Adjuvant Dendritic Cell Immunotherapy Complementing Conventional Therapy for Pediatric Patients With High-grade Glioma and Diffuse Intrinsic Pontine Glioma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (number)
研究概览
简要总结
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.
详细描述
- 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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Months 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
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)
干预措施: Dendritic cell vaccination +- conventional next-line treatment (Biological)
Stratum A (newly diagnosed)
Dendritic cell vaccination plus temozolomide-based chemoradiotherapy
干预措施: Dendritic cell vaccination + temozolomide-based chemoradiation (Biological)
结局指标
主要结局
Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (number)
时间窗: 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)
Feasibility of WT1-targeted DC vaccine production
时间窗: 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)
Safety of DC vaccine administration in pediatric patients with HGG and DIPG: Related (Severe) Adverse Events ((S)AEs)
时间窗: 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
Feasibility of leukapheresis in pediatric patients with HGG and DIPG
时间窗: 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
Feasibility of DC vaccine administration in pediatric patients with HGG and DIPG (administration of 1st vaccine)
时间窗: 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
Feasibility of DC vaccine administration in pediatric patients with HGG and DIPG according to the study treatment schedule
时间窗: 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)
Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (grade)
时间窗: 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
次要结局
- Evaluation of changes in quality of life: How patients experience different phases of the study treatment schedule(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: Best overall response (BOR)(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)(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)(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.)
- Evaluation of changes in quality of life: How patient- and proxy-reported disease-related symptoms evolve over time during the study(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(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))
- Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: Functional WT1-specific T cell responses(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(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))