Efficiency of Vaccination With Lysate-loaded Dendritic Cells in Patients With Newly Diagnosed Glioblastoma (GlioVax)

Phase II Trial of Vaccination With Lysate-loaded, Mature Dendritic Cells Integrated Into Standard Radiochemotherapy in Newly Diagnosed Glioblastoma

The primary objective of the study is to determine whether overall survival of newly diagnosed glioblastoma patients treated with lysate-loaded, mature dendritic cell vaccines as add-on to the standard of care consisting of resection, radiotherapy with concomitant temozolomide chemotherapy and subsequent adjuvant temozolomide chemotherapy is superior to the treatment with the standard of care alone.

Study Overview

• Status: Recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Biological: Autologous, tumor lysate-loaded, mature dendritic cells (DC); Drug: standard therapy

Detailed Description

This is a multicenter, randomized, phase 2 study, integrating vaccination with tumorlysate-loaded mature dendritic cells into standard radio/temozolomide-chemotherapy of newly diagnosed glioblastoma patients with near-complete resection after fluorescence-guided resection. Only patients with confirmed gross-total resection and a residual tumor volume below 5 ml will be eligible for the trial. Vaccination will be performed after radio- and concomitant temozolomide chemotherapy and during the first three cycles of adjuvant TMZ.

• Study Type: Interventional
• Enrollment (Anticipated): 136
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael Sabel, Prof. MD; Phone Number: +49 211 8116276; Email: Michael.Sabel@med.uni-duesseldorf.de
• Study Contact Backup: Name: Marion Rapp, PD MD; Phone Number: +49 211 8107458; Email: Marion.Rapp@med.uni-duesseldorf.de

Study Locations

• Germany
  • Krefeld, Germany, 47805
    • Recruiting
    • Helios Klinikum Krefeld, Klinik für Neurochirurgie
    • Contact: Michael Stoffel, Prof. MD; Phone Number: +492151321320; Email: Michael.Stoffel@helios-gesundheit.de
    • Principal Investigator: Michael Stoffel, Prof. MD
    • Sub-Investigator: Knut Send, MD
  • NRW
    • Lünen, NRW, Germany, 44534
      • Recruiting
      • St. Marien Hospital Lünen, Klinik für Neurochirurgie
      • Contact: Konstantinos Gousias, PD Dr. Dr.; Phone Number: 3151 +49230677; Email: cn@klinikum-luenen.de
  • Northrhine Westphalia
    • Bochum, Northrhine Westphalia, Germany, 44829
      • Recruiting
      • Klinik für Neurologie, Knappschaftskrankenhaus Bochum
      • Contact: Uwe Schlegel, Prof. MD; Phone Number: 00492342993719; Email: neurologie@kk-bochum.de
      • Contact: Rekowski Sylvia; Phone Number: 00492342993719; Email: sylvia.rekowski@kk-bochum.de
      • Sub-Investigator: Thomas Kowalski
      • Principal Investigator: Uwe Schlegel, Prof. MD
    • Duisburg, Northrhine Westphalia, Germany, 47055
      • Recruiting
      • Klinik für Neurochirurgie, Sana Kliniken Duisburg
      • Contact: Jung Su Zin, Dr. med.; Phone Number: 00492037332401; Email: suzin.jung@sana.de
      • Principal Investigator: Catharina Junghans, Dr. med.
      • Sub-Investigator: Jung Su Zin, Dr. med.
    • Düsseldorf, Northrhine Westphalia, Germany, 40225
      • Recruiting
      • Neurochirurgische Klinik, Universitätsklinikum Düsseldorf
      • Contact: Michael C. Sabel, Prof. MD; Phone Number: 00492118116276; Email: michael.sabel@med.uni-duesseldorf.de
      • Contact: Natalie Sevens; Phone Number: 00492118117881
      • Sub-Investigator: Marion Rapp, PD MD
      • Principal Investigator: Michael Sabel, Prof. MD
    • Münster, Northrhine Westphalia, Germany, 48149
      • Recruiting
      • Klinik für Allgemeine Neurologie, Universitätsklinikum Münster
      • Contact: Oliver Grauer, PD Dr. med.; Phone Number: 0492518346814; Email: oliver.grauer@ukmuenster.de
      • Principal Investigator: Oliver Grauer, PD Dr. med.
      • Sub-Investigator: Marc Pawlitzki, Dr. med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Determined at pre-screening (prior to surgery; wk-3 - wk-1):

• Patients ≥ 18 years of age at surgery.
• Patients must be in a cognitive state to understand and sign the informed consent indicating that they are aware of the investigational nature and procedures of the study.
• First written informed consent for screening for eligibility, including tumor tissue collection, transfer and processing, central neuropathological evaluation of Tumor sample, central neuroradiological assessment of extent of resection, infectious disease (HIV, HBV, HCV, Treponema pallidum) testing, determination of MGMT promoter methylation status and pregnancy testing.

