| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed Glioblastoma (IDH wild-type) patients at initial radiological diagnosis eligible for tumor resection and for the standard of care including concurrent temoradiation and adjuvant TMZ. The SonoCloud-9 ultrasound System is intended to locally and transiently increase the permeability of the blood brain barrier to Increase temozolomide (TMZ) brain uptake and endogenous brain immunity. |
| Patiënten met nieuw gediagnosticeerd glioblastoom (IDH wild-type) bij initiële radiologische diagnose die in aanmerking komen voor tumorresectie en voor de standaardbehandeling, inclusief gelijktijdige temoradiatie en adjuvante TMZ. Met echoscopie geïnduceerde tijdelijke opening van de bloed-hersenbarrière (BBB) voor het verhogen van de opname van temozolomide (TMZ) in de hersenen en het vergroten van de endogene immuniteit van de hersenen. |
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| E.1.1.1 | Medical condition in easily understood language |
Newly diagnosed Glioblastoma (IDH wild-type) patients at initial radiological diagnosis eligible for tumor resection and for the standard of care including concurrent temoradiation and adjuvant TMZ.
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| Recent gediagnosticeerde patiëntenmetglioblastoom bijeersteradiologischediagnose,die in aanmerking komenvoor tumorresectie envoor de zorgstandaard inclusief gelijktijdige TemoRadiation enadjuvanteTMZ. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
clinical efficacy based on comparison of median PFS (Progression Free Survival) assessed by local investigator between the standard of
care treatment with ultrasound BBB opening versus standard of care treatment alone. |
| klinische werkzaamheid op basis van de vergelijking van de mediane PFS(progressievrije overleving), bepaald door plaatselijke onderzoeker, tussen de standaard behandeling met echoscopische opening van de BBB en de standaard behandeling op zich. |
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| E.2.2 | Secondary objectives of the trial |
-Survival improvement,
-Patient quality of life preservation,
-Patient intellectual preservation,
-Safety confirmation of SonoCloud-9 induced efficient grade 3 BBB opening. |
-verbetering in overleven,
-behoud van levenskwaliteit van de patiënt,
-behoud intellect van de patiënt,
-bevestiging veiligheid van met SonoCloud-9 geïnduceerde efficiënte Klasse 3 opening BBB.
|
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biomarkers Ancillary study
Goal : tumor biomarkers analysis as a biological monitoring of treatment efficacy or tumor progression, and Impact of usBBB opening on such monitoring
Objective 1: identify tumor tissue biomarkers associated with molecular predictors of treatment response and prognostic. This study will only be done on tumor samples from Pitié-Salpêtrière GBM patients, obtained during regular standard of care debulking surgeries (first surgery/ second surgery atrecurrence).
Tumor tissue biomarkers will include:
- mutational load estimation as determined by cancer gene panel molecular analysis (WES),
- pattern of several proteins in tumor cells and microenvironment (immunohistochemistry)
- tumor associated immune cells
Tumor biomarkers will be correlated with PFS and OS.
Objective 2: monitor brain and tumor blood biomarkers to evaluate treatment response, BBB opening and prognostic. This study will only be done on blood samples from first 14 (7 each arm) Pitié- Salpêtrière GBM patients. Blood samples (represented as X) of 7.5 ml (Cell-Free DNA Collection-CEIVD)
will be collected at different time point :
Blood samples will be performed : Before + 2h after surgery (2 samples / both arm patients), Before + 2h after usBBB: US#1-3-9-13-15 (10 samples/arm1 patients), Before + 2h and 6h after usBBB: US# 6-12 (6 samples/arm1 patients); at C1d15 - C4 d15 - M11 - M15 Medical visit (4 samples / arm2 patients).
Blood biomarkers will include:
- Proteins markers,
- Circulating lymphocytes and immune cell population: High-throughput sequencing of T-cell
receptor markers (TCRseq) and number (temozolomide will reduce). Macrophages/microglial cells and cytokines analysis.
- Circulating DNA for antigens detection: ctDNA from identified targets in the GBM
- Total/targeted circulating μRNAs GBM: RNA-seq in human tumor for antigens repertories (TAA and TSA),
- Circulating tumor exosomes (harvesting and preparation would be done at the same time and analysis would be done later if desired).
Blood biomarkers will be correlated with BBBopening, PFS and OS
Samples taken in the course of the research will be subject to a declaration of biological collection in the context of research. Samples will be analyzed as we go along of the studies. The collection will be declared to the ANSM as part of biomedical research.
Patients will be asked to give written informed consent for the collection and storage of fresh frozen tissue, FFPE tissue and blood samples. Consent will include retention of the material for future ethically approved research.
At the end of the study, the samples (or a component of the samples, tumor sample, blood sample) may be used for further analysis, not described in the initial protocol, which may be useful for our investigation in light of advances in scientific knowledge, provided the participant is informed and does not oppose this use, as stated in the information note/consent form. If the samples are kept at the end of the study, the sample collection will be declared to the ministry of research [and to the director of the competent regional healthcare authority if the entity is a health establishment] (Article L. 1243-3 of the Code de la Santé Publique [French Public Health Code]).
These biological collections (blood samples and tumor samples) will be kept in the molecular biology laboratory “Genetics and development of nervous system tumors” lab, Paris Brain Institute). They will be kept for an unlimited period.
Additionally, during SonoCloud device explantation surgery (on Pitié-Salpêtrière patients only), surrounding subcutaneous tissues will be sampled to evaluate the local tissue effects of the SC9 device for regulation purposes. |
Aanvullende studie over biomarkers:
Doelstelling: analyse van tumorbiomarkers als biologische monitoring van de doeltreffendheid van de behandeling of van de progressie van de tumor en de impact van het openen van de bloed-hersenbarrière geïnduceerd door echografie op dergelijke monitoring. |
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| E.3 | Principal inclusion criteria |
Inclusion criteria
1. Age ≥ 18 years and ≤ 70 years, able and willing to give signed and informed consent
2. MRI with suspicion of GBM or Patient with a newly histologically proven IDHwt GBM by previous stereotaxic biopsy or king size opened biopsy
3. Karnofsky Performance Status ≥ 70
4. Patient eligible for a total or sub-total surgical tumor resection
5. Maximal tumor enhancement diameter at inclusion (pre surgery) ≤ 70 mm in T1W MRI
6. Patient eligible after surgery for the first line standard of care temoradiation and adjuvant TMZ (Stupp protocol, 54)
7. Patient with adequate organ and bone marrow function within 14 days prior to registration, as defined below:
- Hemoglobin ≥ 10.0 g/dL
- Leukocytes ≥ 3,000/L
- Absolute neutrophil count ≥ 1,500/L
- Platelets ≥ 100,000/L
- Total bilirubin < 1.5 x ULN
- AST(SGOT)/ALT(SPGT) ≤ 3 x institutional ULN
- Alkaline phosphatase (ALP) < 3 x ULN
- Normal creatine clearance ≥ 60 mL/minute.
- Prothrombin time and partial thromboplastin time within institutional limits.
8. For women of childbearing potential, a negative pregnancy test before inclusion and a medically acceptable method of birth control used throughout the study are required. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 1 month after the end of study visit
9. A male patient must agree to use contraception as detailed in this Protocol during the treatment period and for at least 6 months after the last cycle of TMZ; he must refrain from donating sperm during this period
10. Patient capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol
11. Patient must be a beneficiary of or affiliated with a social security scheme
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1. patiënt ≥ 18 jaar en ≤ 70 jaar
2. MRI van de hersenen bij vermoeden van recent gediagnosticeerd IDH-wildtype GBM
3. KPS ≥70
4. Supratentoriële tumor
5. T1W contrastverbetering van de tumor van ≤ 70 mm in T1W MRI
6. In aanmerking komend voor gedeeltelijke of volledige chirurgische resectie en gelijktijdige TemoRadiation gevolgd door adjuvante TMZ (volgens Stupp-protocol) |
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| E.4 | Principal exclusion criteria |
1. Patients with multifocal tumor (unless all localized in a 70 mm diameter area accessible to ultrasound field) or located in posterior fossa tumor
2. Patient with diffuse FLAIR abnormalities attributable to Gliomatosis
3. Patients with evidence of uncontrolled intracranial pressure
4. Patients with uncontrolled epilepsy
5. Patients with medical need to continue antiplatelet or antithrombotic treatment
6. Pregnant or breastfeeding women (blood pregnancy test)
7. Patients with contra-indications to MRI or known sensitivity/allergy to gadolinium, or other intravascular contrast agents
8. Known history of hypersensitivity reactions to perflutren lipid microsphere components or to any of the inactive ingredients in Luminity®/Definity®
9. Patients with known intracranial aneurism, with and/or unremovable coils, clips, shunts, intravascular stents, wafer, non resorbable dura substitute, or reservoirs
10. Patients with an uncontrolled intercurrent illness or any pre-existing comorbidities that in the Investigator’s opinion may prevent the implantation of the device or may impair the ability of the patient to receive treatment with SonoCloud or may be cofounding for evaluation of the clinical trial.
11. Patients with the following are not eligible:
- Known arterial hypertension grade 3 or higher without adequate control on medications
- Known or suspected unstable active or chronic infections requiring systemic treatment
- Known significant cardiac disease: right-to-left shunts, Unstable angina pectoris, Symptomatic congestive heart failure, Unstable cardiac arrhythmia
- Known significant pulmonary disease: severe pulmonary hypertension (pulmonary artery pressure > 90 mmHg), uncontrolled systemic hypertension, adult respiratory distress syndrome, or Pneumonitis
- Known Severe renal failure
- Known serious myelosuppression
- Known Psychiatric illness/social situations that would limit compliance with study requirements
- Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient’s safety or study endpoints
- Known immunodeficiency disease or treatments (HIV)
- Known viral or bacterial chronic/acute disease (potential blood borne infections that could result in meningitis or brain abscess)
12. Patients under judicial protection
13. Patients with any following prohibited treatments:
- Any investigational medicinal product within 30 days prior to inclusion and during the study
- Antibiotics with known neurotoxicity (eg, aminoglycosides, cephalosporin, quinolones), unless substitution is not possible,
- Non-absorbable material (dura matter substitute, hemostatic agent…)
- Any other drug according investigator to cause cerebral toxicity due to BBB opening
- Contra-indications to temozolomide
- Dacarbazine hypersensitivity
14. Implantation of the SC-9 not possible according to neurosurgeon (any patient morphological characteristics (e.g. skin thin thickness >9mm), which, from neurosurgeons’ opinion, prevent implantation of the device or may impair the ability of the patient to receive treatment with SonoCloud, would be excluded)
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contra-indicatie voor sonicatie
1. patiënten met multifocale tumor (tenzij allemaal gelokaliseerd in een gebied met een diameter van 70 mm dat toegankelijk is voor een echoschopisch veld) of dat zich in een posterieure fossatumor bevindt
2. patiënt met diffuse aan gliomatose toe te schrijven FLAIR-afwijkingen
3. patiënten met aantoonbare ongecontroleerde intracraniale druk
4. patiënten met ongecontroleerde epilepsie
