A Phase II Study of Nivolumab and Nivolumab Combined With Ipilimumab in Patients With Melanoma Brain Metastases
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 76
- 试验地点
- 4
- 主要终点
- Intracranial response rate
研究概览
简要总结
The purpose of this research project is to test the effectiveness of nivolumab versus nivolumab together with ipilimumab for the treatment of melanoma brain metastases.
Patients are eligible to join this study if they are aged 18 years or above and have been diagnosed with melanoma with brain metastases.
详细描述
BACKGROUND Brain metastases are a common and serious complication of metastatic melanoma. Up to 50% of patients develop brain metastases during the course of their illness, and approximately 20% of patients have them at first presentation with metastatic disease. The prognosis for melanoma patients with brain metastasis is generally very poor with a median overall survival ranging from 2.8 to 4 months and a large proportion of up to 95% of these patients will ultimately die as a direct result of their brain metastases. The prognosis of patients with melanoma brain metastases has not changed between 1986 and 2007. The five year survival rate is 15% for late stage disease.
LOCAL TREATMENT OPTIONS There are 3 treatment modalities used for the local management of brain metastases: surgery, stereotactic radiosurgery (SRS), and whole brain radiotherapy (WBRT). Surgery and SRS are directed to the tumour volume only, whereas WBRT delivers lower-dose radiotherapy to the whole brain, including areas of no overt tumour. Surgery is not limited by the size of the tumour; however, it is dependent on the lesion being surgically accessible. In appropriately selected patients (lesions >3 cm and minimal symptoms), SRS is considered equivalent to surgical resection; however, this has been addressed in only 1 randomised controlled trial that was stopped early because of poor accrual. No statistically significant difference was found in survival or local tumour control. In solid tumours, WBRT remains the treatment modality of choice in those where surgery or SRS are contraindicated because of tumour size, number, or location. The role of WBRT is to palliate symptoms because, despite response rates of 60%, median survival is less than 5 months.
SYSTEMIC THERAPY OPTIONS Systemic chemotherapy has shown little benefit in the treatment of metastatic melanoma, including those with brain metastases. It is usually reserved for those who have central nervous system (CNS) progression despite surgery and/or radiotherapy, or in those patients with rapidly progressing or symptomatic extracranial disease. The response rate in the brain for the most active chemotherapy agents temozolomide and fotemustine is <10% in large clinical trials, thus patients with brain metastases have been excluded from most systemic therapy clinical trials.
Ipilimumab was the first systemic treatment proven to extend survival in patients with metastatic melanoma, and has activity in progressing brain metastases in patients who are not taking corticosteroids for neurological symptoms.
Dabrafenib and vemurafenib are potent selective BRAF inhibitors proven to increase survival in patients with V600 BRAF-mutant metastatic melanoma and have activity in brain metastases. Although there is unprecedented proven activity of the BRAF inhibitor dabrafenib in a large clinical trial of patients with untreated V600 BRAF-mutant brain metastases, this represents only 40% of the metastatic melanoma population, and responses are rarely durable. Brain metastases remain a major clinical problem, and an unmet medical need for patients with both BRAF-mutant and wild-type metastatic melanoma. And yet, all major clinical trials continue to exclude such patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •≥18 years of age.
- •Written informed consent
- •AJCC Stage IV (any T, any N, M1c) histologically confirmed melanoma or unknown primary melanoma. Patients must have at least 1 radiological definitive brain metastasis that is ≥ 5mm and ≤40mm measurable per RECIST version 1.1 guidelines.
- •In patients with prior BRAF inhibitor treatment, intracranial disease progression must be demonstrated (RECIST >20% or new measurable brain metastases) compared with nadir of intracranial response during BRAF inhibitor treatment, and confirmed with a second MRI brain scan at any time from the beginning of the drug washout period (dabrafenib=5 days, trametinib=14 days).
- •No prior localised treatment for brain metastases (eg. surgery or radiotherapy).
- •Neurologically asymptomatic from brain metastases.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2, and life expectancy > 30 days.
- •Able to undergo MRI with Gadolinium contrast agent.
- •Adequate haematological, hepatic and renal organ function.
- •Women of childbearing potential: negative serum pregnancy test and effective contraception from 14 days prior to study treatment until 23 weeks after the last dose.
- •Men with female partner of childbearing potential to use effective contraception from 14 days prior to study treatment until 31 weeks after the last dose.
