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
试验速览
- 阶段
- 1 期
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Most Successful Dose (MSD)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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) ≤
- •Age >18 year
- •Hemoglobin ≥10g/dl
- •Platelets ≥ 100000mm3
- •Neutrophils ≥1500/mm3
- •Creatinine Clearance ≥ 50ml/mn
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: SONOCLOUD (Device)
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.
干预措施: Nivolumab Injection (Drug)
结局指标
主要结局
Most Successful Dose (MSD)
时间窗: 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
次要结局
- 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)
- Extracranial overall response rate (BECORR), M3(Month 3)