Determined at screening (at and post-surgery; d0 - wk3):

• Newly diagnosed, monofocal GBM, IDH wildtype (WHO grade IV), including the histological variants of gliosarcoma and giant cell glioblastoma, confirmed by central neuropathologist according to the WHO classification of central nervous System tumors 2016. Tumors may cross into, but not beyond the corpus callosum.
• Near-complete resection (≤ 5 ml residual contrast enhancing tumor volume) confirmed by central neuroradiologist on MRI scan within 72 h postoperative; awake surgery and second look surgery are possible, if medically indicated.
• Sterile tumor sample of ≥ 150 mg with tumor cell frequency ≥ 60% as determined by central neuropathologist available for vaccine production.
• Successful production of sterile, avital tumor lysate.
• Karnofsky performance status ≥ 70%.
• Adequate hepatic (serum glutamate pyruvate transferase/alanine transaminase (SGPT/ALT), serum glutamic oxaloacetate transaminase/aspartate transaminase (SGOT/AST) and alkaline phosphatase ≤ 3-times upper limit of normal (ULN); bilirubin ≤ 1.5-times ULN) and renal functions (creatinine ≤ 1.5-times ULN).
• Adequate bone marrow function (hemoglobin ≥ 10 g/dl, thrombocytes ≥ 100,000/μl, white blood cell count ≥ 3,000/μl; neutrophil count ≥ 1,500/μl).
• Prothrombin time (PT) and activated partial thromboplastin time (PTT) ≤ 1.6x ULN unless therapeutically warranted. International normalized ratio (INR) (in absence of anticoagulation treatment) ≤ 1.5.
• Systemic corticosteroids tapered down to ≤ 2 mg of dexamethasone or equivalent per day within 7 days postoperative (use of corticosteroids during the treatment period should be avoided, however it is possible if clinically indicated, but may require interruption of dendritic cell vaccination).
• Female patients with reproductive potential and male generative patients and their female partners must agree to be true abstinent or to use a highly effective form of contraception (pearl index < 1%) during the trial.
• Patients must be in a cognitive state to understand and sign the informed consent indicating that they are aware of the investigational nature and procedures of the study.
• Written informed consent to participate in study.

Exclusion Criteria:

determined at pre-screening (prior to surgery; wk-3 - wk-1):