排除标准
- •Any melanoma brain metastasis >40mm.
- •Ocular melanoma.
- •Prior treatment with an anti-PD-1 or anti-PD-L1 , anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
- •Patients with active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
- •Current systemic treatment with corticosteroids, except prednisone at nonimmunosuppressive doses of ≤ 10 mg/day (or equivalent). Past treatment for non-neurological symptoms allowed, if ceased 2 weeks prior to starting study treatment. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient on a stable dose. Non-absorbed intraarticular steroid injections will be permitted.
- •Any investigational drug or other systemic drug therapy for melanoma within 28 days or 5 half-lives from baseline.
- •Known to be HIV positive, or a positive test for hepatitis B and C .
- •Another malignancy or concurrent malignancy unless disease-free for 3 years.
- •Serious or unstable pre-existing medical conditions or other conditions that could interfere with the patient's safety, consent, or compliance.
- •Pregnant or breastfeeding females.
- •Administration of any form of live vaccination (such as influenza vaccine) within 30 days of starting trial and anticipated use during the trial. Administration of any other vaccine is cautionary within 30 days of starting the trial and during the trial.
- •Cohort 2 - per Cohorts 1 & 3, except patients must have at least one of the following:
- •Failed prior local therapy for brain metastases (including surgery, stereotactic radiotherapy or whole brain radiotherapy) where disease has progressed per RECIST (>20% increase in SOD or new measurable brain metastases),
- •Have current neurological symptoms related to brain metastases. IF they have received prior local therapy for brain metastases, the disease must have progressed per RECIST (>20% increase in SOD or new measurable brain metastases),
- •Have leptomeningeal disease concurrently with measurable brain metastases. IF they have had failed prior local therapy for brain metastases, this must have progressed per RECIST (>20% increase in SOD or new measurable brain metastases).
研究组 & 干预措施
Cohort 1 Nivolumab Monotherapy
Nivolumab 3mg/kg every 2 weeks, until disease progression, withdrawn consent, unacceptable toxicity or death.
After 52 weeks, nivolumab dosing can change to 480mg every 4 weeks
干预措施: Nivolumab (Drug)
Cohort 2 Nivolumab Monotherapy
Nivolumab 3mg/kg every 2 weeks, until disease progression, withdrawn consent, unacceptable toxicity or death.
After 52 weeks, nivolumab dosing can change to 480mg every 4 weeks
干预措施: Nivolumab (Drug)
Cohort 3 Nivolumab and Ipilimumab
Nivolumab 1mg/kg every 3 weeks x four doses and ipilimumab 3mg/kg every 3 weeks x four doses. After 12 weeks, nivolumab 3mg/kg alone every 2 weeks until disease progression, withdrawn consent, unacceptable toxicity or death.
After 52 weeks, nivolumab dosing can change to 480mg every 4 weeks
干预措施: Nivolumab (Drug)
Cohort 3 Nivolumab and Ipilimumab
Nivolumab 1mg/kg every 3 weeks x four doses and ipilimumab 3mg/kg every 3 weeks x four doses. After 12 weeks, nivolumab 3mg/kg alone every 2 weeks until disease progression, withdrawn consent, unacceptable toxicity or death.
After 52 weeks, nivolumab dosing can change to 480mg every 4 weeks
干预措施: Ipilimumab (Drug)
结局指标
主要结局
Intracranial response rate
时间窗: Approximately 3 years
Proportion of patients with a complete or partial response in intracranial metastases as measured using RECIST 1.1 criteria (modified for brain metastases - bm RECIST), from week 12.
次要结局
- Extracranial response rate(Approximately 3 years)
- Overall response rate(Approximately 3 years)
- Progression free survival in intracranial disease(Approximately 3 years)
- Progression free survival in extracranial disease(Approximately 3 years)
- Overall progression free survival(Up to 10 years)
- Overall survival(Up to 10 years)
- Safety and tolerability of nivolumab and nivolumab + ipilimumab (verse events by type, frequency and severity using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.)(Approximately 3 years)
- Patient rated quality of life(Approximately 3 years)
- Clinical response using immune related response criteria (irRC)(Approximately 3 years)
- Tissue and blood biomarkers of response and progression(Approximately 3 years)
- FET-PET response in the brain at 6 and 12 weeks on therapy (Proportion of patients with a lower standardised uptake value from baseline in intracranial metastases, following at least ONE dose of study treatment)(Approximately 1 year)