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

NCT ID: NCT04021420

Last Updated: 2020-08-20

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-24
• Study Completion Date: 2023-07-05

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.

Conditions

Melanoma; Metastatic Melanoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

SONOCLOUD

Intervention Type: DEVICE

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).

Nivolumab Injection

Intervention Type: DRUG

Nivolumab (flat dose: 240mg, 30 minutes infusion)

Interventions

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).

Intervention Type: DEVICE

Nivolumab Injection

Nivolumab (flat dose: 240mg, 30 minutes infusion)

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Saint-Louis Hospital

Paris, , France

Site Status: RECRUITING

Countries

France

Central Contacts

LEBBE Celeste, MD, PhD

Role: CONTACT

celeste.lebbe@aphp.fr

142494679 ext. +33

Matthieu RESCHE-RIGON, MD PhD

Role: CONTACT

matthieu.resche-rigon@univ-paris-diderot.fr

142499742 ext. +33

Facility Contacts

Celeste LEBBE, MD-PHD

Role: primary

celeste.lebbe@aphp.fr

142494679 ext. +33

El-Mountacer el-abbassi

Role: backup

el-abbassi.el-mountacer@univ-paris-diderot.fr

142499742 ext. +33

Other Identifiers

P160950J

Identifier Type: -

Identifier Source: org_study_id