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出境医 / 临床实验 / Safety and Efficacy of Sonocloud Device Combined With Nivolumab in Brain Metastases From Patients With Melanoma (SONIMEL01)

Safety and Efficacy of Sonocloud Device Combined With Nivolumab in Brain Metastases From Patients With Melanoma (SONIMEL01)

Study Description
Brief Summary:

Anti PD-1 monoclonal antibodies (nivolumab and pembrolizumab) alone or in association with antiCTLA4 (Ipilimumab) are established as indisputable treatment of metastatic melanoma, with unprecedented overall survival, and are indicated for first-line treatment including patients with BRAF mutation. Given their high molecular weight, their penetration in the brain sanctuary is uncertain and relies on disruption of the Blood Brain Barrier (BBB) which occurs occasionally.

SonoCloud® is an implantable device delivering low intensity pulsed UltraSound (US). Along with systemic injection of an US resonator, SonoCloud® demonstrated safe and efficient at repetitively opening the BBB. The investigators anticipate that BBB opening could help at increasing brain penetration of monoclonal antibodies and potentially boosting immunity in the brain. This could translate in controlling brain disease with the same magnitude as for extra-cranial disease. This would also open avenues for optimizing the treatment of brain metastases in combination with checkpoint inhibitors in many other cancers.


Condition or disease Intervention/treatment Phase
Melanoma Metastatic Melanoma Device: SONOCLOUD Drug: Nivolumab Injection Phase 1 Phase 2

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Blood Brain Barrier Opening With Implantable Device Sonocloud® Combined With Nivolumab Used Alone or an Association With Ipilimumab in Brain Metastases From Patients With Malignant Melanoma
Actual Study Start Date : October 24, 2019
Estimated Primary Completion Date : January 1, 2022
Estimated Study Completion Date : July 5, 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: low intensity pulsed UltraSound
SonoCloud® is an active implantable device (implantation duration until 16 weeks at maximum after inclusion). SonoCloud® delivers low intensity pulsed UltraSound (US). Along with systemic injection of an US resonator, SonoCloud® demonstrated safe and efficient at repetitively opening the BBB.
 Device: SONOCLOUD

The SonoCloud System is an active implantable medical. The SonoCloud is indicated to locally and transiently increase the permeability of the blood brain barrier to facilitate the passage of substances into the cerebral parenchyma.

The SonoCloud System consists of :

  1. an implantable ultrasound transducer,
  2. a needle connection device,
  3. an external radiofrequency generator, and
  4. an ultrasound resonator. The SonoCloud® is designed to be fixed to the skull. The device is placed in a burr hole or in place of a bone flap and ultrasound energy is delivered directly to the brain tissue, without traversing the skull bone. The device is activated by connecting the implant to the external generator system using the transdermal needle. Once connected to the external generator, the implant delivers low-intensity pulsed UltraSound (US) for duration of 120-270 seconds. A total of 3 US dose levels will be evaluated (0.78, 0.9 and 1.03 MPa).

Drug: Nivolumab Injection
Nivolumab (flat dose: 240mg, 30 minutes infusion)
Outcome Measures
Primary Outcome Measures :
  1. Most Successful Dose (MSD) [ Time Frame: Week 6 ]

    Dose with the highest probability of BBB opening efficacy without toxicity directly related to the ultrasound emission.

    Toxicity evaluation:

    Safety will be assessed clinically and using brain Magnetic resonance imaging (MRI). An electroencephalogram will be performed only if clinically needed. Dose-Limiting-Toxicities (DLTs) evaluation will be done during the first 4 weeks of treatment for Nivolumab treatment and 6 weeks for Nivolumab + Ipilimumab treatment. DLTs directly related to the ultrasound emission are defined as occurrence of an adverse effect during the first administration of treatment, such as: :

    • neurological deficit within 2 days after the procedure and persistent at day 15;
    • localized brain edema not preexisting to the procedure;
    • occurrence of cerebral median line deviation not controlled by routine treatment or requiring salvage surgical procedure;
    • partial epilepsy induced or enhanced after the procedure and not control


Secondary Outcome Measures :
  1. Best overall response rate, M3 [ Time Frame: Month 3 ]

    Best clinical objective response (BOR) (defined with the Response assessment in neuro-oncology criteria (RANO) and immunotherapy response assessment for neuro-oncology (iRANO) and the response evaluation criteria in solid tumours (RECIST) version 1.1 and the Immune-Related Response Criteria during the 3 first months

    RANO : Wen, Patrick Y., et al. "Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group." J Clin Oncol 28.11 (2010): 1963-1972.

    iRANO : Okada, Hideho, et al. "Immunotherapy response assessment in neuro-oncology: a report of the RANO working group." The Lancet Oncology 16.15 (2015): e534-e542.


  2. Overall response rate, M3 [ Time Frame: Month 3 ]
    Clinical objective response (defined with the RANO and iRANO and the RECIST version 1.1 and the Immune-Related Response Criteria) during the 3 first months

  3. Best intracranial overall response rate (BICORR), M3 [ Time Frame: Month 3 ]
    Clinical efficacy will be assessed using TEP/TDM Scans (extracranial lesions) and MRI (intracranial metastases) at Month 3

  4. Intracranial overall response rate (ICORR), M3 [ Time Frame: Month 3 ]
    Clinical efficacy will be assessed using TEP/TDM Scans (extracranial lesions) and MRI (intracranial metastases) at Month 3

  5. Best extracranial overall response rate (BECORR), M3 [ Time Frame: Month 3 ]
    Best clinical objective response rate not taking account BICORR

  6. Extracranial overall response rate (BECORR), M3 [ Time Frame: Month 3 ]
    Clinical objective response not taking account ICORR


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with histologically confirmed metastatic melanoma
  • Patients must have recovered from all side effects of their most recent systemic or local treatment for metastatic melanoma (grade ≤ 1).
  • At least one measurable brain metastasis between 5 mm and 35 mm in diameter, not previously treated with surgery and/or radiosurgery and located less than 5 cm from the skull
  • Patients may have received -or not- prior radiosurgery and/or surgery for brain metastases; if they have received prior local treatment, they must have at least 1new RANO and RECIST assessable brain metastases.
  • BRAF status wild type or mutated (and in that case previous treatment with BRAF inhibitor and MEK inhibitor allowed)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
  • Age >18 year
  • Hemoglobin ≥10g/dl
  • Platelets ≥ 100000mm3
  • Neutrophils ≥1500/mm3
  • Creatinine Clearance ≥ 50ml/mn
  • AST <3N
  • ALT<3N
  • Total bilirubin <1.5N
  • Alkaline phosphatase <3N
  • INR < 1.5
  • Prothrombin ≥70%
  • TCA <1.2
  • No Hepatocellular insufficiency
  • No unhealed wound on the head
  • No allergy to poly isoprene
  • Signed informed consent
  • Patient with health insurance coverage
  • Life expectancy > 3 months

Exclusion Criteria:

  • Patient previously treated by antiPD1 (except adjuvant antiPD1 therapy)
  • Ocular melanoma
  • Symptomatic or diffuse leptomeningeal involvement.
  • Symptomatic hemorrhagic brain metastases.
  • Symptoms of incoercible intracranial pressure; patients receiving corticosteroids and patients presenting intermittent seizures can be enrolled if they have a stable dose of corticosteroids (≤ 30mg/day corticotherapy) and anti-epileptic treatment since at least 2 weeks before enrolment.
  • Indication for urgent neurosurgery or radiotherapy
  • Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured or stage I untreated Chronic Lymphoid Leukemia.
  • Known human immunodeficiency viruses (HIV) infection and any ongoing infectious disease or significant background.
  • Concurrent administration of any anticancer therapies other than those administered in this study.
  • Treatment with any cytotoxic and/or investigational drug, antiCTLA4 or targeted therapy ≤ 4 weeks or <5 half lives for targeted therapies or chemotherapy, prior to day 1 of study.
  • Prior whole brain radiotherapy
Contacts and Locations

Contacts
Layout table for location contacts
Contact: LEBBE Celeste, MD, PhD 142494679 ext +33 celeste.lebbe@aphp.fr
Contact: Matthieu RESCHE-RIGON, MD PhD 142499742 ext +33 matthieu.resche-rigon@univ-paris-diderot.fr

