Efficacy of Immunotherapy in Melanoma Patients With Brain Metastases Treated With Steroids
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 80
- 试验地点
- 3
- 主要终点
- 6 months progression-free survival rate
研究概览
简要总结
This clinical trial is to clarify whether treatment with a checkpoint inhibitor alone (pembrolizumab) or two in combination (ipilimumab and nivolumab), results in clinical benefit for MM patients with brain metastases and in need of steroid treatment. Patients will be treated in four arms depending on steroid dose level at inclusion (> 10 < 25 mg prednisolone or > 25 mg prednisolone) and treatment (pembrolizumab alone or the combination of ipilimumab and nivolumab).
详细描述
Cancer immunotherapy with checkpoint inhibitors (CPI) has demonstrated significant response rates, with clinical responses of exceptional duration observed in pivotal clinical trials for multiple types of solid tumors. Results from clinical trials demonstrate a considerable survival benefit of CPI over standard treatments, leading to registration of CPI for lung-, head and neck-, bladder-, renal cancer, lymphomas and metastatic melanoma (MM). To date, CPI appear to hold the key for longterm survival - at least for patients treated in clinical trials.
Patients enrolled in pivotal clinical trials for immunotherapy of MM are highly selected and does not include patients with brain metastases. Small phase II studies lend support to CPI to yield responses in melanoma that has metastasized to the brain. However, a large proportion of patients that develop brain metastasis will require continued systemic treatment with steroids to alleviate symptoms from the central nervous system (CNS). This group of patients are not offered treatment with CPI, as it is generally assumed that steroid treatment hamper their clinical efficacy. Thus, this group of patients face a large unmet need.
Due to the immune inhibiting effects, steroids are used to manage immune-related adverse events (irAEs) induced by CPI treatment. However, patients receiving steroids in this context are still able to achieve and maintain clinical benefit even after stopping treatment.
It is not known whether steroid treatment at the time of initiation of CPI treatment diminishes the treatment effect, as patients in need of steroid treatment are generally excluded from clinical trials.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Histologically confirmed metastatic melanoma with radiologically verified brain metastasis
- •Need for systemic steroid treatment (prednisolone > 10 mg daily; dexamethasone > 1.6 mg daily, hydrocortisone > 40 mg daily or equivalent) due to brain metastasis
- •At least one measurable lesion according to RECIST version 1.1 guidelines
- •Evaluable intracranial disease
- •18 years of age or older
- •Performance status 0-2
- •Able to undergo MRI with gadolinium contrast agent
- •Adequate hematological and organ function
- •No significant toxicity from previous cancer treatments (CTC<1)
- •Women of childbearing potential: Negative serum pregnancy test and must use effective contraception. This applies from screening and until 6 months after treatment. Birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch are all considered effective contraceptives
- •Men with female partner of childbearing potential must use effective contraception from screening and until 6 months after treatment. Effective contraceptives are as described above for the female partner. In addition documented vasectomy and sterility or double barrier contraception are considered effective contraceptives
- •Signed statement of consent after receiving oral and written study information.
- •Willingness to participate in the planned treatment and follow-up and capable of handling toxicities.
- •For arm E specifically: Tumor cells must harbor BRAF mutation.
排除标准
- •Another malignancy or concurrent malignancy unless disease-free for 3 years
- •Ocular melanoma
- •Neurological symptoms from brain metastases present at baseline despite steroid treatment, unless symptoms are related to prior surgery
- •Known hypersensitivity to one of the active drugs or excipients
- •Acute or chronic infections with HIV or hepatitis
- •Any medical condition that will interfere with patient compliance or safety
- •Prior treatment with anti-PD-1/PD-L1/PD-L2/CTLA-4 antibodies in the metastatic setting
- •Prior systemic treatment with anti-PD-1/PD-L1/PD-L2/CTLA-4 antibodies in the adjuvant setting, unless completed more than 6 months before enrolment in this study
- •Simultaneous treatment with other experimental drugs or other anti-cancer drugs
- •Pregnant or breastfeeding females.
- •For arm E specifically: Prior treatment with BRAF/MEK inhibitors.
研究组 & 干预措施
B: Pembrolizumab (Prednisolone >10 mg)
Intravenous infusion of pembrolizumab 2 mg/kg every third week for up to two years.
干预措施: Pembrolizumab Injection [Keytruda] (Drug)
C: Ipilimumab/nivolumab (Prednisolone 11-25 mg)
Intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
干预措施: Ipilimumab Injection [Yervoy] (Drug)
C: Ipilimumab/nivolumab (Prednisolone 11-25 mg)
Intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
干预措施: Nivolumab Injection [Opdivo] (Drug)
D: Ipilimumab/nivolumab (Prednisolone >25 mg)
Intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
干预措施: Ipilimumab Injection [Yervoy] (Drug)
D: Ipilimumab/nivolumab (Prednisolone >25 mg)
Intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
干预措施: Nivolumab Injection [Opdivo] (Drug)
E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg)
Induction treatment with BRAF/MEK inhibitors (either the combination of encorafenib/binimetinib or dabrafenib/trametinib) orally for 28 days followed by intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
干预措施: Ipilimumab Injection [Yervoy] (Drug)
E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg)
Induction treatment with BRAF/MEK inhibitors (either the combination of encorafenib/binimetinib or dabrafenib/trametinib) orally for 28 days followed by intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
干预措施: Nivolumab Injection [Opdivo] (Drug)
E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg)
Induction treatment with BRAF/MEK inhibitors (either the combination of encorafenib/binimetinib or dabrafenib/trametinib) orally for 28 days followed by intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
干预措施: Encorafenib (Drug)
E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg)
Induction treatment with BRAF/MEK inhibitors (either the combination of encorafenib/binimetinib or dabrafenib/trametinib) orally for 28 days followed by intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
干预措施: Binimetinib (Drug)
E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg)
Induction treatment with BRAF/MEK inhibitors (either the combination of encorafenib/binimetinib or dabrafenib/trametinib) orally for 28 days followed by intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
干预措施: Dabrafenib (Drug)
E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg)
Induction treatment with BRAF/MEK inhibitors (either the combination of encorafenib/binimetinib or dabrafenib/trametinib) orally for 28 days followed by intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
干预措施: Trametinib (Drug)
结局指标
主要结局
6 months progression-free survival rate
时间窗: 6 months
Proportion of patients who did not progress or die within 6 months from commencing study treatment.
6 months overall survival rate
时间窗: 6 months
Proportion of patients who did not die within 6 months from commencing study treatment.
次要结局
- Overall response rate(4 years)
- Blood and tissue biomarkers of response and progression(5 years)
- Overall progression-free survival(4 years)
- Intracranial response rate(4 years)
- Extracranial response rate(4 years)
- Intracranial clinical benefit rate(4 years)
- Overall survival(4 years)
研究者
Inge Marie Svane
Professor, MD, PhD
Herlev Hospital