Neoplasms

All Conditions

Rare Diseases

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Multidisciplinary and innovative approach based on plasma markers of inflammation (cytokines, circulating RNA, and extracellular microvesicles), and multimodal imaging using 18F-GE-180 positron emission tomography (PET) and advanced MRI techniques,

PET examination of glioblastoma using 18F-GE-180 PET radio-metabolic marker

18F-GE-180 PET

MRI examination using advanced sequences to characterize tumor microstructure and function

Advanced MRI

Hematopoietic stem cells will be collected by the aspiration of bone marrow during the surgical intervention for tumor resection

Collection of hematopoietic stem cells

blood withdrawal for evaluation of plasma biomarkers of inflammation, circulating microvesicles, and RNA

Blood withdrawal

Glioblastoma stem cells (GSCs) will be isolated from the tumor

Collection of Cancer Stem Cells

Letterio S Politi, MD

Luca A Cappellini, MD

The goal of this interventional study is the development and validation of imaging markers, MRI and PET, plasma biomarkers, and/or cell markers that could support clinicians and researchers in differentiating pseudoprogression from true tumor progression in routine clinical activities and clinical trials in patients affected by glioblastoma.

The endpoints of the study are:

* the elaboration of predictive models using imaging advanced biomarkers, PET and MRI, biological serum markers, and cancer cell derived makers to differentiate tumor pseudoprogression or real progression in patients affected by glioblastoma who underwent therapeutical protocol as per treating physicians' indications (Stupp or hypofractionated RT)
* to establish an in vivo murine model of pseudoprogression by orthotopic transplantation of glioblastoma stem cells derived from thirty-five patient subjected to subsequent treatment with irradiation and temozolomide administration.

Participants will undergo:

* baseline MRI and 18F-GE-180 PET imaging, and blood withdrawal
* surgery
* collection of glioblastoma stem cells (and hematopoietic stem cells from a sub-group of subjects)
* standard treatment with radiotherapy and chemotherapy
* MRI every 3 months
* PET and blood withdrawal in case of MRI evidence of either suspected tumor progression or pseudoprogression
* second surgery OR stereotactic biopsy OR clinico-radiological follow-up as for standard of care according to the Institutional Multidisciplinary Brain Tumor Board

Rationale

Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous system characterized by an extremely severe prognosis with a median survival of 14-16 months from diagnosis. Patients affected by high-grade gliomas are treated with a combination of radiotherapy and temozolomide chemotherapy. To date, the efficacy of the treatment is assessed through MRI which shows evidence of early radiological progression in up to 50% of all patients. Importantly, signs of tumor progression on MRI images may actually represent pseudoprogression in up to 64% of cases meaning that within 6 months from the end of the radiation treatment 20-30% of patients show increased contrast enhancement that resolves on subsequent MRI scans without changes in the treatment. Pseudoprogression is a phenomenon likely related to inflammation and disruption of the blood-brain barrier (BBB) caused by radiation and by the concurrent temozolomide treatment. Being a self-resolving consequence of the therapy rather than a sign of tumor growth, mistaking pseudoprogression for real progression leads to premature discontinuation of therapy and inappropriate evaluation of progression free survival and response rate in clinical trials impairing clinical practice.

Therefore, the differentiation of pseudoprogression from true progression is both a challenge in everyday clinical activity and a relevant problem in clinical trials and research.

A major limitation to the development and assessment of efficacy of current and new therapies in the setting of brain tumors, both at preclinical and clinical levels, however, is the lack of reliable trial endpoints.

A combination of advanced imaging methods, MRI and PET, with innovative techniques investigating cancer-specific biology will allow a holistic characterization of the tumor from multiple aspects crucial to enable a personalized diagnostic and therapeutical approach.

Objective

The main goal of the project is the development and validation of imaging markers, MRI and PET, plasma biomarkers, and/or cell markers that could support clinicians and researchers in differentiating pseudoprogression from true tumor progression in routine clinical activities and clinical trials in patients affected by GBM.

