hematological blood values and sufficient recovery from treatment-related toxicities (> grade 1) following previous anti-glioma treatments, as judged by the treating physician
  • Written informed consent of parents or legal guardian. Written informed consent of patients aged 12 years or older (written informed consent of patients younger than 12 years is optional).
  • Willing and able to comply with the protocol, as judged by the treating physician
  • Female patients of child bearing potential must have a negative serum or urine pregnancy test at the time of screening. Female patients of child bearing potential and male patients must agree to use effective contraception before, during and for at least hundred days after the last study treatment administration. Female subjects who are breastfeeding should discontinue nursing prior to the first dose of study treatment and until at least hundred days after the last study treatment administration.

Exclusion Criteria:

  • Use of any investigational agents ≤ 4 weeks before the planned day of leukapheresis.
  • Concomitant malignancy or history of another malignancy (unless the Investigator rationalizes otherwise)
  • Known concomitant presence of any active immunosuppressive disease (e.g. HIV) or any active autoimmune condition, except for vitiligo
  • Any pre-existing contra-indication for contrast-enhanced MRI
  • Pregnant or breastfeeding
  • Any other condition, either physical or psychological, or reasonable suspicion thereof on clinical or special investigation, which contraindicates the use of the vaccine, or may negatively affect patient compliance, or may place the patient at higher risk of potential treatment complications

Information from the National Library of Medicine

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): NCT04911621


Contacts
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Contact: Zwi N Berneman, MD, PhD 0032 3 821 39 15 zwi.berneman@uza.be
Contact: CCRG 0032 3 821 39 28 ccrg@uza.be

Locations
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Belgium
Unitversity Hospital Antwerp Recruiting
Edegem, Belgium
Contact: Zwi Berneman       zwi.berneman@uza.be   
Contact: CCRG       CCRG@uza.be   
Sponsors and Collaborators
University Hospital, Antwerp
Kom Op Tegen Kanker
Stichting Semmy
Olivia Hendrickx research Fund vzw
Investigators
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Principal Investigator: Zwi N Berneman, MD, PhD Antwerp University Hospital, Division of Hematology and Center for Cell Therapy and Regenerative Medicine
Additional Information:
Publications:
Z. Berneman, A. Van de Velde, S. Anguille, Y. Willemen, M. Huizing, P. Germonpré, K. Saevels, G. Nijs, N. Cools, A. Van Driessche, B. Stein, H. De Reu, W. Schroyens, A. Gadisseur, A. Verlinden, K. Vermeulen, M. Maes, M. Lammens, H. Goossens, M. Peeters, V. Van Tendeloo, E. Smits. Vaccination with Wilms' Tumor Antigen (WT1) mRNA-Electroporated Dendritic Cells as an Adjuvant Treatment in 60 Cancer Patients: Report of Clinical Effects and Increased Survival in Acute Myeloid Leukemia, Metastatic Breast Cancer, Glioblastoma and Mesothelioma. Cytotherapy 2016, 18(6), p. S13-14
Z. Berneman, S. Anguille, Y. Willemen, A. Van de Velde, P. Germonpré, M. Huizing, V. Van Tendeloo, K. Saevels, L. Rutsaert, K. Vermeulen, A. Snoeckx, B. Op de Beeck, N. Cools, G. Nijs, B. Stein, E. Lion, A. van Driessche, M. Peeters, E. Smits. Vaccination of cancer patients with dendritic cells electroporated with mRNA encoding the Wilms' Tumor protein (WT1): correlation of clinical effect and overall survival with T-cell response. Cytotherapy 2019, 21(5), p. S10.

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Responsible Party: University Hospital, Antwerp
ClinicalTrials.gov Identifier: NCT04911621    
Other Study ID Numbers: CCRG19-002
First Posted: June 3, 2021    Key Record Dates
Last Update Posted: September 20, 2021
Last Verified: May 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital, Antwerp:
childhood glioma
dendritic cells
adjuvant therapy
immunotherapy
Wilms' tumor protein 1
Additional relevant MeSH terms:
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Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Brain Stem Neoplasms
Infratentorial Neoplasms
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Glioma
Diffuse Intrinsic Pontine Glioma
Central Nervous System Diseases
Nervous System Diseases
Temozolomide
Vaccines
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs