Clinical Trials /

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

NCT04021420

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy of Sonocloud Device Combined With Nivolumab in Brain Metastases From Patients With Melanoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: P160950J
  • NCT ID: NCT04021420

Conditions

  • Melanoma
  • Metastatic Melanoma

Interventions

DrugSynonymsArms
Nivolumab Injectionlow intensity pulsed UltraSound

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
low intensity pulsed UltraSoundExperimentalSonoCloud® 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.
  • Nivolumab Injection

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Most Successful Dose (MSD)
Time Frame:Week 6
Safety Issue:
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

Secondary Outcome Measures

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Assistance Publique - Hôpitaux de Paris

Last Updated

July 15, 2019