A Phase I Study of Adoptive Tumor-infiltrating Lymphocyte Transfer in Combination With Nivolumab in Patients With Advanced Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Change in body temperature (Degree Celsius)
研究概览
简要总结
This study is to investigate safety and feasibility of a combination therapy of a tumor infiltrating lymphocytes (TIL) transfer with anti-programmed cell death protein (PD)-1 therapy in patients with metastatic melanoma that failed immunotherapy.Tumor-infiltrating lymphocytes will be expanded from resected melanoma samples from the patient and expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose Interleukin (IL)-2 and nivolumab anti-PD-1 treatment.
The study uses a personalized Investigational Medicinal Product (IMP), i.e. TIL product and in combination with IL-2 treatment and nivolumab.
详细描述
Adoptive cell therapy has been previously shown to be an effective treatment option for patients with melanoma. Due to an immunosuppressive microenvironment, not all patients respond to this therapy. In this trial, the immune suppressive microenvironment will be targeted by adding a PD-1 blocking antibody in combination with a TIL Transfer. Tumor-infiltrating lymphocytes will be expanded from resected melanoma samples from the patient and expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose IL-2 and nivolumab anti-PD-1 treatment. The study uses a personalized IMP, i.e. TIL product and in combination with IL-2 treatment and nivolumab.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed unresectable or metastatic melanoma
- •At least 1 PD-1 targeted immunotherapy and BRAF inhibition in case of BRAF mutated melanoma
- •Resectable tumor mass and measurable disease by CT or MRI per RECIST 1.1 criteria (in addition to the resected lesion)
- •World Health Organization (WHO) clinical performance Status (ECOG) 0-1
- •Adequate organ function
- •Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for five months after receiving the last dose of nivolumab for women and seven months for men
- •Patients must be able to understand and sign the Informed consent document
- •Hematology: Absolute neutrophil count greater than 1.5 x 109/L without support of filgrastim. Platelet count greater than 100 x 109/L. Hemoglobin greater than 5 mmol/L, or 80 g/L.
- •Chemistry: Serum alanine aminotransferase (ALAT)/ aspartate transaminase (ASAT) less than 3 times the upper limit of normal, unless patients have liver metastases (< 5 times ULN). Serum creatinine clearance 50 ml/min or higher. Total Bilirubin less than or equal to 20 micromol/L, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 50 micromol/L. Lactate dehydrogenase (LDH) ≤ 2x ULN
- •Serology: Seronegative for HIV antibody. Seronegative for hepatitis B antigen, and hepatitis C antibody. Seronegative for syphilis.
排除标准
- •Life expectancy of less than three months
- •Patients with metastatic ocular/ mucosal or other non-cutaneous melanoma.
- •Requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive drugs within the last 3 weeks prior to randomization
- •Uncontrolled central nervous system (CNS) metastases. Controlled CNS metastases must be for at least 4 weeks stable.
- •Documented Forced expiratory volume at one second (FEV1) less than or equal to 50% predicted for patients with:
- •A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years)
- •Symptoms of respiratory distress
- •All patients' toxicities due to prior non-systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or focal palliative radiotherapy (to non-target lesions) within the past 4 weeks, as long as all toxicities have recovered to grade 1 or less.
- •Women who are pregnant or breastfeeding, because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
- •Any active systemic infections, coagulation disorders or other active major medical illnesses.
- •Contraindication for IL-2 or nivolumab (allergies etc.).
- •Any autoimmune disease: patients with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, autoimmune thyroiditis (e.g. Hashimoto's disease), autoimmune hepatitis, systemic progressive sclerosis (scleroderma), Systemic Lupus Erythematosus, autoimmune vasculitis (e.g., Wegener's Granulomatosis). Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barré Syndrome) are excluded from this study. Patients with vitiligo are eligible to enter the study
研究组 & 干预措施
Tumor-infiltrating lymphocyte product (TIL) transfer
The TIL product will be produced from excised tumor lesions from the patient. Expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose IL-2 and nivolumab anti-PD-1 treatment. The transplant product will be produced in the Good Manufacturing Practice (GMP) facility of the University Hospital in Basel. TIL transfer to Patient at Day 0.
干预措施: Combination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2 (Drug)
结局指标
主要结局
Change in body temperature (Degree Celsius)
时间窗: at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing)
Change in Vital signs ( body temperature) to analyze the safety of the combination of TIL transfer with IL-2 therapy
Change in blood pressure (mmHg)
时间窗: at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing)
Change in Vital signs ( blood pressure) to analyze the safety of the combination of TIL transfer with IL-2 therapy
Change in heart beat (beats/minute)
时间窗: at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing)
Change in Vital signs (heart beat) to analyze the safety of the combination of TIL transfer with IL-2 therapy
Change in full blood Counts (number of cells)
时间窗: at each treatment visit (every 2 weeks) from Day 0= Baseline to week 42
Change in Laboratory Parameter (full blood counts) to analyze haematological toxicity
Number of Adverse Events
时间窗: First 3 months during treatment
Number of Adverse Events to analyze safety of the combination of TIL transfer with IL-2 therapy
Change in respiratory frequency (inspiration/minute)
时间窗: at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing)
Change in Vital signs (respiratory frequency) to analyze the safety of the combination of TIL transfer with IL-2 therapy
次要结局
- Progression Free Survival (PFS)(between pre-treatment and 3-months post-treatment)
- Tumor response according to revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria(between pre-treatment and 3-months post-treatment)
- Objective response rate (ORR)(2 years after TIL transfer)
- Number of Adverse Events according to CTCAE 4.0(2 years after TIL transfer)
- Metabolic Response(during the first 3 months after TIL transfer)
- Number of Serious Adverse Events according to CTCAE 4.0(2 years after TIL transfer)
- Overall Response Rate (ORR) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan(First 3 months after TIL administration)
- Overall Survival (OS) defined as the time between registration to death due to any cause(2 years after TIL transfer)