Locations
Layout table for location information
France
Saint-Louis Hospital Recruiting
Paris, France, 75010
Contact: Celeste LEBBE, MD-PHD    142494679 ext +33    celeste.lebbe@aphp.fr   
Contact: El-Mountacer el-abbassi    142499742 ext +33    el-abbassi.el-mountacer@univ-paris-diderot.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Tracking Information
First Submitted Date  ICMJE July 1, 2019
First Posted Date  ICMJE July 16, 2019
Last Update Posted Date August 20, 2020
Actual Study Start Date  ICMJE October 24, 2019
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 15, 2019) 		Most Successful Dose (MSD) [ Time Frame: Week 6 ]
Dose with the highest probability of BBB opening efficacy without toxicity directly related to the ultrasound emission. Toxicity evaluation: Safety will be assessed clinically and using brain Magnetic resonance imaging (MRI). An electroencephalogram will be performed only if clinically needed. Dose-Limiting-Toxicities (DLTs) evaluation will be done during the first 4 weeks of treatment for Nivolumab treatment and 6 weeks for Nivolumab + Ipilimumab treatment. DLTs directly related to the ultrasound emission are defined as occurrence of an adverse effect during the first administration of treatment, such as: :
  • neurological deficit within 2 days after the procedure and persistent at day 15;
  • localized brain edema not preexisting to the procedure;
  • occurrence of cerebral median line deviation not controlled by routine treatment or requiring salvage surgical procedure;
  • partial epilepsy induced or enhanced after the procedure and not control
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
  • Best overall response rate, M3 [ Time Frame: Month 3 ]
    Best clinical objective response (BOR) (defined with the Response assessment in neuro-oncology criteria (RANO) and immunotherapy response assessment for neuro-oncology (iRANO) and the response evaluation criteria in solid tumours (RECIST) version 1.1 and the Immune-Related Response Criteria during the 3 first months RANO : Wen, Patrick Y., et al. "Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group." J Clin Oncol 28.11 (2010): 1963-1972. iRANO : Okada, Hideho, et al. "Immunotherapy response assessment in neuro-oncology: a report of the RANO working group." The Lancet Oncology 16.15 (2015): e534-e542.
  • Overall response rate, M3 [ Time Frame: Month 3 ]
    Clinical objective response (defined with the RANO and iRANO and the RECIST version 1.1 and the Immune-Related Response Criteria) during the 3 first months
  • Best intracranial overall response rate (BICORR), M3 [ Time Frame: Month 3 ]
    Clinical efficacy will be assessed using TEP/TDM Scans (extracranial lesions) and MRI (intracranial metastases) at Month 3
  • Intracranial overall response rate (ICORR), M3 [ Time Frame: Month 3 ]
    Clinical efficacy will be assessed using TEP/TDM Scans (extracranial lesions) and MRI (intracranial metastases) at Month 3
  • Best extracranial overall response rate (BECORR), M3 [ Time Frame: Month 3 ]
    Best clinical objective response rate not taking account BICORR
  • Extracranial overall response rate (BECORR), M3 [ Time Frame: Month 3 ]
    Clinical objective response not taking account ICORR
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of Sonocloud Device Combined With Nivolumab in Brain Metastases From Patients With Melanoma
Official Title  ICMJE Safety and Efficacy of Blood Brain Barrier Opening With Implantable Device Sonocloud® Combined With Nivolumab Used Alone or an Association With Ipilimumab in Brain Metastases From Patients With Malignant Melanoma
Brief Summary

Anti PD-1 monoclonal antibodies (nivolumab and pembrolizumab) alone or in association with antiCTLA4 (Ipilimumab) are established as indisputable treatment of metastatic melanoma, with unprecedented overall survival, and are indicated for first-line treatment including patients with BRAF mutation. Given their high molecular weight, their penetration in the brain sanctuary is uncertain and relies on disruption of the Blood Brain Barrier (BBB) which occurs occasionally.

SonoCloud® is an implantable device delivering low intensity pulsed UltraSound (US). Along with systemic injection of an US resonator, SonoCloud® demonstrated safe and efficient at repetitively opening the BBB. The investigators anticipate that BBB opening could help at increasing brain penetration of monoclonal antibodies and potentially boosting immunity in the brain. This could translate in controlling brain disease with the same magnitude as for extra-cranial disease. This would also open avenues for optimizing the treatment of brain metastases in combination with checkpoint inhibitors in many other cancers.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Melanoma
  • Metastatic Melanoma
Intervention  ICMJE
  • Device: SONOCLOUD

    The SonoCloud System is an active implantable medical. The SonoCloud is indicated to locally and transiently increase the permeability of the blood brain barrier to facilitate the passage of substances into the cerebral parenchyma.

