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Ongoing studies after disease
GLORIA (Glioblastoma initial diagnosis)
Glioblastoma Treatment With Irradiation and Olaptesed Pegol (NOX-A12) in MGMT Unmethylated Patients (GLORIA). NCT No: 04121455
The purpose of this study is to obtain first, exploratory information on the safety and efficacy of (i) olaptesed pegol in combination with radiation therapy in patients with newly diagnosed glioblastoma of unmethylated MGMT promoter status either not amenable to resection (biopsy only) or after incomplete tumor resection, (ii) olaptesed pegol in combination with radiation therapy and bevacizumab in patients with newly diagnosed glioblastoma of unmethylated MGMT promoter status either not amenable to resection (biopsy only) or after incomplete or complete tumor resection, (iii) olaptesed pegol in combination with radiation therapy in patients with newly diagnosed glioblastoma of unmethylated MGMT promoter status after complete tumor resection, and (iv) olaptesed pegol in combination with radiation therapy and pembrolizumab in patients with newly diagnosed glioblastoma of unmethylated MGMT promoter status after either complete or incomplete tumor resection.
IMPROVE CODEL (Oligodendroglioma initial diagnosis)
The IMPROVE-CODEL trial will compare the combination of radiotherapy and procarbazine, CCNU, and vincristine (PCV) (standard therapy) with CCNU and temozolomide (CETEG) (experimental therapy). A randomized treatment allocation will be performed. The aim of the NOA-18 study is to find out which therapy combination leads to the longest possible overall survival without relevant functional limitations in the short and long term.
INTERCEPT H3 (K27M altered midline glioma initial diagnosis)
A MultIceNTER Phase I Peptide VaCcine Trial to Exploit NeoePitope-Specific T Cells for the Treatment of H3-Mutated Gliomas – (INTERCEPT H3)
EudraCT Nummer: 2018-002874-40
The clinical trial will primarily address safety and immunogenicity of an H3K27M-specific peptide vaccine in combination with the humanized anti-PD-L1 checkpoint inhibitor Atezolizumab and standard radiotherapy 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 patient-specific T cell responses.
INTRAGO-II (Glioblastoma initial diagnosis)
INTRAGO-II: 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.
AMPLIFY-NEOVAC/NOA-21 (IDH-mutated gliomas recurrence)
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.
CAR2BRAIN (Glioblastoma recurrence)
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.
NOA-13 (PZNSL) (Primary CNS lymphoma)
Prospective observational study of chemotherapy in nonspecifically pretreated patients with primary CNS lymphoma (PZNSL)
The NOA-13 study is a prospective registry to assess current treatment practice in first-line therapy of patients with primary CNS lymphoma.
All patients with non-specifically pre-treated primary CNS lymphoma who are scheduled to receive guideline-guided, i.e. methotrexate-based, high-dose chemotherapy without whole-brain irradiation will be included. Response to therapy (death during therapy, progression, stable disease, partial remission (PR), complete remission (CR)), progression-free and overall survival (PFS, OS) and toxicity according to WHO grade will be recorded.
Break B5 (NSCLC)
Breaking the big Five Barriers of Brain Metastasis (Break B5-BM NSCLC Trial): A prospective phase II, open-label, multi-center trial of combined nivolumab, ipilimumab and bevacizumab together with 2 cycles of induction chemotherapy in patients with non-squamous non-small-cell lung cancer (NSCLC) metastatic to the brain
Eudra-CT Nummer: 2020-000693-18
Due to the so-called blood-brain barrier, it is difficult for classical chemotherapies to reach a sufficiently high drug dose in the brain to achieve an effective outcome. This study will test the safety and efficacy of a new combination treatment of immunotherapy and chemotherapy for the treatment of patients with non-surgical brain metastases from non-small cell lung cancer as the primary tumor.
INTRAMET (operable brain metastases)
INTRAMET: 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.
IT-PD1 (Meningeosis neoplastica)
Intrathecal Application of PD1 Antibody in Metastatic Solid Tumors With Leptomeningeal Disease (IT-PD1/ NOA 26)
EudraCT Number: 2021-001795-42
To determine the safety of intrathecal (IT) PD1 antibody nivolumab for Intrathecal application of PD1 antibody in metastatic solid tumors with leptomeningeal disease of solid tumors.
Leptmeningeal disease (LMD) is an aggressive subtype of metastatic disease in the central nervous system (CNS) and has a poor prognosis with a median overall survival of a few months. The IT-PD1 trial group wants to contribute to an improvement of this situation for LMD patients by using an intrathecal application route for the PD1 antibody, i.e. a drug that has shown clinical efficacy in the underlying tumor via the intravenous route.
GBM-Agile (Glioblastoma recurrence)
A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma
EudraCT Number: 2020-002250-24
Glioblastoma (GBM) adaptive, global, innovative learning environment (GBM AGILE) is an international, seamless Phase II/III response adaptive randomization platform trial designed to evaluate multiple therapies in newly diagnosed (ND) and recurrent GBM. Its goals are to identify effective therapies for glioblastoma and match effective therapies with patient subtypes. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to Arms based on their performance. The primary endpoint is overall survival (OS).
GBM AGILE is designed to efficiently evaluate therapies. The trial will be conducted under a single Master Investigational New Drug Application/Clinical Trial Application and Master Protocol, allowing multiple drugs and drug combinations from different pharmaceutical companies to be evaluated simultaneously. The plan is to add experimental therapies as new information about promising new drugs are identified and remove therapies as they complete their evaluation.
EORTC 1634 PersoMed-I (Medulloblastoma)
Personalized Risk- Adapted Therapy in Post-Pubertal Patients with Newly Diagnosed Medulloblastoma
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.
This study investigates whether personalized, risk-adapted therapy improves treatment outcomes and reduces toxicity in post-pubertal patients with medulloblastoma.
The study also aims to ensure that clinical data, magnetic resonance imaging (MRI) data, and voxel-based radiotherapy planning, as well as biomarkers from liquid biopsies and tumor tissue samples, can be processed to improve diagnosis and treatment and reduce toxicity.
To compare progression-free survival (PFS) by centrally reviewing personalized intensity-modulated therapy (experimental arm; sonidegib) with standard therapy (modified NOA-07) in the SHH-activated subgroup in post-pubertal patients with newly diagnosed standard-risk medulloblastoma.
Completed studies after disease
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.
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).
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
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.
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.
GLARIUS: 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, 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 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: 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.
NOA-12: 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.
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.
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Certified by the German Cancer Society e.V.
EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood
Weller, M., van den Bent, M., … Platten, M., et al., Nat Rev Clin Oncol (2020).