Dendritic Cell Immunotherapy Against Cancer Stem Cells in Glioblastoma Patients Receiving Standard Therapy (DEN-STEM)

• ClinicalTrials.gov Identifier: NCT03548571
• Recruitment Status: Recruiting
• First Posted: June 7, 2018
• Last Update Posted: October 22, 2019
• Sponsor: Oslo University Hospital
• Information provided by (Responsible Party): Einar Vik-Mo, Oslo University Hospital

Tracking Information

• First Submitted Date: April 30, 2018
• First Posted Date: June 7, 2018
• Last Update Posted Date: October 22, 2019
• Actual Study Start Date: April 26, 2018
• Estimated Primary Completion Date: May 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 5, 2018)

Progression free survival [ Time Frame: 2 years ]

Defined as time from first surgery to first certain progress of contrast enhancing tumor or clinical progression, according to the Response Assessment in Neuro-Oncology (RANO) criteria.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 5, 2018)

• Overall survival [ Time Frame: 2 years from inclusion ]
  Survival from the time of diagnosis.
• Patient reported quality of life, overall [ Time Frame: 2 years from inclusion ]
  Evaluated by EORTC Quality of Life Questionaire (QLQ-C30), a questionnaire developed to assess the quality of life of cancer patients. Scale 30 to 120 points, where higher is worse.
• Patient reported quality of life, brain specific [ Time Frame: 2 years from inclusion ]
  Evaluated by EORTC Quality of Life Questionaire, Brain module (QLQ-BN20). The brain cancer module is meant for use among brain cancer patients varying in disease stage and treatment modality. Scale 20 to 80 points, where higher is worse. It should always be complemented by the QLQ-C30.
• Immunological response, skin [ Time Frame: 2 years from inclusion ]
  Evaluated by delayed type hypersensitivity reaction in skin.
• Immunological response, cellular [ Time Frame: 2 years from inclusion ]
  Evaluated by lymphocyte clonal analysis.
• Adverse events [ Time Frame: 2 years from inclusion ]
  Classified according to Common Terminology Criteria for Adverse Events (CTCAE).

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Dendritic Cell Immunotherapy Against Cancer Stem Cells in Glioblastoma Patients Receiving Standard Therapy
• Official Title: Open Label Randomized Phase II/III Trial of Dendritic Cell Immunotherapy Against Cancer Stem Cells in Glioblastoma Patients Receiving Standard Therapy (DEN-STEM)
• Brief Summary: Open, randomized study of a trivalent dendritic cell therapy compared to standard therapy in primary treated patients with IDH wild-type, MGMT-promotor methylated glioblastoma. The IMP is dendritic cells transfected with mRNA of survivin, hTERT og autologous tumor stem cells derived from tumorspheres.

Detailed Description

Autologous leukapheresis for enrichment of PBMCs is performed after enrollment of the patient into the trial. Ex vivo generated DCs will be frozen and stored in the vapour phase of liquid nitrogen.

At first surgery, tumor biopsies will be cultured under sphere-forming conditions under ex vivo conditions for enrichment of glioblastoma stem cells. mRNA will purified and amplified from these autologous tumor stem cells.

At specified intervals patients randomized to the vaccine group will receive intradermal injections of DCs transfected with mRNA from autologous tumor stem cells, survivin and hTERT. Injections will be given as three separate injections at three separate sites.

Vaccination will be continued for as long as there are vaccines available.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Open label, randomized

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Glioblastoma

Intervention

• Biological: Dendritic cell immunization
  Intradermal injection
• Drug: Adjuvant temozolomide
  After a 4-week break, patients were then to receive up to six cycles of adjuvant temozolomide according to the standard 5-day schedule every 28 days at 150 mg per square meter for the first cycle and thereafter increase to 200 mg per square meter beginning with the second cycle.
  Other Name: Standard therapy

Study Arms

• Experimental: DC immunization
  Leukapheresis before start of radiotherapy. Immunization with DCs starting first week after finalizing radiotherapy (2Gy x 30) and concomitant temozolomide.
  Intervention: Biological: Dendritic cell immunization
• Active Comparator: Standard therapy
  Radiotherapy (2 Gy x30) with concomitant and adjuvant temozolomide.
  Intervention: Drug: Adjuvant temozolomide

