Clinical studies

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): 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.