5. patiënten met een medische noodzaak voor een voortgezette plaatjesremmende of antitrombosebehandeling
6. zwangere vrouwen of vrouwen die borstvoeding geven (zwangerschapstest in bloed)
7. patiënten met contra-indicaties voor MRI of bekende gevoeligheid/allergie voor gadolinium, of andere intravasculaire contrastmiddelen
8. bekende eerder doorgemaakte hypergevoeligheidsreacties op perflutren lipide microbolletjes-componenten of een of meer van de niet-actieve ingrediënten van Luminity®/Definity®
9. patiënten met bekend intracraniaal aneurisma, met en/of permanente spiralen, klemmen, shunts, intravasculaire stents, wafeltje, niet- resorbeerbaar durasubstituut, of reservoirs
10. patiënten met een niet-gecontroleerde tussenkomende ziekte of reeds bestaande tegelijk optredende aandoeningen die naar mening van de onderzoeker de implantatie van het hulpmiddel kunnen belemmeren of waardoor de patiënt de behandeling medicatie met SonoCloud minder goed kan doorstaan of hetgeen verwarrend kan werken voor de evaluatie van de klinische trial
11. Patiënten met de volgende aspecten komen niet in aanmerking:
• bekende arteriële hypertensie klasse 3 of hoger zonder adequate controle door medicatie
• bekende of vermoede niet-stabiele actieve of chronische infecties die een systemische behandeling vereisen
• bekende significante cardiale aandoening: rechts-links shunts, instabiele angina, symptomatisch congestief hartfalen, niet-stabiele aritmie
• bekende significante longaandoening: ernstige pulmonale hypertensie (longslagaderdruk > 90 mmHg), niet-gecontroleerde systemisch hypertensie, ARDS (adult respiratory distress syndrome) of pneumonie
• bekende ernstig nierfalen
• bekende ernstige myelosuppressie
• bekende psychiatrische ziekte/sociale situaties waardoor men zich niet kan houden aan de vereisten voor het onderzoek
• een andere ziekte of aandoening waardoor de patiënt zich naar de mening van de behandelende onderzoeker minder goed aan de vereisten voor het onderzoek kan houden of die de veiligheid van de patiënt of de eindpunten van het onderzoek in gevaar zou brengen
• bekende immunodeficiëntie of medicatie (HIV)
• bekende virus- of bacteriële chronische/acute aandoening (potentiële in het bloed voorkomende infecties die kunnen leiden tot meningitis of hersenabces)
12. patiënten onder gerechtelijke bescherming
13. Patiënten met een of meer van de volgende verboden behandelingen:
• elk medisch onderzoeksproduct binnen 30 dagen vóór inclusie en tijdens het onderzoek
• antibiotica met bekende neurotoxiciteit (zoals aminoglycoside, cefalosporine, quinolonen), tenzij substitutie niet mogelijk is,
• niet-absorbeerbaar materiaal (dura-mater-substituut, hemostaticum…)
• elk ander geneesmiddel dat volgens de onderzoeker cerebrale toxiciteit kan veroorzaken door opening van de BBB
• contra-indicaties voor temozolomide
• hypergevoeligheid voor dacarbazine
14. implantatie van de SC-9 niet mogelijk volgens neurochirurg (morfologische patiëntkenmerken (bijv. huiddikte >9mm), die, naar mening van de neurochirurg, implantatie van het hulpmiddel belemmert of kan maken dat de patiënt niet met SonoCloud kan worden behandeld, zouden reden voor uitsluiting zijn)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression Free Survival (PFS) is defined as the time between randomization and disease progression which is the first documented tumor progression (per local Investigator assessment according to the RANO) or death due to any cause. PFS rate at 6, 12, 18 and 24 months and median-PFS will be described.
The “baseline MRI” is performed 1 month after radiotherapy completion. The disease progression is judge on the subsequent MRI performed every 2 months, with comparison to the “baseline MRI”.
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| klinische werkzaamheid op basis van de vergelijking van de mediane PFS (progressievrije overleving), bepaald door plaatselijke onderzoeker, tussen de standaard behandeling met echoscopische opening van de BBB en de standaard behandeling op zich. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- crPFS: central review Progression Free Survival according to RANO criteria assessed by central review
- iPFS: immune Progression Free Survival according to iRANO criteria assessed by local investigator
- OS : Overall Survival
- KPS: Karnofsky Performance Status assessed at all visits until progression by assessed by local investigator or nurses.
- MMSE: Mini Mental Status Examination mean score assessed at randomization, pre-TemoRadiation visit, C1 (baseline after surgery/radiotherapy), C3, C6, M11 and M18 until progression by local investigator or nurses and patient.
