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Clinical studies

Ongoing studies after disease

Initial diagnosis glioblastoma WHO IV

INTRAGO-II-Study

INTRAGO-II study: Additive intraoperative irradiation in patients with newly diagnosed glioblastoma

Multi-center, prospective, open, randomized, two-armed phase III clinical trial of additive intraoperative radiation in patients with newly diagnosed glioblastoma. Study is recruiting patients. NCT No: NCT02685605

With the introduction of spherical irradiation devices like the Intrabeam® system (Carl-Zeiss Meditec AG, Oberkochen, Germany), even complex cavities can be adequately covered with irradiation during IORT. INTRAGO II is based on the successful completion of the phase I/II clinical trial (Giordano et al., Neurosurgery 2018; Giordano et al., BMC Cancer 2014). It is intended to determine the effectiveness of intraoperative radiotherapy in patients with newly diagnosed glioblastoma. The study compares patients with additive intraoperative radiation to the standard procedure with patients treated according to the standard procedure. The standard procedure includes surgical removal of the tumor, followed by combined radiation chemotherapy and subsequent chemotherapy with temozolomide.

GAMMA-GBM-Study

GAMMA-GBM study: Early radiosurgical follow-up with Gamma Knife in patients who cannot have a complete resection of the glioblastoma

Monocentric, prospective, open, single-arm study with early radiosurgical follow-up with Gamma Knife in patients where complete resection of the glioblastoma is not possible. Study recruits patients. NCT No: NCT03055208

A complete tumor resection is an important factor for the further prognosis of patients with glioblastoma. However, sometimes a complete resection is not possible, as the patient would otherwise suffer severe neurological deficits. The GAMMA-GBM study is designed to test the effectiveness of early (up to 72 hours after surgery) radiosurgical treatment with the Gamma Knife of non-removable tumor tissue after glioblastoma surgery.

N2M2 (NCT Neuro Master Match)

N2M2 (NCT Neuro Master Match): Personalized therapy option for patients with glioblastoma with non-methylated MGMT promoter

Multi-center, prospective, open-label, phase I/II clinical umbrella study. Identification of a personalized therapy option for patients with glioblastoma using non-methylated MGMT promoter. Study is recruiting patients. NCT No: NCT03158389

The increasing individualization of cancer therapy is also reflected in clinical trials by new study concepts such as umbrella or basket studies. While basket studies treat patients with different tumour indications but the same genetic alteration in a common protocol, umbrella studies examine patients with one tumour indication for different alterations, for which different targeted therapies are then offered.

The feasibility of the study has already been demonstrated in a pilot study (Pfaff E. et al., Neuro Oncol, 2017). In patients with MGMT unmethylated glioblastomas, a complex molecular genetic characterization of the tumor is performed. On the basis of the molecular changes, a personalized, targeted therapy is performed for the patient from 8 different biomarker-supported study arms in parallel to the irradiation as part of the primary therapy.

EORTC-1709-BTG

EORTC-1709-BTG: Additive administration of the proteasome inhibitor marizomib for guideline-based therapy

Prospective, open, randomized, two-armed phase III study for patients with glioblastoma in which the efficacy of the proteasome inhibitor marizomib additive to the guideline-based therapy is investigated. Study is recruiting patients. EudratCT number: 2017-003908-50

In this phase III study, the efficacy of the proteasomic inhibitor marizomib in combination with temozolomide radiochemotherapy in the primary situation in patients with glioblastoma is being investigated. Marizomib has already been investigated in a phase I and II clinical trial in patients with newly diagnosed and relapsed glioblastoma (NCT02330562). Based on these observations, a phase I/II clinical trial was initiated to evaluate Marizomib in combination with combined radiochemotherapy and adjuvant chemotherapy with temozolomide according to the guidelines versus exclusive therapy according to the guidelines. The safety and tolerability of this therapy regimen could be demonstrated, so that in a larger phase III clinical trial only the therapeutic benefit for the progression-free interval and overall survival will be determined.

