Clinical trial NCT04911621: Adjuvant Dendritic Cell Immunotherapy for Pediatric Patients With High-grade Glioma or Diffuse Intrinsic Pontine Glioma
Official title: Adjuvant Dendritic Cell Immunotherapy Complementing Conventional Therapy for Pediatric Patients With High-grade Glioma and Diffuse Intrinsic Pontine Glioma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: High Grade Glioma
Diffuse Intrinsic Pontine Glioma
Keywords: childhood glioma
dendritic cells
adjuvant therapy
immunotherapy
Wilms' tumor protein 1
Lead sponsor: University Hospital, Antwerp
Sponsor class: OTHER
Collaborators: name: Kom Op Tegen Kanker
name: Stichting Semmy
name: Olivia Hendrickx research Fund vzw
First posted: 2021-06-03
Enrollment: 10
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Detailed description: 1. Overview of the study treatment scheme

   1.1 Newly diagnosed HGG and DIPG patients (stratum A)

   Patients will be screened and registered in the study following diagnosis, which is based on either histological confirmation or radiographic criteria. Maximal safe resection prior to study entry is strongly recommended, but not required.

   Eligible patients will undergo leukapheresis prior to temozolomide-based chemoradiation and subsequent chemo-immunotherapy with maintenance temozolomide and autologous WT1 mRNA-loaded DC vaccination. Chemoradiation with subsequent maintenance temozolomide is considered best available treatment and therefore not considered investigational. The investigational treatment, i.e. adjuvant DC vaccination, is administered in 2 phases:
   * an induction phase, consisting of 3 weekly (-1 day, +2 days) DC vaccines, which is initiated after chemoradiation, but before maintenance temozolomide therapy, and
   * a booster phase, consisting of 6 4-weekly (±3 days) DC vaccines, which are administered during temozolomide maintenance cycles.

   1.2 Non-treatment naïve HGG and DIPG patients (stratum B)

   Patients who have undergone previous anti-glioma treatments can be included in the study, provided they are eligible according to the in- and exclusion criteria.

   The decision to start, continue or re-initiate conventional anti-glioma treatment, including radio- and/or chemotherapy, and, if applicable, the treatment dose and scheme, are at the Investigator's discretion. The backbone DC immunotherapy scheme for the induction and booster phase will be maintained with minor modifications:
   * during the induction phase, 3 DC vaccines will be administered on a weekly (-1 day, +2 days) basis
   * during the booster phase, 6 DC vaccines will be administered at regular intervals. It is recommended that the time between subsequent vaccinations is no longer than 4 weeks

   1.3 Continuation of DC vaccination

   While the study treatment schedule consists of 9 DC vaccinations (i.e. 3 induction and 6 booster vaccines), continuation of DC vaccination after the booster phase is allowed, on the conditions that (1) the Investigator judges that the participant's clinical situation justifies additional vaccinations, (2) consent for continuation of DC vaccination of the parents/guardian and the participant (if aged 12 years or older) has been obtained, and (3) residual vaccine aliquots are available.
2. Response assessment

   Disease evolution will be assessed radiologically according to the Response Assessment in Neuro-Oncology (RANO) criteria. In addition, blood samples will be collected for immunomonitoring purposes on the day of the first, fourth and seventh DC vaccine. Tumor resection or biopsy specimens, if available, will be used for local immunological and biomarker analysis. At regular time points throughout the study scheme, parents and participants will be asked to fill out questionnaires on general and disease-specific quality-of-life, as well as on executive function.
3. Follow-up

Patients will be followed-up until 90 days after administration of the final DC vaccine or 24 months after study entry, whichever occurs later.

Eligibility 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

Primary outcomes:
measure: Feasibility of leukapheresis in pediatric patients with HGG and DIPG
timeFrame: Vaccine production and quality testing (i.e. from leukapheresis until 4 weeks after)
measure: Feasibility of WT1-targeted DC vaccine production
timeFrame: Vaccine production and quality testing (i.e. from leukapheresis until 4 weeks after)
measure: Feasibility of DC vaccine administration in pediatric patients with HGG and DIPG (administration of 1st vaccine)
timeFrame: At the administration of the 1st vaccine (i.e. +- 2 months after leukapheresis)
measure: Feasibility of DC vaccine administration in pediatric patients with HGG and DIPG according to the study treatment schedule
timeFrame: Study treatment scheme (i.e. from leukapheresis to administration of the 9th vaccine, +- 34 weeks)
measure: Safety of DC vaccine administration in pediatric patients with HGG and DIPG: Related (Severe) Adverse Events ((S)AEs)
timeFrame: 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)
measure: Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (number)
timeFrame: 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)
measure: Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (grade)
timeFrame: 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)
Secondary outcomes:
measure: Indicators of clinical efficacy: Best overall response (BOR)
timeFrame: 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).
measure: Indicators of clinical efficacy: Progression-free survival (PFS)
timeFrame: 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.
measure: Indicators of clinical efficacy: Overall survival (OS)
timeFrame: 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.
measure: Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: occurrence of WT1-specfic CD8+ T cells
timeFrame: 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)
measure: Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: occurrence of WT1-specfic CD8+ T cells
timeFrame: 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)
measure: Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: Functional WT1-specific T cell responses
timeFrame: 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)
measure: Evaluation of changes in quality of life: How patients experience different phases of the study treatment schedule
timeFrame: 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)
measure: Evaluation of changes in quality of life: How patient- and proxy-reported disease-related symptoms evolve over time during the study
timeFrame: 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)
measure: Evaluation of changes in quality of life: How patient- and proxy-reported general quality of life evolves over time during the study
timeFrame: 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)
Other outcomes:
measure: Biomarker identification
timeFrame: 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)
measure: Evaluation of changes in executive function
timeFrame: 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
Locations:
city: Edegem
country: Belgium
facility: Unitversity Hospital Antwerp
Study officials:
affiliation: Antwerp University Hospital, Division of Hematology and Center for Cell Therapy and Regenerative Medicine
name: Zwi N Berneman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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