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

Study Overview
=================
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
-----------------
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. 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. 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.

Official Title
-----------------
Adjuvant Dendritic Cell Immunotherapy Complementing Conventional Therapy for Pediatric Patients With High-grade Glioma and Diffuse Intrinsic Pontine Glioma

Conditions
-----------------
High Grade Glioma, Diffuse Intrinsic Pontine Glioma

Intervention / Treatment
-----------------
* Biological: Dendritic cell vaccination +- conventional next-line treatment
* Biological: Dendritic cell vaccination + temozolomide-based chemoradiation


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 12 Months
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum A (newly diagnosed)<br>Dendritic cell vaccination plus temozolomide-based chemoradiotherapy | Biological: Dendritic cell vaccination + temozolomide-based chemoradiation<br>* Leukocyte apheresis (before chemoradiation): for dendritic cell (DC) vaccine production. 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. 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. 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.<br>|
| Experimental: Stratum B (prior treatment)<br>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<br>* 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. Induction immunotherapy: intradermal vaccination with autologous WT1 mRNA-loaded DCs weekly (-1 day, +2 days) for 3 weeks, starting ≥ 4 weeks after apheresis. Booster immunotherapy: 6 DC booster vaccinations administered at regular intervals (+- 4 weeks), starting ≥ 3 weeks after the last induction vaccine. (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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of leukapheresis in pediatric patients with HGG and DIPG | Proportion of patients in the intention-to-treat (ITT) population that had successful leukapheresis | Vaccine production and quality testing (i.e. from leukapheresis until 4 weeks after) | 
| Feasibility of WT1-targeted DC vaccine production | 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) | Vaccine production and quality testing (i.e. from leukapheresis until 4 weeks after) | 
| Feasibility of DC vaccine administration in pediatric patients with HGG and DIPG (administration of 1st vaccine) | Proportion of efficacy evaluable patients (i.e. having received at least 1 vaccine + no major protocol violation) in the intention-to-treat (ITT) population | At the administration of the 1st vaccine (i.e. +- 2 months after leukapheresis) | 
| Feasibility of DC vaccine administration in pediatric patients with HGG and DIPG according to the study treatment schedule | Proportion of patients in the ITT population who completed the study treatment (i.e. from leukapheresis until administration of the 9th vaccine) | Study treatment scheme (i.e. from leukapheresis to administration of the 9th vaccine, +- 34 weeks) | 
| Safety of DC vaccine administration in pediatric patients with HGG and DIPG: Related (Severe) Adverse Events ((S)AEs) | Proportion of patients of the safety population that experienced (S)AEs possibly, probably or definitely related to DC vaccination | 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) | 
| Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (number) | Number of (S)AEs in the safety population (i.e. having received at least 1 DC vaccine) | 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) | 
| Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (grade) | Grade of (S)AEs in the safety population | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Indicators of clinical efficacy: Best overall response (BOR) | 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). | 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). | 
| Indicators of clinical efficacy: Progression-free survival (PFS) | 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. | 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. | 
| Indicators of clinical efficacy: Overall survival (OS) | OS is defined as the time (in months) between diagnosis/study entry and death due to any cause. | 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. | 
| Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: occurrence of WT1-specfic CD8+ T cells | Occurrence of WT1-specific CD8+ T cells as assessed by tetramer staining (% positive cells) | 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) | 
| Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: occurrence of WT1-specfic CD8+ T cells | Occurrence of WT1-specific CD8+ T cells as assessed by TCR sequencing | 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) | 
| Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: Functional WT1-specific T cell responses | Functional WT1-specific T cell responses as assessed by multiparametric flow cytometry following antigen-specific stimulation (% positive cells) | 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) | 
| Evaluation of changes in quality of life: How patients experience different phases of the study treatment schedule | PedsQL Generic core scale and PedsQL Cancer Module. Higher scores indicate better health-related quality of life/lower problems. | 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) | 
| Evaluation of changes in quality of life: How patient- and proxy-reported disease-related symptoms evolve over time during the study | PedsQL Cancer Module. Higher scores indicate lower problems. | 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) | 
| Evaluation of changes in quality of life: How patient- and proxy-reported general quality of life evolves over time during the study | PedsQL Generic core scale. Higher scores indicate better health-related quality of life. | 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
childhood glioma, dendritic cells, adjuvant therapy, immunotherapy, Wilms' tumor protein 1