Recurrent glioma / recurrent glioblastoma

AMPLIFY-NEOVAC/NOA-21

AMPLIFY-NEOVAC/NOA-21: Mutation-specific IDH1 peptide vaccine in combination with a checkpoint inhibitor

Multi-center, prospective, open-label, randomized, three-arm phase I study for the treatment of patients with first recurrence of IDH mutant astrocytoma WHO°II, III and IV without 1p/19q co-deletion. (AMPLIFYing NEOepitope-specific VACcine). Study recruits patients. EudratCT number: 20147000587-15

The NOA-21 / AMPLIFY-NEOVAC study compares in a multi-center open, randomized phase I design to evaluate the safety and immunogenicity of the mutation-specific IDH1 peptide vaccine from the NOA-16 trial in combination with checkpoint inhibition with Avelumab with Avelumab therapy alone and a single IDH1 peptide vaccine in patients with first imaging recurrence of a diffuse glioma with IDH1R132H mutation, without 1p/19q coding or with loss of ATRX expression and an indication for resection.

Patients will initially receive 3 peptide vaccinations (arm 1), 3 peptide vaccinations together with 3 Avelumab infusions (arm 2) or 3 Avelumab infusions (arm 3) over a period of 6 weeks before the planned resection. The tumor tissue is extensively classified immunologically and molecular genetically. Postoperatively, the immunotherapy of the individual treatment arms is continued until the tumour has progressed.

VXM01-AVE-INT

VXM01-AVE-INT: Oral vaccine against the VEGF receptor and checkpoint inhibitor Avelumab for patients with progressive glioblastoma

Multi-center, prospective, open-label, randomized Phase I/II clinical trial with an oral vaccine against the VEGF receptor and the checkpoint inhibitor Avelumab for patients with progressive glioblastoma disease after approved guideline-based therapy with or without renewed indication for surgical therapy Study is recruiting patients.

VXM01 is an oral T-cell immunotherapy designed to activate T-cells that attack the tumor vasculature and directly attack cancer cells in various tumor types. It is based on an attenuated, safe, orally administered bacterial vaccine strain modified to carry the vascular endothelial growth factor receptor-2 (VEGFR2) as the target gene. VXM01 stimulates the patient's immune system to activate VEGFR2-specific cytotoxic T cells (so-called killer cells). These killer cells in turn actively destroy the cells of the tumor vascular system, which leads to increased infiltration of various immune cells into the tumor. In preclinical studies, an analogous VXM01 vaccine showed broad anti-tumor activity in different tumor types. This activity was associated with a VEGFR-2 specific T-cell response and correlated with tumor vascular destruction and increased immune cell infiltration. A double-blind, randomized, placebo-controlled Phase I study in 71 patients with advanced pancreatic cancer confirmed good safety and tolerability of VXM01 and also demonstrated activation of VEGFR-2-specific cytotoxic T cells, which was associated with a significantly improved survival rate.

In this VXM01 trial, patients with a recurrence of glioblastoma will be treated with an oral vaccine against human vascular endothelial growth factor receptor 2 (VEGFR-2) and the checkpoint inhibitor Avelumab (anti-PD-L1 monoclonal antibody) prior to scheduled recurrence surgery. The tissue removed during the operation will provide important information about the response of the body's immune system to the tumour and the effectiveness of the therapies. The aim of the study is to investigate the safety and feasibility of these immunotherapies and to obtain information on immunological reactions and effectiveness

GLIAA/NOA-10

GLIAA/NOA-10: FET-PET versus MRI-based re-irradiation in patients with glioblastoma recurrence

Randomized, prospective, open randomized phase II clinical trial in which FET-PET versus MRI based re-irradiation is performed in patients with glioblastoma recurrence. Study is recruiting patients.

After successful completion of the pilot study, the GLIAA study will evaluate the value of high-precision FET-PET re-irradiation versus high-precision MRI T1+KM re-irradiation in patients with recurrent glioblastoma (Oehlke O. et al., BMC Cancer 2016). Two different diagnostic imaging methods are used to plan the irradiation. Magnetic resonance imaging (MRI) and positron emission tomography with amino acids (AS-PET). Both methods make it possible to distinguish areas affected by tumours from healthy tissue. The aim of the GLIAA study is to find out to what extent the consideration of these two imaging methods can improve radiation treatment. The aim is to irradiate the tumours in a very targeted manner and to protect healthy areas well. This could increase the chances of cure and at the same time significantly reduce the burden on patients.

