Trial Title:
Imaging and Biological Markers for Prediction and Identification of Glioblastoma Pseudoprogression: a Prospective Study.
NCT ID:
NCT06113705
Condition:
Glioblastoma
Conditions: Official terms:
Glioblastoma
Study type:
Interventional
Study phase:
N/A
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Diagnostic
Masking:
None (Open Label)
Intervention:
Intervention type:
Diagnostic Test
Intervention name:
18F-GE-180 PET
Description:
PET examination of glioblastoma using 18F-GE-180 PET radio-metabolic marker
Arm group label:
Experimental Arm
Intervention type:
Diagnostic Test
Intervention name:
Advanced MRI
Description:
MRI examination using advanced sequences to characterize tumor microstructure and
function
Arm group label:
Experimental Arm
Intervention type:
Other
Intervention name:
Collection of hematopoietic stem cells
Description:
Hematopoietic stem cells will be collected by the aspiration of bone marrow during the
surgical intervention for tumor resection
Arm group label:
Experimental Arm
Intervention type:
Other
Intervention name:
Blood withdrawal
Description:
blood withdrawal for evaluation of plasma biomarkers of inflammation, circulating
microvesicles, and RNA
Arm group label:
Experimental Arm
Intervention type:
Other
Intervention name:
Collection of Cancer Stem Cells
Description:
Glioblastoma stem cells (GSCs) will be isolated from the tumor
Arm group label:
Experimental Arm
Summary:
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
Detailed description:
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Patients of both sex and any race age >= 18.
2. Histologically proven glioblastoma multiforme wild type for IDH1-2 mutation with
MGMT promoter methylated or unmethylated OR subjects with medical history, clinical
sign and symptoms and MRI findings highly consistent with the diagnosis of IDH wild
type glioblastoma.
3. Patient eligible to undergo treatment with TMZ and RT (Stupp protocol or
hypofractionated protocol as per Institutional Multidisciplinary Brain Tumor Board's
decision)
4. Willingness and ability to sign the informed consent and participate to the trial.
Exclusion Criteria:
1. Patient age <18.
2. Patient not eligible to undergo treatment with TMZ and RT (Stupp protocol or
hypofractionated protocol as per Institutional Multidisciplinary Brain Tumor Board's
decision).
3. Patient presenting contraindication to undergo contrast-enhanced MRI (pacemaker or
allergy to gadolinium).
4. Patient HIV1-2 positive.
5. Patient affected by other systemic infective or inflammatory diseases or involving
the central nervous system (multiple sclerosis, lupus, Chron, rheumatoid arthritis).
6. Patients that are pregnant or breast-feeding. -
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
IRCCS Istituto Clinico Humanitas
Address:
City:
Rozzano
Zip:
20089
Country:
Italy
Contact:
Last name:
Letterio S Politi, MD
Phone:
+390282245644
Email:
letterio.politi@hunimed.eu
Investigator:
Last name:
Letterio S Politi, MD
Email:
Principal Investigator
Start date:
November 1, 2023
Completion date:
December 31, 2026
Lead sponsor:
Agency:
Istituto Clinico Humanitas
Agency class:
Other
Collaborator:
Agency:
Mediolanum Cardio Research
Agency class:
Other
Source:
Istituto Clinico Humanitas
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06113705