• Medical history of severe acute or chronic disease with poor prognosis, e.g. severe coronary heart disease, heart failure (New York Heart Association classes III/IV), severe poorly controlled diabetes, severe mental retardation or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator).
• Medical history of severe autoimmune disorder or immunodeficiency or patients with organ allograft.
• Medical history of bleeding diathesis or coagulopathy.
• Prior malignancy during the last three years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer or cured, early-stage prostate cancer in a patient with prostate-specific antigen (PSA) level less than ULN.
• Previous radiotherapy to head and neck.
• Known allergy or intolerability to TMZ, dacarbazine, the contrast agent or to components of the dendritic cell vaccine.
• Current treatment of glioblastoma in another clinical trial with therapeutic intervention or current use of any other investigational agent.
• Known pregnancy or breast feeding.
• No known severe infection requiring treatment.
• Accommodation in an institution due to legal orders (§40(4) AMG).
• Evidence of current drug or alcohol abuse. determined at screening (at and post-surgery; d0 - wk3):
• Infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or Treponema pallidum or other severe infection requiring treatment.
• Accommodation in an institution due to legal orders (§40(4) AMG).
• Pregnant or breast feeding female patients. From pre-menopausal female patients with childbearing potential a negative pregnancy test must be obtained.
• Any psycho-social condition hampering compliance with the study protocol.
• MGMT promoter methylation status equivocal.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental intervention; Fluorescence-guided surgery (day 0) Leukapheresis (wk4) Fractionated radiotherapy (60 Gy: 2 Gy/d, 5/7 d, 6 wks; wk5 10) and concomitant TMZ chemotherapy (75 mg/m2/d; 6 wks; wk5-10) vaccination with autologous, tumor lysate-loaded, mature dendritic cells (DC) (7x, 2 - 10 x 106 DC each, intradermal injection, weekly wk11-14, wk17, 21, 25)Adjuvant TMZ chemotherapy (150-200 mg/m2/d, 6x, days 1 5 of 28 d cycle: wk15, 19, 23, 27, 31, 35)	Biological: Autologous, tumor lysate-loaded, mature dendritic cells (DC); Advanced therapy medicinal product (ATMP) produced at the University Hospital Düsseldorf according to Good Manufacturing Practice (GMP) with production permission according §13 AMG (German Drug Law) of the local authorities (Bezirks¬regierung Düsseldorf); Other Names: dendritic cell vaccination
Other: Control intervention; Standard therapy: Fluorescence-guided surgery (day 0) Fractionated radiotherapy (60 Gy: 2 Gy/d, 5/7 d, 6 wks; wk5 10) and concomitant TMZ chemotherapy (75 mg/m2/d; 6 wks; wk5-10) Adjuvant TMZ chemotherapy (150-200 mg/m2/d, 6x, days 1 5 of 28 d cycle: wk15, 19, 23, 27, 31, 35)	Drug: standard therapy; temozolomide, fractionated radiochemotherapy; Other Names: temozolomide, fractionated radiochemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Overall survival as measured from the day of surgery until death from any cause assessed up to 34 months	Day of surgery until death of any cause assessed up to 34 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS)	Progression-free survival as measured from the day of surgery until diagnosis of tumor progression by MRI scan according to modified Response Assessment in Neuro-Oncology (RANO) criteria assessed up to 34 months	Day of surgery until day of diagnosis of tumor progression assessed upto 34 months
OS rates	OS rates at 6, 12 and 24 months after the day of surgery	6, 12 and 24 months after the day of surgery
PFS rates	PFS rates at 6, 12 and 24 months after the day of surgery	6, 12 and 24 months after the day of surgery
Frequency and severity of adverse events	Safety based on the frequency and severity of adverse events (AE) with toxicity graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 4.03 (CTCAE 4.03)	34 months
Karnofsky Performance Status	Overall and neurological performance based on the Karnofsky performance status (MMSE-2)	34 months
MMSE-2	Overall and neurological performance based on the Minimal Mental State Examination 2 (MMSE-2)	34 months
Quality of life of cancer patients	Quality of life as determined by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 3.0	34 months
Quality of life in patients with brain cancer	Quality of life as determined by the European Organization for Research and Treatment of Cancer (EORTC) Brain Cancer Module QLQ-BN20	34 months
Psychological distress in oncology patients	Quality of life as determined by the Distress Thermometer (DT)	34 months
Psychological distress, anxiety and depression	Quality of life as determined by the Hospital Anxiety and Depression Scale (HADS) for psycho-oncological strain assessment	34months

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf
• Collaborators: German Federal Ministry of Education and Research
• Investigators: Principal Investigator: Michael Sabel, Prof. MD, Department of Neurosurgery

Publications and helpful links

General Publications

• Rapp M, Grauer OM, Kamp M, Sevens N, Zotz N, Sabel M, Sorg RV. A randomized controlled phase II trial of vaccination with lysate-loaded, mature dendritic cells integrated into standard radiochemotherapy of newly diagnosed glioblastoma (GlioVax): study protocol for a randomized controlled trial. Trials. 2018 May 25;19(1):293. doi: 10.1186/s13063-018-2659-7.

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2018
• Primary Completion (Anticipated): September 6, 2024
• Study Completion (Anticipated): June 6, 2025

Study Registration Dates

• First Submitted: October 26, 2017
• First Submitted That Met QC Criteria: January 9, 2018
• First Posted (Actual): January 10, 2018

Study Record Updates

• Last Update Posted (Actual): December 23, 2022
• Last Update Submitted That Met QC Criteria: December 22, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: immunotherapy; vaccination; glioblastoma,; dendritic cells
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: GlioVax

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No