EOBGM1_Rosalie

A MulticenteR, Open-Label, First-in-Human, PhaSe lb/Ila Trial of E02401, a Novel Multipeptide Therapeutic VAccine, with and without PD-1 Check Point Inhibitor, Following Standard Treatment in Patients with ProgrEssive Glioblastoma

EudraCT number: 2018-002279-16

Currently, therapeutic modalities are insufficient to control high-grade glioma progression overall due to its aggressive nature. Surgical resection is not always possible, and regrowth of tumors as well as acute morbidity is likely. Radiotherapy has high toxicity and retreating recurrences carry a higher risk due to loss in neurogeneration potential. Although chemotherapy has been shown to improve prognosis and time of progression, there are important drawbacks to this treatment modality. The major issues include bypassing the blood-brain barrier, interactions with antiseizure medications, resistance to therapy, recurrent tumors, and intrinsic factors. Enterome is developing an innovative, microbiome-based approach for the development of therapeutic cancer vaccines. E02401 is a multicomponent therapeutic peptide vaccine that will be administered as a monotherapy and in combination with nivolumab to assess the safety and tolerability, and to generate preliminary efficacy data in patients with progressive glioblastoma (GB).

AGIOS 881

A Phase 3, Multicenter, Randomized, Double-blind, Placebo-Controlled Study of AG-881 in Subjects With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation

EudraCT number: AG881-C-004

The primary objective of the study is to demonstrate the efficacy of AG-881 based on radiographic progression-free survival (PFS) per blinded independent review committee (BIRC) compared with placebo in subjects with residual or recurrent Grade 2 oligodendroglioma and astrocytoma with an IDH1 or IDH2 mutation who have undergone surgery as their only treatment.

Brain metastasis

INTRAMET-Study

INTRAMET study: intraoperative radiation in patients with newly diagnosed brain metastasis

Monocentric, prospective, open, single-arm phase I/II clinical trial for intraoperative radiation in patients with newly diagnosed brain metastasis. NCT No: NCT03226483

After surgical removal of brain metastases, follow-up radiation is absolutely necessary to prevent recurrence of the metastasis. With the introduction of spherical irradiation devices such as the Intrabeam® system (Carl-Zeiss Meditec AG, Oberkochen, Germany), even complex cavities can be adequately covered with irradiation during IORT. The INTRAMET study tests whether the intraoperative irradiation is equivalent and compatible with the irradiation otherwise performed after the completion of wound healing.


Future studies

CAR2BRAIN

Multicenter, open label, phase I study of intracranial injection of NK-92/5.28.z cells in patients with recurrent HER2-positive glioblastoma.

EudraCT number: 2016-000225-39

The main objective of this clinical study is to evaluate the safety and tolerability of NK-92/5.28.z (HER2.taNK) and to determine the maximum tolerated dose or maximum feasible dose (MFD). Recommended phase 2 doses both for intraoperative injections only (RP2Diio) and repetitive injections (RP2Dri) will be determined. Frequent side effects and target organs of toxicity and their severity, duration and reversibility will be determined. Furthermore, pharmacokinetics and pharmacodynamics will be examined. In addition, potential signs of anti-tumor activity of NK-92/5.28.z cells will be analyzed.

EORTC 1634 PersoMed-I

Personalized Risk- Adapted Therapy in Post-Pubertal Patients with Newly Diagnosed Medullablastoma

Study number: EORTC-1634-BTG

To compare progression free survival (PFS) of a personalized intensitymodulated therapy (experimental arm; LDE225) vs. standard therapy in the SHH-dependent subgroup in post-pubertal patients with newly diagnosed standard risk medulloblastoma.

EORTC-1721

Rational: Patients diagnosed with oligodendroglioma with IDH mutation and lp/19q codeletion represent rare tumour groups (about 10% of adult gliomas) with relatively favourable prognosis (median survival between 8 and 12 years). These patients are often treated with surgery, chemotherapy and/or radiotherapy. However, as patients live for a long period of time, they may also experience long-term toxic side-effects of treatment. The long-term consequences of treatment- and disease-related factors on healthrelated quality of life and neurocognitive functioning of these patients are largely unknown.

Objective: To describe health-related quality of life and neurocognitive functioning in long-term survivors of oligodendroglioma (with IDH mutation and lp/19q codeletion). This knowledge can Support healthcare Professionals prepare patients for any long-term consequences of treatment. Study design: Cross-sectional study involving questionnaire completion and neuropsychological tests. Study population: Adult (>18 years of age) patients diagnosed with a histologically confirmed oligodendroglioma with IDH mutation and lp/19q co-deletion at least 5 years previously. Target sample size: 200 patients in total. We anticipate approximately 35 centres will take part, bringing the expected number of patients per centre to 6.

