Neoplasms

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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

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Early Temozolomide (TMZ) Concomitant TMZ Adjuvant TMZ Prolonged TMZ

Concomitant Temozolomide (TMZ) Adjuvant TMZ

Early Temozolomide (TMZ) 1 cycle (150 mg/m²/ day X 5 days, per os) Started between day 2 and 15 after surgery/ biopsy RT (60 Gy, 2 Gy/fraction) + concomitant TMZ (75 mg/m2/day X 42 days, per os) Started between W4 and W6 after surgery/ biopsy Adjuvant TMZ 6 cycles (150-200 mg/m2 X 5 days /month, per os) Started 1 month after the end of the concomitant TMZ Prolonged TMZ Until progression, intolerance, patient's or physician's decision (150-200 mg/m2 every 4 weeks, per os)

Intensified protocol

RT (60 Gy, 2 Gy/fraction) + concomitant Temozolomide (75 mg/m2/day X 42 days, per os) Started between W4 and W6 after surgery/ biopsy Adjuvant TMZ 6 cycles (150-200 mg/m2 X 5 days /month, per os) Started 1 month after the end of the concomitant TMZ

Stupp protocol

Marie VANSEYMORTIER

BOONE Mathieu, MD, PhD

Alexandre COUTTE, MD

Etienne FESSART, MD

Christine DESENCLOS, MD

Mathieu BOONE, MD

Soraya RAMDANE, MD

Farid BELKHIR, MD

Iona HRAB, MD

Lien BEKAERT, MD

Julien GEFFRELOT, MD

Dinu STEFAN, MD

Evelyne EMERY, MD

David Hassanein BERRO, MD

Xavier DURANDO, MD

Maureen BERNADACH, MD

Guillaume DUPIC, MD

Toufic KHALIL, MD

Guido AHLE, MD

Claude GAULTIER, MD

David ATLANI, MD

Jimmy VOIRIN, MD

François GHIRINGELLI, MD, PhD

Julie VINCENT, MD

Jean-François GUION, MD

Gilles TRUC, MD

Walid FARAH, MD

Julien PAVILLET, MD

Coralie FRENOUX, MD

Emmanuel DE SCHLICHTING, MD

Elise DELUCHE, MD

François CAIRE, MD

Pierre CLAVERE, MD

Sandrine LAVAU-DENES, MD

Alice BONNEVILLE-LEVARD, MD

Didier FRAPPAZ, MD, PhD

Marie Pierre SUNYACH, MD

Coralie MONCHARMONT, MD

Ronan TANGUY, MD

Anne DURAND, MD

Olivier CHINOT, MD

Maryline BARRIE, MD

Chantal CAMPELLO, MD

Gregorio PETRIRENA, MD

Emeline TABOURET, MD

Xavier MURACCIOLE, MD

Henry DUFOUR, MD

Thomas GRAILLON, MD

Pierre Hugues ROCHE, MD

Michel FABBRO, MD, PhD

Marie CHASSIROUX, MD

Christine KERR, MD

Amélie DARLIX, MD

Luc BAUCHET, MD

Luc TAILLANDIER, MD

Patrick BEAUCHESNE, MD

Fabien RECH, MD

Guillaume VOGIN, MD

Véronique BOURG, MD

Christine LEBRUN-FRENAY, MD

Fabien ALMAIRAC, MD

Khe HOANG XUAN, MD

Ahmed IDBAIH, MD

Florence LAIGLE-DONADEY, MD

Agusti ALENTORN, MD

Caroline DEHAIS, MD

Caroline HOUILLIER, MD

Dimitri PSIMARAS, MD

Loïc FEUVRET, MD

Alexandre CARPENTIER, MD

Claudia RIZZO, MD

Denis NGUYEN, MD

Emmanuel MANDONNET, MD

Carole RAMIREZ, MD

Romain RIVOIRARD, MD

Jane Chloé TRONE, MD

Nicolas MAGNE, MD

François VASSAL, MD

Marie Jeannette MOTUO-FOTSO, MD

Roland SCHOTT, MD

Georges NOEL, MD, PhD

Hélène CEBULA, MD

Ilyess ZEMMOURA, MD

Christophe DESTRIEUX, MD

Bérengère NARCISO, MD

Sophie CHAPET, MD

Florence LEFRANC, MD

Bruno CHAUFFERT, MD

Due to conflicting data on the optimal moment to start TMZ chemotherapy and the impact of prolongation of the adjuvant phase with TMZ, the ANOCEF (Association des Neuro-Oncologues d'Expression Francophone) group proposes this randomized trial comparing an intensified arm (early TMZ and extended adjuvant TMZ until toxicity, progression or patient refusal) versus the classical EORTC regimen as control (RT and concomitant TMZ started 4-6 weeks after surgery followed by a number of adjuvant TMZ cycles strictly limited to 6) for primary GBM adult patients.

