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Adjuvant Dendritic Cell-immunotherapy Plus Temozolomide in Glioblastoma Patients (ADDIT-GLIO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02649582
Recruitment Status : Recruiting
First Posted : January 7, 2016
Last Update Posted : December 11, 2019
Sponsor:
Information provided by (Responsible Party):
Zwi Berneman, University Hospital, Antwerp

Tracking Information
First Submitted Date  ICMJE January 23, 2015
First Posted Date  ICMJE January 7, 2016
Last Update Posted Date December 11, 2019
Actual Study Start Date  ICMJE December 2015
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 6, 2019)
Overall survival [ Time Frame: Through study completion with follow-up until 90 days after final DC vaccine administration or 24 months after apheresis, whichever occurs later ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 5, 2016)
Overall survival [ Time Frame: Through study completion (anticipated 2 years) with 2-year follow-up ]
Patients will be followed for survival, from diagnosis and from start of treatment, for which the accurate date and reason of death (cancer-related or non-related) will be recorded for every patient.
Change History Complete list of historical versions of study NCT02649582 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 6, 2019)
  • Number of glioblastoma patients post surgical resection with feasible and safe DC vaccine production [ Time Frame: Vaccine production and quality testing (i.e. 4 weeks after leukapheresis) ]
    Production of autologous DC vaccines from newly diagnosed glioblastoma patients that underwent maximal, safe surgical resection will be evaluated for:
    1. feasibility, assessed by success of leukapheresis and production of sufficient and qualified (phenotypic and functional requirements) vaccines.
    2. Safety, assessed by microbiological testing (bacteria, yeast, fungi, mycoplasma, endotoxin) of the DC vaccines.
  • Feasibility of DC vaccine administration to glioblastoma patients combined with chemotherapy [ Time Frame: Upon maintenance chemotherapy treatment (i.e. +/- 12 weeks post leukapheresis) ]
    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.
  • Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: Through study completion with follow-up until 90 days after final DC vaccine administration or 24 months after apheresis, whichever occurs later ]
    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).
  • Immunological responses to the DC vaccine [ Time Frame: At first DC vaccination + day 1 of first and fourth temozolomide treatment cycles ]
    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.
  • Objective clinical responses by tumor evaluation (clinical efficacy) [ Time Frame: Through study completion with follow up until 90 days after final DC vaccine administration or 24 months after apheresis, whichever occurs later ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 5, 2016)
  • Number of glioblastoma patients post surgical resection with feasible and safe DC vaccine production [ Time Frame: Vaccine production and quality testing (i.e. 4 weeks after leukapheresis) ]
    Production of autologous DC vaccines from newly diagnosed glioblastoma patients that underwent maximal, safe surgical resection will be evaluated for:
    1. feasibility, assessed by success of leukapheresis and production of sufficient and qualified (phenotypic and functional requirements) vaccines.
    2. Safety, assessed by microbiological testing (bacteria, yeast, fungi, mycoplasma, endotoxin) of the DC vaccines.
  • Feasibility of DC vaccine administration to glioblastoma patients combined with chemotherapy [ Time Frame: Upon maintenance chemotherapy treatment (i.e. +/- 12 weeks post leukapheresis) ]
    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.
  • Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: Through study completion (anticipated 2 years) with 2-year follow-up ]
    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).
  • Immunological responses to the DC vaccine [ Time Frame: At first DC vaccination + day 1 of first and fourth temozolomide treatment cycles ]
    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.
  • Objective clinical responses by tumor evaluation (clinical efficacy) [ Time Frame: Through study completion (anticipated 2 years) with 2-year follow-up ]
    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.
Current Other Pre-specified Outcome Measures
 (submitted: December 6, 2019)
General and disease-specific quality of life [ Time Frame: Through study completion with follow up until 90 days after final DC vaccine administration or 24 months after apheresis, whichever occurs later ]
Patients will be asked to fill out general and disease-specific quality of life questionnaires to assess changes in general and disease-specific quality of life during the study at regular time points.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Adjuvant Dendritic Cell-immunotherapy Plus Temozolomide in Glioblastoma Patients
Official Title  ICMJE Adjuvant Dendritic-Cell Immunotherapy Plus Temozolomide Following Surgery and Chemoradiation in Patients With Newly Diagnosed Glioblastoma
Brief Summary 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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma Multiforme of Brain
Intervention  ICMJE Biological: Dendritic cell vaccine plus temozolomide chemotherapy

When eligible after total or subtotal resection (as assessed by neurosurgeon and post-operative brain MRI):

  1. Leukocyte apheresis (before chemoradiation): for DC vaccine production
  2. 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)
  3. Induction immunotherapy: intradermal vaccination with autologous WT1 mRNA-loaded DCs weekly (+/-1 day) for 3 weeks, starting ≥ 1 week after radiotherapy
  4. 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
Study Arms  ICMJE Experimental: Single Arm
Dendritic cell vaccine plus temozolomide chemotherapy
Intervention: Biological: Dendritic cell vaccine plus temozolomide chemotherapy
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 5, 2016)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Zwi N Berneman, MD, PhD 0032 3 821 39 15 zwi.berneman@uza.be
Contact: Pol Specenier, MD, PhD 0032 3 821 40 14 pol.specenier@uza.be
Listed Location Countries  ICMJE Belgium
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02649582
Other Study ID Numbers  ICMJE CCRG14-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Zwi Berneman, University Hospital, Antwerp
Study Sponsor  ICMJE University Hospital, Antwerp
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Zwi N Berneman, MD, PhD Antwerp University Hospital, Division of Hematology and Center for Cell Therapy and Regenerative Medicine
Principal Investigator: Pol Specenier, MD, PhD Antwerp University Hospital (UZA), Division of Oncology
Principal Investigator: Yannick Willemen, MD University of Antwerp, Laboratory of Experimental Hematology
Principal Investigator: Evelien LJ Smits, MSc, PhD University of Antwerp, Laboratory of Experimental Hematology
Investigator: Barbara Stein, MSc Antwerp University Hospital, Division of Hematology
Investigator: Eva Lion, MSc, PhD University of Antwerp, Laboratory of Experimental Hematology
PRS Account University Hospital, Antwerp
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP