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

NCT04021420 | Unknown Phase 1 DMC

• 1 other identifier: P160950J
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• 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

  Week 6

Secondary Outcomes (6)

• Best overall response rate, M3

  Month 3

• Overall response rate, M3

  Month 3

• Best intracranial overall response rate (BICORR), M3

  Month 3

• Intracranial overall response rate (ICORR), M3

  Month 3

• Best extracranial overall response rate (BECORR), M3

  Month 3

Study Arms (1)

low intensity pulsed UltraSound

EXPERIMENTAL

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; Drug: Nivolumab Injection

Interventions

SONOCLOUD 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).

low intensity pulsed UltraSound

Nivolumab Injection DRUG

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

low intensity pulsed UltraSound

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Saint-Louis Hospital

Paris, 75010, France

RECRUITING

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

LEBBE Celeste, MD, PhD

CONTACT

142494679; celeste.lebbe@aphp.fr

Matthieu RESCHE-RIGON, MD PhD

CONTACT

142499742; matthieu.resche-rigon@univ-paris-diderot.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 1, 2019
• First Posted: July 16, 2019
• Study Start: October 24, 2019
• Primary Completion: January 1, 2022
• Study Completion: July 5, 2023
• Last Updated: August 20, 2020

Record last verified: 2020-08

Locations

FR (1)