| 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. |
Les patients atteints d'un glioblastome nouvellement diagnostiqué (IDH non mutée) au moment du diagnostic radiologique initial sont admissibles à la résection de la tumeur et aux soins standard, c’est-à-dire la TémoRadiation concomitante et la phase adjuvante avec le TMZ.
Les ultrasons induisent l’ouverture transitoire de la Barrière Hémato-Encéphalique (BHE) permettant d’augmenter la pénétration du témozolomide (TMZ) dans le cerveau et de stimuler l'immunité cérébrale. |
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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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Patients atteints d'un glioblastome nouvellement diagnostiqué (IDH non mutée) éligibles à la résection de la tumeur, aux soins standards: la TémoRadiation concomitante + la phase adjuvante avec TMZ.
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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. |
| efficacité clinique basée sur la comparaison de la médiane de la PFS (survie sans progression) évaluée par l'investigateur local entre le traitement standard de soins avec ouverture de la BHE par ultrasons et le traitement de soin standard seul. |
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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. |
-Amélioration de la survie,
-Préservation de la qualité de vie des patients,
-Préservation intellectuelle des patients,
-Confirmation de la sécurité de la procédure d'ouverture de la BHE avec le système SonoCloud-9 |
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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. |
Étude ancillaire sur les biomarqueurs:
Objectif: analyse de biomarqueurs tumoraux comme suivi biologique de l'efficacité du traitement ou de la progression de la tumeur
p et impact de l'ouverture de la barrière hémato-encéphalique induite par ultrasons sur une telle surveillance. |
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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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• IRM cérébral avec suspicion de GBM nouvellement diagnostiqué IDH non muté
• Tumeur supratentoriale
• Extension de la tumeur ≤ 7cm (T1W)
• Patients admissibles pour une résection chirurgicale partielle ou complète et pour la TemoRadiation suivie du TMZ adjuvant (selon le protocole de soin standard actuel Stupp)
• Patient ≥ 18 ans et ≤ 70 ans
• KPS ≥70
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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-indication pour la sonication
1. Les patients atteints d'une tumeur multifocale (à moins qu'elles ne soient toutes localisées dans une zone de 70 mm de diamètre accessible au champ ultrasonore) ou situées dans la fosse tumorale postérieure,
2. Patient présentant des anomalies FLAIR diffuses attribuables à la gliomatose,
3. Patients présentant des signes de pression intracrânienne non contrôlée,
4. Patients souffrant d'épilepsie non contrôlée,
5. Les patients ayant besoin de poursuivre un traitement antiplaquettaire ou antithrombotique,
6. Femmes enceintes ou qui allaitent (test de grossesse sanguin),
7. Patients présentant des contre-indications à l'IRM ou une sensibilité/allergie connue au gadolinium ou à d'autres agents de contraste intravasculaire,
8. Antécédents connus de réactions d'hypersensibilité aux composants des microsphères de lipides de perflutrène ou à l'un des ingrédients inactifs de Luminity®/Definity®,
9. Patients présentant un anévrisme intracrânien connu, avec et/ou sans spirales, clips, shunts, stents intravasculaires, wafer, substitut de dure-mère non résorbable ou reservoirs,
10. Les patients souffrant d'une maladie intercurrente non contrôlée ou de toute comorbidité préexistante qui, de l'avis de l'investigateur, peut empêcher l'implantation du dispositif ou peut nuire à la capacité du patient à recevoir le traitement avec le SonoCloud ou peut être créer pour l'évaluation de l'essai clinique,
11. Les patients présentant les caractéristiques suivantes ne sont pas éligibles :
• Hypertension artérielle connue de grade 3 ou supérieur sans contrôle adéquat des medicaments,
• Infections connues ou suspectées ou infections chroniques instables, nécessitant un traitement systémique,
• Maladies cardiaques importantes connues : shunts droite-gauche, angine de poitrine instable, insuffisance cardiaque congestive symptomatique, arythmie cardiaque instable,
• Maladie pulmonaire importante connue : hypertension pulmonaire grave (pression artérielle pulmonaire > 90 mmHg), hypertension systémique non contrôlée, syndrome de détresse respiratoire de l'adulte ou pneumonie
• Insuffisance rénale grave connue,
• Myélosuppression grave connue,
• Maladies psychiatriques/ situations sociales connues qui limiteraient le respect des exigences de l'études,
• Toute autre maladie ou affection qui, selon l'investigateur local, interférerait avec la conformité à l'étude ou compromettrait la sécurité du patient ou les résultats de l'étude,
• Maladie ou traitements connus de l'immunodéficience (VIH),
• Maladies chroniques/actives virales ou bactériennes connues (infections sanguines potentielles pouvant entraîner une méningite ou un abcès cérébral),
12. Patients sous protection judiciaire,
13. Les patients qui suivent un traitement prohibé tel que:
• Tout médicament expérimental dans les 30 jours précédant l'inclusion et pendant l'étude,
• Antibiotiques dont la neurotoxicité est connue (par exemple, aminoglycosides, céphalosporine, quinolones), à moins que la substitution ne soit pas possible,
• Matériel non-absorbable (substitut de la dure-mère, agent hémostatique...)
• Tout autre médicament qui, selon l'investigateur, causerait une toxicité cérébrale due à l'ouverture du BHE,
• Contre-indications à la prise du temozolomide,
• Hypersensibilité à la dacarbazine,
• Implantation du SC-9 impossible selon le neurochirurgien (toute caractéristique morphologique du patient (par exemple, une épaisseur de peau >9mm) qui, de l'avis des neurochirurgiens, empêche l'implantation de l'appareil ou peut nuire à la capacité du patient à recevoir un traitement avec le SonoCloud, serait exclue).
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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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| Critère d'évaluation principal: la PFS est définie entre la randomisation et la progression de la maladie qui est définie comme la première progression tumorale (selon l'évaluation de l'investigateur local selon les critères RANO) ou le décès, quelle qu'en soit la cause. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| 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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- crPFS: central review Progression Free Survival : survie sans progression selon les critères RANO évalués par lecture centralisée
- iPFS: immune Progression Free Survival : immune-survie sans progression selon les critères RANO immun, évalués par l’investigateur local
- OS: Overall Survival :Survie Globale
- KPS: L’indice de performance de Karnofsky est évalué à toutes les visites jusqu'à la progression
- MMSE: Mini examen de l'état mental: score moyen évalué à la randomization, lors de la visite pré-TemoRadiation, C1 (ligne de base après chirurgie/radiothérapie), C3, C6, M11 et M18 jusqu'à la progression.
- QLQ-C30: le questionnaire C30 sur la qualité de vie (QLQ) sera évalué à l'aide de l'Organisation européenne pour la recherche et le traitement du cancer, à la randomization, lors de la visite pré-TemoRadiation, C1 (ligne de base après chirurgie/radiothérapie), C3, C6, M11 et M18 jusqu'à la progression.
- QLQ-BN20PROM: le questionnaire BN20 sur la qualité de vie (QLQ) sera évalué à l'aide de l'Organisation européenne pour la recherche et le traitement du cancer, à la randomization, lors de la visite pré-TemoRadiation, C1 (ligne de base après chirurgie/radiothérapie), C3, C6, M11 et M18 jusqu'à la progression.
- DouleurPROM: score de douleur de la zone chirurgicale au moment de la randomisation, visite pré-TemoRadiation, C1 (ligne de base après chirurgie/radiothérapie), C3, C6, M11 et M18 jusqu'à la progression. Ce score sera évalué à l'aide d'une échelle visuelle analogique.
- EsthetiquePROM: score de confiance en soi concernant la dimension esthétique de la cicatrice chirurgicale à la randomisation, à la visite pré-TemoRadiation, C1 (ligne de base après chirurgie/radiothérapie), C3, C6, M11 et M18 jusqu'à la progression en utilisant la question équivalente à la q39 de confort esthétique du questionnaire QLQ-BR23.
- Confirmation de la sûreté est évalué en fonction de la fréquence et de la gravité des EI (incidence des EI résumée par classe des parties du système et/ou par terme et gravité) sur la base des Critères de terminologie commune pour les événements indésirables, version 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 |
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| 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 | 7 |
| 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 |
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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 | 30 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 30 |
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