Main trial endpoints

The primary endpoint of the study is the elaboration of predictive models (evaluation of specificity and sensitivity) using imaging advanced biomarkers, PET and MRI, biological serum markers, and cancer cell derived makers to differentiate tumor pseudoprogression or real progression in patients affected by GBM who underwent therapeutical protocol as per treating physicians' indications (Stupp or hypofractionated RT).

Secondary trial endpoints

We aim to establish an in vivo murine model of pseudoprogression by orthotopic transplantation of GSCs derived from thirty-five patient subjected to subsequent treatment with irradiation and temozolomide administration.

Trial design

This is a pilot prospective interventional clinical trial using a novel 18F-GE-180 PET radio-metabolic marker (AxMP) and MRI with advanced sequences with no modification of standard of care treatment and additional diagnostic procedures that do not pose more than minimal additional risk or burden to the subjects compared to normal clinical practice. The trial will enroll 75 patients in 42 months and will be concluded in 60 months.

Trial population

The trial will prospectively enroll 75 patients affected by isocitrate dehydrogenase gene (IDH)-wild type Glioblastoma, with an age above 18 years old , who will undergo standard of care treatment.

Interventions

Before surgery and starting the standard treatment with RT and chemotherapy, all subjects will undergo baseline MRI and 18F-GE-180 PET imaging, and blood withdrawal for evaluation of plasma biomarkers of inflammation, circulating microvesicles, and RNA. MRI exams will then be performed as per standard practice of care every 3 months and in case of clinical deterioration suggesting possible disease recurrence/progression. A second PET-scan along with plasma sample collection will be performed only in case of MRI evidence of either suspected tumor progression or pseudoprogression. In case of MRI evidence of an increase in tumor size (either suspected true tumor progression or pseudoprogression), as for standard of care, the Institutional Multidisciplinary Brain Tumor Board (composed of neurosurgeons, neuro-oncologists, neuroradiologists, radiotherapists) will discuss each patient for determining clinical indication and feasibility of second surgery. In those patients in whom second surgery is not indicated, a stereotactic biopsy will be considered if feasible, safe, and clinically useful. If a stereotactic biopsy is not feasible and safe, a 3-month follow-up will be planned before a change in treatment. When available, pathology will be considered as the gold standard for differentiation pseudoprogression from true tumor progression. In all other subjects, follow-up and overall survival data will be evaluated for this differentiation. In all the subjects, overall survival data will be also recorded for statistical analyses.

Cancer Stem Cells /CSC) will be collected form 35 patients and Hematopoietic Stem Cells (HSC) from 10 patients for the creation of a vitro and in vivo murine model.

Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of patients represented by the trial subjects as well as the nature and extent of burden and risks This trial will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guideline as well as international and national legal and regulatory requirements.

All study participants will receive the standards of care for GBM. The additional diagnostic procedures (PET scan with a novel tracer and high resolution 3 Tesla scanner MRI) do not entail specific risks for the patient. At every time point (at least before surgery, before RT and in case of pseudoprogression) additional blood samples for the determinations of markers of inflammation and the isolation of circulating microvesicles and RNA will be collected from the patients. Glioblastoma stem cells will be isolated from the tumoral mass excised during glioblastoma surgery in 35 patients; hematopoietic stem cells will be obtained from 10 consenting patients at the time of surgery by aspiration of 30-40ml of bone marrow from the iliac crests, as per standard clinical practice. Since the biopsy will be performed under general anesthesia, the patient should not experience discomfort.

There are no expected benefits for the individual patient, but the study results might provide important advances for the treatment of future patients.

Imaging and Biological Markers for Prediction and Identification of Glioblastoma Pseudoprogression: a Prospective Study.