Outcomes: Information on disease and treatment (medical records), health-related quality of life, mood, fatigue, subjective neurocognitive functioning (patient-reported outcomes), and objective neurocognitive functioning (neuropsychological tests).

IMPROVE

Improvement of functional outcome for patients with newly diagnosed grade II or III glioma with co-deletion of 1p/19q - Improve Codel: the NOA-18 trial

EudraCT number: 2018-005027-16

A very simple and reproducible test for the codeletion of chromosomes 1p and 19q in tumor tissue allows the identification of the prognostically most favorable group of patients with WHO grade II and III gliomas. These patients have shown a survival advantage for radiochemotherapy with PCV over radiotherapy alone in studies separated for WHO grades. Updated molecular genetic studies no longer allow biological differentiation between WHO grade II and III gliomas, so that for the present study a WHO grade II or III glioma with isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion is used as the molecular entry criterion.

This corresponds to the principles of the revision of the fourth edition of the WHO classification of brain tumours (Louis et al, Acta Neuropathologica 2016) published in May 2016. The WHO classification is a cornerstone of the current study concept. Subgroup analyses from the NOA-04 study conducted in 2016 suggest that temozolomide treatment with PCV treatment appears to be inferior to treatment with PCV in the most favorable subgroup in terms of prognosis and thus in the NOA-18 study population.

The valence of PCV versus PCV + radiotherapy has never been randomized. In the international context, the attempt to show that PCV chemotherapy is not inferior to a combination of PCV and radiotherapy is viewed extremely critically. This approach is being pursued by the French ANOCEF study group (POLCA). After consultation with this study group in January 2016, we decided against switching from temozolomide to PCV in order to avoid duplication of the study, but especially for content considerations. However, the sole use of temozolomide was also no longer a majority option in the German study group. For this reason, we have defined the drug combination of CCNU (lomustine) and temozolomide, which has a similarity of action to procarbazine, as the combination for experimental intervention. This combination is used in the CETEG study, which is also funded by the BMBF and led by Prof. Herrlinger from Bonn.

The aim of the NOA-18 study is to demonstrate superiority of initial temozolomide plus CCNU chemotherapy followed by partial brain irradiation plus PCV for progression over radiochemotherapy with PCV in overall survival without permanent functional deterioration. The study is in the late design phase and will soon be submitted to the authorities for review.

INTERCEPT H3

A MultIceNTer PhasE I VaCcine Trial to Exploit NeoePitope-Specific T Cells for the Treatment of H3-Mutated Gliomas

EudraCT number: 2018-002874-40

The clinical trial will primarily address safety and secondarily immunogenicity of an H3K27M-specific vaccine in combination with the human anti-PD-L1 checkpoint inhibitor Atezolizumab in an orphan disease with poor prognosis. Due to the rareness of the disease 15 patients will be enrolled to determine safety, defined as regime-limiting toxicity (RLT), with reasonable confidence of 95%. Immunogenicity will be assessed by patientspecific T cell responses.


Completed studies after disease

Glioblastoma

GLARIUS-Study

GLARIUS Study: Bevacizumab/Irinotecan therapy vs. standard TMZ therapy in the primary care of patients with newly diagnosed MGMT unmethylated glioblastoma

Randomized phase II trial of bevacizumab/irinotecan therapy vs. standard TMZ therapy in the primary care of patients with newly diagnosed MGMT unmethylated glioblastoma. Status of study 07/2014: Study completed, follow-up completed. Sponsor: Roche. EudraCT No.: 2009-010390-21

In the Glarius study, a 2:1 randomization was performed between the experimental arm (bevacizumab + irinocetan (BEV/IRI)) vs. the standard arm with temozolomide therapy according to the Stupp scheme. Since the study only included patients with non-methylated MGMT promoter (ratio < 0.6) and temozolomide is at best only very slightly effective in this population, temozolomide therapy in the experimental arm could be dispensed with. From June 2010 to August 2012, 182 patients were recruited in 22 German centers. The evaluation of the primary endpoint (PFS-6) and key secondary endpoints (PFS, OS, quality of life) has been performed and published. (Schaub et al., J Cancer Res Clin Oncol. 144(8):1581-1589, 2018). There was no significant difference in tumor progression between the two treatment arms in patients with non-methylated glioblastoma.