Treatment Intensification With Temozolomide in Adults With a Glioblastoma

Phase III Randomised Trial Evaluating Treatment Intensification With Temozolomide in Adults With a Glioblastoma

time interval from randomization to death whatever the cause

from randomization until disease progression - reported and graded using the NCI-CTCAE v5.0 classification

time interval from randomization to the first occurrence of progression according to RANO criteria as assessed by the treating physician, or death whatever the cause

Association de Neuro-Oncologues d'Expression Francaise

Erasme University Hospital

Centre Oscar Lambret

Nervous System Diseases

Brain Neoplasms

Antineoplastic Agents, Alkylating

Alkylating Agents

Standard of Care + 15 Ultrasound BBB opening

daily temozolomide (TMZ) during Radiation, followed by 6 months of adjuvant TMZ (5 days/months) with 6 concomitant Blood Brain Barrier opening sessions by ultrasound

+ 9 Blood Brain Barrier opening sessions by ultrasound without any associated drug

SonoCloud-9 (SC9) device

daily temozolomide (TMZ) during Radiation, followed by 6 months of adjuvant TMZ (5 days/months)

Temozolomide according Stupp protocol

Ahmed IDBAIH, MD, PhD

Alexandre CARPENTIER, MD, PhD

Steve DE VLEESCHOUWER, MD, PhD

Philippe MENEI, MD, PhD

Charlotte BRONNIMANN, MD

François DUCRAY, MD, PhD

Olivier CHINOT, MD, PhD

Andreas HOTTINGER, MD, PhD

Glioblastoma (GBM) is an aggressive cancer with a progression-free survival (PFS) of 7 months and an overall survival (OS) of 15 months. Many therapeutic approaches have failed to improve the prognosis of patients to date. One of the main reasons is the presence of blood brain barrier (BBB) which limits therapeutic agents uptake in the brain. GBM is also considered to have a "cold" (unresponsive) immunological microenvironment due to factors released by the tumor and the presence of BBB limiting the transit of immune cells from the systemic circulation. Therefore, by-passing the BBB appears as a promising strategy.

The objective of the Phase II clinical trial, SonoFIRST, is to evaluate if the use of therapeutic ultrasound device, sonoCloud-9 (SC9) could improve the progression free survival of newly diagnosed GBM patients, treated by concurrent temoradiation and adjuvant temozolomide. The transient opening of the BBB by ultrasound with the SonoCloud-9 (SC9) device, predicts the increase in the penetration of temozolomide (TMZ) into the brain and the stimulation of cerebral immunity with the prospect of improving the survival of 160,000 new brain tumor patients each year in Europe and the United States.

This will be an open-label, Phase 2, multicenter, double arm, randomized, interventional trial that will evaluate primarily the clinical efficacy of the device and will be to compare Progression Free Survival (PFS) between the standard of care treatment with concomitant ultrasound BBB opening versus standard of care alone. Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Currently, prognosis is very poor, with a survival of about 15 months with current therapies. Although intensive treatments combining surgery, radiotherapy and chemotherapy, the prognosis of GBM patients remains poor. New treatment strategies are urgently needed.

In the brain, the presence of the blood-brain barrier (BBB) limits the uptake of therapeutic agents. To encounter this BBB issue, Professor Alexandre Carpentier and his team developed an ultrasound medical device (SonoCloud), implanted in the skull during surgery. This highly innovative technique temporarily permeates the BBB, increasing drug delivery to the brain by five times. The SonoCloud, a low-intensity pulsed ultrasound device developed by CarThera, is one of the major innovations in this field, as shown by the encouraging results obtained in studies in recurrent GBM.

The expected benefits of using the SonoCloud-9 experimental device prior to TMZ chemotherapy are the stabilization or reduction of GBM tumor volume on the one hand, and stabilization or improvement of the patient's neurological status on the other hand.

Participation in the clinical trial will contribute to a better understanding of the safety and efficacy of opening the BBB. It will be possible to determine whether the BBB opening using low-intensity pulsed ultrasound can be effective in treating GBM, in addition to the standard of care protocol.

Innovative SonoCloud-9 Device for Blood Brain Barrier Opening in First Line Temozolomide Glioblastoma Patients.

Multisite Open-label Randomized Phase II Clinical Trial in Newly Diagnosed Glioblastoma Treated by Concurrent Temoradiation and Adjuvant Temozolomide +/- Ultrasound-induced Blood Brain Barrier Opening.

Progression will be assessed by local investigator according to the RANO criteria

OS is defined as the time from the date of randomization to the date of death due to any cause.

The central review Progression Free Survival is evaluated by a central assessment (independent imaging core lab) at the end of study and is defined as the time between randomization and tumor progression which is the first documented tumor progression according to the radiological RANO criteria or death due to any cause

The iPFS is evaluated according to iRANO (immune-related modifications / pseudo-progression ) criteria assessed by local investigator

Quality of Life Questionnaire (QLQ) according to the European Organization for Research and Treatment of Cancer will be assessed by mean scores of the EORTC QLQ C-30 questionnaire (30 questions, score from 30 to 126) by local investigator or nurses and patient

Quality of Life Questionnaire (QLQ) according to the European Organization for Research and Treatment of Cancer will be assessed will be assessed by means of the EORTC BN20 questionnaire (30 questions, score from 1 to 80) by local investigator or nurses and patient

Mini Mental Status Examination (30-point questionnaire, score from 1 to 30) mean score assessed by local investigator or nurses and patient

pain score from surgical area using visual analogic scale (score 0 to 10. Zero indicates the absence of pain, while 10 represents the most intense pain possible).

score in self-confidence concerning esthetical dimension of surgical scar using esthetical comfort question equivalent to q39 of QLQ-BR23 questionnaire: 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 of efficient blood brain barrier opening procedure with the SonoCloud-9 system. Safety confirmation is assessed by the frequency and severity of Adverse Events (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.

Assistance Publique - Hôpitaux de Paris

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Treatment Intensification With Temozolomide in Adults With a Glioblastoma	NCT03663725	Glioblastoma	Intensified pro... Stupp protocol	18 Years -	Centre Oscar Lambret
Innovative SonoCloud-9 Device for Blood Brain Barrier Opening in First Line Temozolomide Glioblastoma Patients.	NCT04614493	Initial Radiolo... Initial Radiolo... Eligible for th...	SonoCloud-9 (SC... Temozolomide ac...	18 Years - 70 Years	Assistance Publique - Hôpitaux de Paris

Spots Global Cancer Trial Database for stupp protocol