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

Primary Purpose

Melanoma, Metastatic Melanoma

Status
Unknown status
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
SONOCLOUD
Nivolumab Injection
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Melanoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Saint-Louis HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

low intensity pulsed UltraSound

Arm Description

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.

Outcomes

Primary Outcome Measures

Most Successful Dose (MSD)
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

Best overall response rate, M3
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
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
Clinical efficacy will be assessed using TEP/TDM Scans (extracranial lesions) and MRI (intracranial metastases) at Month 3
Intracranial overall response rate (ICORR), M3
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
Best clinical objective response rate not taking account BICORR
Extracranial overall response rate (BECORR), M3
Clinical objective response not taking account ICORR

Full Information

First Posted
July 1, 2019
Last Updated
August 19, 2020
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT04021420
Brief Title
Safety and Efficacy of Sonocloud Device Combined With Nivolumab in Brain Metastases From Patients With Melanoma
Acronym
SONIMEL01
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Unknown status
Study Start Date
October 24, 2019 (Actual)
Primary Completion Date
January 1, 2022 (Anticipated)
Study Completion Date
July 5, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma, Metastatic Melanoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
low intensity pulsed UltraSound
Arm Type
Experimental
Arm Description
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.
Intervention Type
Device
Intervention Name(s)
SONOCLOUD
Intervention Description
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 : an implantable ultrasound transducer, a needle connection device, an external radiofrequency generator, and 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).
Intervention Type
Drug
Intervention Name(s)
Nivolumab Injection
Intervention Description
Nivolumab (flat dose: 240mg, 30 minutes infusion)
Primary Outcome Measure Information:
Title
Most Successful Dose (MSD)
Description
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
Time Frame
Week 6
Secondary Outcome Measure Information:
Title
Best overall response rate, M3
Description
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.
Time Frame
Month 3
Title
Overall response rate, M3
Description
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
Time Frame
Month 3
Title
Best intracranial overall response rate (BICORR), M3
Description
Clinical efficacy will be assessed using TEP/TDM Scans (extracranial lesions) and MRI (intracranial metastases) at Month 3
Time Frame
Month 3
Title
Intracranial overall response rate (ICORR), M3
Description
Clinical efficacy will be assessed using TEP/TDM Scans (extracranial lesions) and MRI (intracranial metastases) at Month 3
Time Frame
Month 3
Title
Best extracranial overall response rate (BECORR), M3
Description
Best clinical objective response rate not taking account BICORR
Time Frame
Month 3
Title
Extracranial overall response rate (BECORR), M3
Description
Clinical objective response not taking account ICORR
Time Frame
Month 3

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
LEBBE Celeste, MD, PhD
Phone
142494679
Ext
+33
Email
celeste.lebbe@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Matthieu RESCHE-RIGON, MD PhD
Phone
142499742
Ext
+33
Email
matthieu.resche-rigon@univ-paris-diderot.fr
Facility Information:
Facility Name
Saint-Louis Hospital
City
Paris
ZIP/Postal Code
75010
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Celeste LEBBE, MD-PHD
Phone
142494679
Ext
+33
Email
celeste.lebbe@aphp.fr
First Name & Middle Initial & Last Name & Degree
El-Mountacer el-abbassi
Phone
142499742
Ext
+33
Email
el-abbassi.el-mountacer@univ-paris-diderot.fr

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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

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