    The SonoCloud System consists of :

    1. an implantable ultrasound transducer,
    2. a needle connection device,
    3. an external radiofrequency generator, and
    4. an ultrasound resonator. The SonoCloud® is designed to be fixed to the skull. The device is placed in a burr hole or in place of a bone flap and ultrasound energy is delivered directly to the brain tissue, without traversing the skull bone. The device is activated by connecting the implant to the external generator system using the transdermal needle. Once connected to the external generator, the implant delivers low-intensity pulsed UltraSound (US) for duration of 120-270 seconds. A total of 3 US dose levels will be evaluated (0.78, 0.9 and 1.03 MPa).
  • Drug: Nivolumab Injection
    Nivolumab (flat dose: 240mg, 30 minutes infusion)
Study Arms  ICMJE Experimental: low intensity pulsed UltraSound
SonoCloud® is an active implantable device (implantation duration until 16 weeks at maximum after inclusion). SonoCloud® delivers low intensity pulsed UltraSound (US). Along with systemic injection of an US resonator, SonoCloud® demonstrated safe and efficient at repetitively opening the BBB.
Interventions:
  • Device: SONOCLOUD
  • Drug: Nivolumab Injection
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 15, 2019) 		21
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 5, 2023
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with histologically confirmed metastatic melanoma
  • Patients must have recovered from all side effects of their most recent systemic or local treatment for metastatic melanoma (grade ≤ 1).
  • At least one measurable brain metastasis between 5 mm and 35 mm in diameter, not previously treated with surgery and/or radiosurgery and located less than 5 cm from the skull
  • Patients may have received -or not- prior radiosurgery and/or surgery for brain metastases; if they have received prior local treatment, they must have at least 1new RANO and RECIST assessable brain metastases.
  • BRAF status wild type or mutated (and in that case previous treatment with BRAF inhibitor and MEK inhibitor allowed)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
  • Age >18 year
  • Hemoglobin ≥10g/dl
  • Platelets ≥ 100000mm3
  • Neutrophils ≥1500/mm3
  • Creatinine Clearance ≥ 50ml/mn
  • AST <3N
  • ALT<3N
  • Total bilirubin <1.5N
  • Alkaline phosphatase <3N
  • INR < 1.5
  • Prothrombin ≥70%
  • TCA <1.2
  • No Hepatocellular insufficiency
  • No unhealed wound on the head
  • No allergy to poly isoprene
  • Signed informed consent
  • Patient with health insurance coverage
  • Life expectancy > 3 months

Exclusion Criteria:

  • Patient previously treated by antiPD1 (except adjuvant antiPD1 therapy)
  • Ocular melanoma
  • Symptomatic or diffuse leptomeningeal involvement.
  • Symptomatic hemorrhagic brain metastases.
  • Symptoms of incoercible intracranial pressure; patients receiving corticosteroids and patients presenting intermittent seizures can be enrolled if they have a stable dose of corticosteroids (≤ 30mg/day corticotherapy) and anti-epileptic treatment since at least 2 weeks before enrolment.
  • Indication for urgent neurosurgery or radiotherapy
  • Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured or stage I untreated Chronic Lymphoid Leukemia.
  • Known human immunodeficiency viruses (HIV) infection and any ongoing infectious disease or significant background.
  • Concurrent administration of any anticancer therapies other than those administered in this study.
  • Treatment with any cytotoxic and/or investigational drug, antiCTLA4 or targeted therapy ≤ 4 weeks or <5 half lives for targeted therapies or chemotherapy, prior to day 1 of study.
  • Prior whole brain radiotherapy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: LEBBE Celeste, MD, PhD 142494679 ext +33 celeste.lebbe@aphp.fr
Contact: Matthieu RESCHE-RIGON, MD PhD 142499742 ext +33 matthieu.resche-rigon@univ-paris-diderot.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04021420
Other Study ID Numbers  ICMJE P160950J
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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