Adjuvant Dendritic Cell-immunotherapy Plus Temozolomide in Glioblastoma Patients

Study Overview
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Brief Summary
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In this phase I/II trial, the primary objective is to determine overall and progression-free survival of patients with newly diagnosed glioblastoma when autologous Wilms' tumor 1 (WT1) messenger (m)RNA-loaded dendritic cell (DC) vaccination is added to adjuvant temozolomide maintenance treatment following (sub)total resection and temozolomide-based chemoradiation.

Detailed Description
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Glioblastoma multiforme (GBM), a microscopically infiltrative disease, is the most common malignant brain tumor worldwide. Despite optimized standard of care treatment median survival and prognosis remain poor with a median survival of only 15% and five year survival after diagnosis of 5%. In this single arm single centre phase I/II trial the investigators will determine the overall and progression free survival of patients with newly diagnosed GBM when autologous WT1 mRNA loaded dendritic cell vaccination is added to standard of care treatment. During recruitment, the investigators will include 20 patients with newly diagnosed, histologically verified glioblastoma (WHO grade IV) who have received a total or subtotal resection of the tumor. Patients who underwent prior radiation or chemotherapy or with a history of other malignancy will be excluded. In addition to standard of care consisting of adjuvant chemoradiation with temozolomide and temozolomide maintenance patients will receive an intradermal vaccination with autologous WT1 mRNA-loaded dendritic cells commencing 1 week after radiotherapy. The dendritic cell therapy product will be generated and administered in the Antwerp University Hospital, more specifically the Center for Cell Therapy and Regenerative Medicine (CCRG) and the Division of Hematology, both headed by Prof. Zwi Berneman. Recruitment began in December 2015 and is intended to continue until the end of 2020 or when 20 patients are enrolled. After a follow-up period (until 90 days after final DC vaccine administration or 24 months after apheresis , whichever occurs later), overall and progression free survival analysis will be performed and this will be compared with the published data of standard of care treatment without vaccination. In addition the investigators will look for feasibility, incidence of adverse events and immunogenicity.

Official Title
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Adjuvant Dendritic-Cell Immunotherapy Plus Temozolomide Following Surgery and Chemoradiation in Patients With Newly Diagnosed Glioblastoma

Conditions
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Glioblastoma Multiforme of Brain

Intervention / Treatment
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* Biological: Dendritic cell vaccine plus temozolomide chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed, histologically verified glioblastoma (WHO grade IV) Aged ≥ 18 years Total or subtotal resection: Total resection: macroscopic complete resection as assessed by the neurosurgeon and absence of any residual contrast-enhancing mass on post-operative (≤ 72h) brain MRI Subtotal resection: macroscopic complete resection as assessed by the neurosurgeon, but with residual contrast-enhancement ≤ 2 cm³ on post-operative (≤ 72h) brain MRI Signed informed consent Willing and able to comply with the protocol as judged by the Investigator Estimated to start with chemoradiation ≥ 28 days and ≤ 49 days following surgical resection Fit to undergo: leukapheresis, chemoradiation, chemotherapy and immunotherapy No corticosteroid treatment ≤ 1 week before apheresis WHO performance status ≤ 2 Life expectancy ≥ 3 months as estimated by the Investigator Exclusion Criteria: History of another malignancy, except for adequately controlled basal cell skin carcinoma, squamous skin carcinoma, or carcinoma in situ of the uterine cervix or unless the investigator rationalizes otherwise Prior radiation or chemotherapy Any pre-existing contraindication for temozolomide treatment Any pre-existing contraindication for contrast-enhanced brain MRI Pregnant or breast-feeding Documented immune deficiency or systemic immune-suppressive treatment Known positive viral serology for HIV, HBV, HCV, or syphilis 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
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Dendritic cell vaccine plus temozolomide chemotherapy | Biological: Dendritic cell vaccine plus temozolomide chemotherapy<br>* When eligible after total or subtotal resection (as assessed by neurosurgeon and post-operative brain MRI): Leukocyte apheresis (before chemoradiation): for DC vaccine production Chemoradiation (standard treatment: initiated as soon as the patient's hematological blood values are adequate after apheresis): 2 Gy once daily 5 days/week for 6 weeks with 75 mg/m² temozolomide daily from the first until the last day of radiotherapy (no longer than 49 days in total) Induction immunotherapy: intradermal vaccination with autologous WT1 mRNA-loaded DCs weekly (+/-1 day) for 3 weeks, starting ≥ 1 week after radiotherapy Chemo-immunotherapy: 150-200 mg/m²/d temozolomide days 1-5 every 28 days +/- 2 days (max. 12 months) starting ≥3 days after the third vaccine of the induction immunotherapy + DC vaccination on day 21±3 days of every 28-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Patients will be followed for survival, from apheresis (  diagnosis), for which the accurate date and reason of death (cancer-related or non-related) will be recorded for every patient. | Through study completion with follow-up until 90 days after final DC vaccine administration or 24 months after apheresis, whichever occurs later | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of glioblastoma patients post surgical resection with feasible and safe DC vaccine production | Production of autologous DC vaccines from newly diagnosed glioblastoma patients that underwent maximal, safe surgical resection will be evaluated for: feasibility, assessed by success of leukapheresis and production of sufficient and qualified (phenotypic and functional requirements) vaccines. Safety, assessed by microbiological testing (bacteria, yeast, fungi, mycoplasma, endotoxin) of the DC vaccines. | Vaccine production and quality testing (i.e. 4 weeks after leukapheresis) | 
| Feasibility of DC vaccine administration to glioblastoma patients combined with chemotherapy | Administration of 3 weekly DC vaccines following adjuvant chemoradiation (induction phase) and additional DC vaccination at day 21 of each maintenance chemotherapy cycle (booster phase) will be evaluated for feasibility, assessed by successful DC vaccine administration of the proposed treatment scheme. | Upon maintenance chemotherapy treatment (i.e. +/- 12 weeks post leukapheresis) | 
| Number of participants with adverse events as a measure of safety and tolerability | Monitoring the incidence of adverse events to evaluate the safety profile and tolerability of the treatment. The severity of adverse events will be assessed according to the NCI CTCAE scale (v4.03, published June 14, 2010). | Through study completion with follow-up until 90 days after final DC vaccine administration or 24 months after apheresis, whichever occurs later | 
| Immunological responses to the DC vaccine | Immunological responses to the vaccine will be evaluated ex vivo. Blood samples will be collected from patients on the day of the first DC vaccine, and on day 1 of the first and fourth maintenance temozolomide treatment cycles and will be examined for cell subset distribution and activation status and antigen-specific immunity. | At first DC vaccination + day 1 of first and fourth temozolomide treatment cycles | 
| Objective clinical responses by tumor evaluation (clinical efficacy) | Disease evolution and progression-free survival will be assessed according to the Response Assessment in Neuro-Oncology (RANO) criteria, based on imaging findings (MRI, CT), clinical status and corticosteroid use. Disease will be assessed following chemoradiation (≤ 2 weeks after completing chemoradiation), after every two cycles of temozolomide maintenance treatment and at least every 12 weeks during the booster phase, and every 9-12 weeks during follow-up after treatment discontinuation. | Through study completion with follow up until 90 days after final DC vaccine administration or 24 months after apheresis, whichever occurs later | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dendritic cells, Chemoimmunotherapy, Adjuvant therapy