Publications *

• Vik-Mo EO, Nyakas M, Mikkelsen BV, Moe MC, Due-Tønnesen P, Suso EM, Sæbøe-Larssen S, Sandberg C, Brinchmann JE, Helseth E, Rasmussen AM, Lote K, Aamdal S, Gaudernack G, Kvalheim G, Langmoen IA. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. Cancer Immunol Immunother. 2013 Sep;62(9):1499-509. doi: 10.1007/s00262-013-1453-3. Epub 2013 Jul 2.
• Woroniecka K, Fecci PE. Immuno-synergy? Neoantigen vaccines and checkpoint blockade in glioblastoma. Neuro Oncol. 2020 Sep 29;22(9):1233-1234. doi: 10.1093/neuonc/noaa170.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 5, 2018): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 1, 2023
• Estimated Primary Completion Date: May 1, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

All of the following conditions must apply:

• Must be at least 18 years and less than 70 years of age.
• Must be ambulatory with a ECOG performance status 0 or 1
• Must have histologically confirmed glioblastoma IDH wild-type, with unmethylated MGMT-gene promotor, and a candidate for combined radiation therapy and chemotherapy ("Stupps Regimen").
• Must have accessible volume and quality of tumor tissue for vaccine production (proliferation of cells and extraction of tumor mRNA) at first surgery.
• Must have postoperative MRI after surgery with contrast enhancing tumor remnant of less than 1 cm3 or less than 10% of original tumor volume.
• Normal organ function defined by laboratory values as following: ANC > 1.5 x 109/L; platelets >100 x109/L, Hb >9g/dL (> 5.6 mmol/L). Creatinine < 140 µmol/L (1.6 mg/dL); if borderline, the creatinine clearance >40 mL/min, Bilirubin < 20% above the upper limit of normal, ASAT and ALAT < 2.5 the upper limit of normal. Albumin >2.5 g/L.
• Serology indicating contagious HIV, HBV, HCV and Treponema pallidum must be negative.
• Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to ICH GCP, and national/local regulations.

Exclusion Criteria:

• Tumor in a localization where a modest increase in size due to reactive oedema may have a large impact on the patient's neurological condition, i.e. brain stem.
• History of prior malignancy other than glioblastoma, with the exception of curatively treated basal cell or squamous cell carcinoma of the skin and ca. cervicis stage IB.
• Active infection requiring antibiotic therapy.
• Significant cardiac or other medical illness that would limit activity or survival, such as severe congestive heart failure, unstable angina, or serious cardiac arrhythmia.
• Prior splenectomy.
• Glucocorticoid treatment not possible to terminate due to autoimmune disease or increased intracranial pressure.
• Adverse reactions to vaccines such as asthma, anaphylaxis or other serious reactions.
• History of immunodeficiency or autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis-dermatomyositis, juvenile onset insulin dependent diabetes, or a vasculitic syndrome.
• Chemotherapy or other potentially immune-suppressive therapy outside protocol that has been administered within the last 4 weeks prior to vaccination.
• Positive pregnancy test in women of childbearing potential (within 7 days before the first vaccination). Women of childbearing potential and sexually active male participants must use reliable methods of contraception during the whole treatment period and 3 months after the last trial drug dose. Reliable methods of contraception are defined in section .
• Any reason why, in the opinion of the investigator, the patient should not participate.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Einar O Vik-Mo, MD, PhD; +47 23074340; uxvieb@ous-hf.no

Contact: Soveig Bringsli; solbri@ous-hf.no

• Listed Location Countries: Norway

Administrative Information

• NCT Number: NCT03548571
• Other Study ID Numbers: DEN-STEM
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Einar Vik-Mo, Oslo University Hospital
• Study Sponsor: Oslo University Hospital
• Collaborators: Not Provided

Investigators

• Principal Investigator: Iver A Langmoen, MD, PhD; Oslo University Hospital

• PRS Account: Oslo University Hospital
• Verification Date: October 2019