To establish and characterize in vivo murine models of pseudoprogression by orthotopic transplantation of patient-derived GSCs in nonobese diabetic scid gamma (NSG) mice previously repopulated with individual patients' hematopoietic stem and progenitor cells to reproduce a humanized environment and to correlate in vivo imaging findings and plasma markers with pathology

predictive models (evaluation of specificity and sensitivity) using imaging advanced biomarkers, PET and MRI, biological serum markers, and cancer cell derived makers to differentiate tumor pseudoprogression or real progression in patients affected by GBM who underwent therapeutical protocol as per treating physicians' indications (Stupp or hypofractionated RT)

Glioblastoma stem cells (GSCs) will be isolated from the tumors of the patients enrolled, characterized at the molecular and functional level before and after in vitro treatment with radiations and TMZ, to identify candidate cellular phenotypes and molecular pathways possibly associated with pseudoprogression

Mediolanum Cardio Research

Istituto Clinico Humanitas

Research Administrator Manager

The MRI-scan time is extended with 15-20 minutes.

Extension of the brain tumor MRI-protocol

Extended MRI

Patrick Tang, MSc

Laurens Groenendijk

Esther Warnert, PhD

After surgery, a key step in treatment of patients diagnosed with glioblastoma (high grade brain tumour) is radiotherapy. The ideal clinical target volume (CTV) for radiotherapy treatment planning includes all tumour cells remaining after surgery. Currently, the GTV is delineated on conventional imaging techniques that are only visualizing macroscale structural changes due to the presence of a large number of tumour cells. After delineating these visible macroscale changes, the GTV is expanded in all directions with 1.5cm into visibly healthy tissue to account for microscale tumour invasion. This standard CTV therefore also contains healthy tissue that should not be receiving radiation, causing side effects of treatment, hereby reducing quality of life for patients.

Generating a physiological CTV, in which microscale invasion of tumour cells is taken into account specifically whilst sparing healthy tissue that is not in need of radiation, is essential for reducing side effects of radiotherapy. To do so, visualisation is necessary of physiological processes of tumour cells, which are present before macroscale structural changes occur. State-of-the-art MRI techniques are now in use at the Erasmus MC that can assess these physiological processes, including oxygenation status and cell proliferation.

We aim to generate proof-of-concept of using a physiological CTV for radiotherapy treatment planning for patients with brain tumours. By extending the clinical standard MRI session used for radiotherapy planning in 10 patients diagnosed with glioblastoma with advanced MRI techniques that assess oxygenation status and cell proliferation, we will generate the physiological CTV including this information and illustrate that it is more precise in capturing microscale tumour invasion. This proof-of-principle work will be used to obtain external funding to perform the much needed, and the first of its kind globally, clinical trial to show the benefit of a physiological CTV for radiotherapy treatment planning in glioblastoma.

Introduction: After surgery, a key step in treatment of patients diagnosed with glioblastoma (high grade brain tumour) is radiotherapy. The ideal clinical target volume (CTV) for radiotherapy treatment planning includes all tumour cells remaining after surgery. Currently, the GTV is delineated on conventional imaging techniques that are only visualizing macroscale structural changes due to the presence of a large number of tumour cells. After delineating these visible macroscale changes, the GTV is expanded in all directions with 1.5cm into visibly healthy tissue to account for microscale tumour invasion. This standard CTV therefore also contains healthy tissue that should not be receiving radiation, causing side effects of treatment, hereby reducing quality of life for patients.

Generating a physiological CTV, in which microscale invasion of tumour cells is taken into account specifically whilst sparing healthy tissue that is not in need of radiation, is essential for reducing side effects of radiotherapy. To do so, visualisation is necessary of physiological processes of tumour cells, which are present before macroscale structural changes occur. State-of-the-art MRI techniques are now in use at the Erasmus MC that can assess these physiological processes, including oxygenation status and cell proliferation.

We aim to generate proof-of-concept of using a physiological CTV for radiotherapy treatment planning for patients with brain tumours. By extending the clinical standard MRI session used for radiotherapy planning in 10 patients diagnosed with glioblastoma with advanced MRI techniques that assess oxygenation status and cell proliferation, we will generate the physiological CTV including this information and illustrate that it is more precise in capturing microscale tumour invasion. This proof-of-principle work will be used to obtain external funding to perform the much needed, and the first of its kind globally, clinical trial to show the benefit of a physiological CTV for radiotherapy treatment planning in glioblastoma.