- QLQ-C30: The C30 Quality of Life Questionnaire (QLQ) according to the European Organization for Research and Treatment of Cancer will be assessed at randomization, pre-TemoRadiation visit, C1 (baseline after surgery/radiotherapy), C3, C6, M11 and M18 until progression by local investigator or nurses and patient.
- QLQ-BN20PROM: The BN20 Quality of Life Questionnaire (QLQ) according to the European Organization for Research and Treatment of Cancer will be assessed at randomization, pre-TemoRadiation visit, C1 (baseline after surgery/radiotherapy), C3, C6, M11 and M18 until progression by local investigator or nurses and patient.
- PainPROM: Pain score from surgical area according to visual analogic scale will be assessed at randomization, pre-TemoRadiation visit, C1 (baseline after surgery/radiotherapy), C3, C6, M11 and M18 until progression, by local investigator or nurses and patient
- EstheticalPROM: score in self-confidence concerning esthetical dimension of surgical scar will be assessed at randomization, pre-TemoRadiation visit, C1 (baseline after surgery/radiotherapy), C3, C6, M11 and M18 until progression according to esthetical comfort question equivalent to q39 of QLQ-BR23 questionnaire by local investigator or nurses and patient:
Does your skull scar induce any esthetic burden to you?
1-Not at all
2-A little
3-Quite a bit
4-Very much
- Safety confirmation is assessed by the frequency and severity of AE (incidence of AE summarized by system organ class and/or preferred term and severity) based on the Common Terminology Criteria for Adverse Events, version 5.0.
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Secundaire eindpunten:
-crPFS: centrale beoordeling van progressievrije overleving overeenkomstig RANO-criteria bepaald door centrale onafhankelijke beoordeling
-iPFS: immune progressievrije overleving overeenkomstig iRANO-criteria bepaald door plaatselijke onderzoeker
-OS: Overall Survival (totale overlevingscijfers)
-KPS: Karnofsky-prestatiestatus bepaald bij alle bezoeken tot progressie.
-MMSE: Mini Mental Status Examination gemiddelde score bepaald bij randomisering, pre-TemoRadiation bezoek, C1 (uitgangswaarde na de operatie/bestraling), C3, C6, M11 en M18 tot progressie.
-QLQ-C30: de C30-vragenlijst over levenskwaliteit (QLQ) wordt bepaald bij gebruik van de Europese organisatie voor research en de behandeling van kanker, bij de randomisering, bij het pre-TemoRadiation bezoek, C1 (uitgangswaarde na de operatie/radiotherapie/bestraling), C3, C6, M11 en de M18 tot uitbreiding.
-QLQ-BN20PROM: de BN20-vragenlijst over levenskwaliteit (QLQ) wordt bepaald bij gebruik van de Europese organisatie voor research en de behandeling van kanker, bij de randomisering, bij het pre-TemoRadiation bezoek, C1 (uitgangswaarde na de operatie/radiotherapie/bestraling), C3, C6, M11 en M18 tot progressie.
-PijnPROM: pijnscore van het operatiegebied bij randomisering, pre-TemoRadiation bezoek, C1 (uitgangswaarde na de operatie/bestraling), C3, C6, M11 en M18 tot progressie. Dit wordt bepaald met behulp van een visuele analoge schaal.
-EsthetischePROM: score voor zelfvertrouwen met betrekking tot esthetische afmetingen van operatielitteken bij randomisering, pre-TemoRadiation bezoek, C1 (uitgangswaarde na de operatie/bestraling), C3, C6, M11 en M18 tot progressie met behulp van vraag over esthetisch comfort gelijk aan v39 van QLQ-BR23-vragenlijst.
-De bevestiging van de veiligheid wordt bepaald door de frequentie en de ernst van AE (incidentie van complicaties, samengevat per systeemorgaanklasse en/of voorkeursterm en ernst) op basis van de Common Terminology Criteria for Adverse Events, versie 5.0.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Switzerland |
| Belgium |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 44 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 54 |
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