Publication: About the Glarius study

CeTeG-Study, NOA-09

CeTeG study, NOA-09: Combined CCNU/tempozolomide therapy vs. standard temozolomide therapy in the primary care of patients with newly diagnosed MGMT-methylated glioblastoma

Randomized phase III trial of combined CCNU/tempozolomide (TMZ) therapy vs. standard temozolomide therapy in the primary care of patients with newly diagnosed MGMT-methylated glioblastoma Recruitment completed (04/2014), 141 patients recruited. EudraCT number: 2009-011252-22

The CeTeG study investigates whether, in addition to standard radiotherapy, a combined CCNU/TMZ therapy is superior to standard TMZ therapy (Stupp scheme) in terms of overall survival. Only patients in whom a methylated MGMT promoter could be detected in the tumor were included. This is due to the fact that in a one-armed preliminary study (UKT-03, Glas et al., J Clin Oncol 27:1257-1261, 2009) indications for an effectiveness of the combination therapy were only found in this subgroup. From 06/2011 to 08/2014, 141 patients were enrolled in 17 German centers (1:1 randomization). The results of the CeTeG study were presented at the SNO Congress and confirm the efficacy and tolerability of the combined chemotherapy of CCNU and temozolomide

APG 101-Study

APG 101 study Therapy with the CD95 receptor blocker APG101 plus re-irradiation versus re-irradiation alone in the treatment of patients with first or second glioblastoma progression.

Randomized, open-label, multicenter phase II study with APG101 (weekly) plus re-irradiation versus re-irradiation alone in the treatment of patients with first or second glioblastoma progression. Invoicing completed. 5 patients recruited. Main sponsor Apogenix GmbH. EudraCT number: 2009-013421-42

The study investigated the tolerability of the CD95 receptor blocker APG101. Patients with recurrent glioblastoma were treated either with a re-irradiation and once weekly administration of APG101 or with radiotherapy alone. Inhibition of the CD95 signaling cascade in combination with radiotherapy seems to be an innovative therapeutic concept which will be further developed and investigated in future clinical trials and scientific studies (Wick et al., Clin Cancer Res. 20(24):6304-13, 2014).

INTRAGO-I-Study

INTRAGO-I study: Dose-escalation study on additive intraoperative radiation in patients with newly diagnosed glioblastoma

Monocentric, prospective, open, single-arm dose escalation study on additive intraoperative radiation in patients with newly diagnosed glioblastoma. Recruitment completed, 15 patients recruited.

With the introduction of spherical irradiation devices like the Intrabeam® system (Carl-Zeiss Meditec AG, Oberkochen, Germany), even complex cavities can be adequately covered with irradiation during IORT. The safety of intraoperative radiotherapy in patients with newly diagnosed glioblastoma could be confirmed in addition to guideline-based treatment (Giordano et al., Neurosurgery 2018; Giordano et al., BMC Cancer 2014). Based on the successful completion of the Phase I/II clinical trial, a larger Phase III trial has been initiated, which is currently recruiting patients.

Glioblastoma recurrence

NOA-12 Study

NOA-12 study: Combination theory with BIBF1120, an inhibitor of VEGFR2, FGFR and PDGFR and re-irradiation for patients with the first or second progress of glioblastoma

Multi-center, prospective, open-label, randomized, two-arm study for patients with first or second glioblastoma recurrence will compare combination therapy with BIBF1120 and re-irradiation with re-irradiation alone. 19 patients recruited. Recruitment completed EudraCT number: 2011-000921-61

The NOA-12 / NONK-03 study investigates the question of the maximum tolerated dose of the multityrosine kinase receptor inhibitor BIBF1120 (inhibitor for VEGFR2, FGFR and PDGFR) in addition to re-irradiation in a prospective and randomized multicenter phase II study after a unicentric phase I in which the maximum tolerated dose was determined, whether a combination theory with BIBF1120 (inhibitor for VEGFR2, FGFR and PDGFR) and re-irradiation with 18 x 2.4 Gy for patients with the first or second progression of a glioblastoma gives a favourable signal for freedom from progression after six months In the control arm, a single re-irradiation with 18 x 2.4 Gy is performed. The planned interim analysis after observation of 19 patients in the experimental arm over a period of six months showed no improvement in tumor progression compared to the control arm, so that the study was terminated prematurely. Evaluation and publication are expected.

Context Column

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