Rationale: Current treatment management of patients with IDH-wildtype glioblastoma is sub-optimal because of two main issues: (1) Creating an accurate target volume for radiotherapy, a key aspect of glioblastoma treatment, containing all remaining tumour cells after surgery that is impossible with the conventional CT and MRI imaging techniques currently used and (2) in the follow-up of patients after radiotherapy, conventional MRI is incapable of distinguishing tumour progression from treatment effects. The solution to these issues lies in accurate and non-invasive assessment of physiological processes of tumour cells to enable delineation of the true physiological clinical target volume (CTV) for radiotherapy planning and to allow for early detection of true tumour progression during treatment follow-up.

Objective: Generate proof-of-concept of using a physiological CTV for radiotherapy treatment planning for patients with brain tumours.

Study design: By extending the clinical standard MRI session used for radiotherapy planning in patients diagnosed with glioblastoma with advanced MRI techniques that assess oxygenation status and cell proliferation, a physiological CTV will be generated for each patient in addition to the standard CTV. Treatment for each patient will be according to the current standard in which the standard CTV is used. Initial analysis will include comparing both CTVs in terms of volume and location. Patient follow-up will occur according to the clinical standard, including the standard MRI scan protocols, for a maximum of 2 years. Pattern-of-failure analysis will be done to compare the standard CTV and physiological CTV. It is hypothesized that the physiological CTV will be smaller than the standard CTV, whilst having the same pattern-of-failure.

Study population: 10 patients (\> 18 years), diagnosed with IDH-wildtype glioblastoma, as confirmed by molecular or immunohistochemistry analysis post resection/biopsy and referred to outpatient clinic of the department of Radiotherapy to undergo standard treatment with radiotherapy.

Intervention (if applicable): Each patient will have an extension to their standard, radiotherapy planning MRI scan taken for regular clinical care. This scan will last at maximum 60 minutes.

Main study parameters/endpoints: Equal prediction of pattern of failure (locations of tumour recurrence) based on the physiological CTV compared to the standard CTV used for radiotherapy planning, with the physiological CTV being smaller in volume.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The patients the burden of prolonged scan time (+ 30 minutes, scan will last 60 mins in total) during their standard RT planning scan. The remainder of their clinical care will not be altered: RT will be given to these patients based on standard CTVs. Follow-up will follow the clinical protocol . There will be no personal benefit for the patients in this research project.

Physiological MRI for Precision Radiotherapy IDH-wildtype Glioblastoma

Volume and location analysis (Dice correlation coeffcient) will be done to compare the physiological CTVs to standard CTVs generated pre-radiotherapy, where it is hypothesized that the physiological CTVs will be overall smaller in volume and better match microinvasion of the tumour than the standard CTV.

In the standard follow-up of patients, repeat MRI scans are made every 3 to 4 months. RANO criteria will be used to do response assessment and to determine if and when tumour recurrence is occurring. Pattern-of-failure analysis will then be done with the physiological CTV and the standard CTV, where the percentage of overlap of the recurrence volume with the physiological and standard CTV will be assessed. The hypothesis is that the percentage overlap will not be worse for the physiological CTV compared to the standard CTV, whilst the physiological CTV will be smaller in volume than the standard CTV.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Imaging and Biological Markers for Prediction and Identification of Glioblastoma Pseudoprogression: a Prospective Study.	NCT06113705	Glioblastoma	18F-GE-180 PET Advanced MRI Collection of h... Blood withdrawa... Collection of C...	18 Years -	Istituto Clinico Humanitas
Physiological MRI for Precision Radiotherapy IDH-wildtype Glioblastoma	NCT05970757	Glioblastoma	Extended MRI	18 Years -	Erasmus Medical Center

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