Multicenter Phase 1b/2 Trial Testing Neoadjuvant Intradermal Ipilimumab and Nivolumab in High Risk Stage II Melanoma - MARIANE
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 96
- 试验地点
- 6
- 主要终点
- Feasibility of application of studytreatment
研究概览
简要总结
This open label, single country trial will test if local injection of low-dose ipilimumab and nivolumab, is safe and reduces the sentinel node positivity in high-risk stage II melanoma patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Men and women, at least 18 years of age;
- •World Health Organization (WHO) Performance Status 0 or 1;
- •Histologically confirmed, stage pT3-4 cutaneous melanoma (Breslow thickness >2.0mm; according to AJCC criteria 8th edition);
- •Having ≥44% risk for SN positivity as assessed by the MIA Sentinel Node Metastasis Risk prediction tool (melanomarisk.org.au/SNLForm)1;
- •Excision of primary melanoma took place ≤4 weeks prior to informed consent;
- •Naïve for re-excision of the primary melanoma site and for sentinel node procedure;
- •No other solid, distantly metastasized malignancies, no hematological malignancies and no malignancies for which systemic treatment is administered within 6 months prior to study inclusion;
- •No prior immunotherapy targeting CTLA-4, PD-1, PD-L1 or LAG-3;
- •No prior targeted therapy with BRAF/MEK inhibition;
- •No immunosuppressive medications within 6 months prior to study inclusion (steroids equivalent to prednisolone ≤10 mg are allowed);
- •Screening laboratory values must meet the following criteria: WBC ≥2.0x109/L, neutrophils ≥1.5x109/L, platelets ≥100x109/L, hemoglobin ≥5.5 mmol/L, creatinine ≤1.5xupper limit of normal (ULN), AST ≤1.5x ULN, ALT ≤1.5x ULN, bilirubin ≤1.5x ULN (except for subjects with Gilbert syndrome who must have a total bilirubin <3.0 mg/dL)
- •LDH level ≤ULN;
- •Women of childbearing potential (WOCP) must use appropriate method(s) of contraception, i.e. methods with a failure rate of <1% per year when used consistently and correctly, to avoid pregnancy for 23 weeks post last ipilimumab + nivolumab infusion;
- •Patient willing and able to understand the protocol requirements and comply with the treatment schedule, scheduled visits, electronic patient outcome reporting, tumor biopsies and extra blood withdrawal during screening, and other requirements of the study;
排除标准
- •Acral, uveal/ocular, mucosal or or lentigo maligna melanoma;
- •A concurrent second, primary melanoma;
- •Regionally or distantly metastasized melanoma, including in-transit metastases and macroscopic lymph node metastases;
- •No suspect lymph nodes detectable by ultrasound in the draining lymph node region(s);
- •Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications. Subjects with resolved childhood asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, are permitted to enroll;
- •Prior surgery, including prior sentinel node procedure or lymph node dissection, in the affected lymph node region(s);
- •Prior radiotherapy targeting the affected lymph node region(s);
- •Subjects will be excluded if they test positive for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection. Subjects treated and being at least one year free from HCV are allowed to participate;
- •Subjects will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
- •Subjects with history of allergy to study drug components or history of severe hypersensitivity reaction to monoclonal antibodies;
- •Subjects with underlying medical conditions or active infection that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events;
- •Women who are pregnant or breastfeeding;
- •Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids >10 mg prednisolone daily equivalent;
- •Use of other investigational drugs before study drug administration 30 days or 5 half-times before study inclusion;
- •Psychological, familial, sociological, or geographical conditions that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial.
研究组 & 干预措施
A: 2x low dose intradermal
2 cycles of intradermal ipilimumab 0.5 mg + nivolumab 1 mg every 3 weeks
干预措施: Nivolumab (Drug)
A: 2x low dose intradermal
2 cycles of intradermal ipilimumab 0.5 mg + nivolumab 1 mg every 3 weeks
干预措施: Ipilimumab (Drug)
B: 6x low dose intradermal
6 cycles of intradermal ipilimumab 0.5 mg + nivolumab 1 mg every week
干预措施: Ipilimumab (Drug)
B: 6x low dose intradermal
6 cycles of intradermal ipilimumab 0.5 mg + nivolumab 1 mg every week
干预措施: Nivolumab (Drug)
C: 2x higher dose intradermal
2 cycles of intradermal ipilimumab 10 mg + nivolumab 20 mg every 3 weeks
干预措施: Ipilimumab (Drug)
C: 2x higher dose intradermal
2 cycles of intradermal ipilimumab 10 mg + nivolumab 20 mg every 3 weeks
干预措施: Nivolumab (Drug)
D: intradermal + intravenous
intradermal ipilimumab + nivolumab according to the optimal intradermal regimen plus 2 cycles of intravenous nivolumab 240mg every 3 weeks
干预措施: Ipilimumab (Drug)
D: intradermal + intravenous
intradermal ipilimumab + nivolumab according to the optimal intradermal regimen plus 2 cycles of intravenous nivolumab 240mg every 3 weeks
干预措施: Nivolumab (Drug)
结局指标
主要结局
Feasibility of application of studytreatment
时间窗: Up to 100 days after treatment
Feasibility as measured by the adherence to the timelines in the study protocol. A treatment arm will be declared as not feasible if 3/11 or 6/24 patients cannot adhere to the planned time of surgery due to treatment-related adverse events.
Rate of effectiveness of the studytreatment
时间窗: Up to 5 years after randomization
Pathological response as assessed by blinded central review, adapted from the INMC criteria, including pCR, near-pCR, or pPR (0-50% residual viable tumor in resection material), or sentinel node negativity for melanoma.
次要结局
- treatment-related adverse events(Up to 5 years after randomization)
- EFS(Up to 5 years after start of treatment)
- DMFS(Up to 5 years after randomization)
- OS(Up to 5 years after start of treatment)