A Phase 2 Study to Evaluate the Efficacy and Safety of Adoptive Transfer of Autologous Tumor Infiltrating Lymphocytes in Patients With Metastatic Uveal Melanoma
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 34
- 试验地点
- 2
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
This is a Phase 2 study in which the efficacy of a non-myeloablative lymphodepleting preparative regimen followed by infusion of autologous TIL and high-dose aldesleukin in patients with metastatic uveal melanoma will be evaluated.
Metastatic uveal melanoma (UM) carries a poor prognosis with estimated survival of 4-6 months. There are no known effective systemic therapies. Metastatic UM is classified as an "orphan" disease and there are currently few clinical trial options for these patients. Thus, novel systemic approaches are desperately needed.
A recent pilot study has found that administration of autologous tumor infiltrating lymphocytes (TIL) generated from resected metastases can induce objective tumor response and durable complete response in metastatic uveal melanoma patients. These encouraging results require confirmation to determine if this immunotherapy is of future benefit in treating this disease.
详细描述
STUDY DESIGN
The Phase 2 study will be conducted in conjunction with companion protocol (Cell Harvest and Preparation to Support Adoptive Cell Therapy Clinical Protocols and Pre-Clinical Studies) as described below:
Cell Preparation:
Patients with evaluable metastatic uveal melanoma who have lesions that can be resected with minimum morbidity will undergo resection of tumor. TIL will be obtained while enrolled on the companion protocol (Cell Harvest and Preparation to Support Adoptive Cell Therapy Clinical Protocols and Pre-Clinical Studies). Separate tumor procurements may be performed under a protocol to obtain TIL if initial tumor procurements could not successfully generate TIL. The TIL will be grown and expanded for this trial according to standard operating procedures submitted in the IND. The TIL will be assessed for potency by interferon-gamma release.
Treatment Phase:
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
- •Measurable metastatic uveal melanoma.
- •Patients must be co-enrolled on the companion protocol HCC 17-220 (Cell Harvest and Preparation to Support Adoptive Cell Therapy Clinical Protocols and Pre-Clinical Studies) and have available TIL cultures for therapy.
- •Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
- •Greater than or equal to 18 years of age and less than or equal to age 75
- •Able to understand and sign the Informed Consent Document
- •Clinical performance status of ECOG 0 or 1
- •Life expectancy of greater than three months
- •Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after receiving the treatment.
- •Serology:
- •Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
- •Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
- •Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
- •Hematology
- •Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim
- •WBC ≥ 3000/mm3
- •Platelet count ≥ 100,000/mm3
- •Hemoglobin > 8.0 g/dl
- •Chemistry
- •Serum ALT/AST ≤ to 3.5 times the upper limit of normal
- •Serum creatinine ≤ to 1.6 mg/dl
- •Total bilirubin ≤ to 2.0 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.
- •More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a clinically manageable level (except for toxicities such as alopecia or vitiligo). (Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less)
排除标准
- •Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
- •Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
- •Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
- •Active systemic infections (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses.
- •History of clinically significant major organ autoimmune disease
- •Concurrent systemic steroid therapy.
- •History of severe immediate hypersensitivity reaction to any of the agents used in this study.
- •History of active coronary or ischemic symptoms.
- •Documented LVEF of less than or equal to 45%; note: testing is required in patients with:
- •Age > 65 years old
- •Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or have a history of ischemic heart disease, chest pain.
- •Documented FEV1 less than or equal to 60% predicted tested in patients with:
- •A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years).
- •Symptoms of respiratory dysfunction
- •Patients who are receiving any other investigational agents.
研究组 & 干预措施
Tumor Infiltrating Lymphocytes (TIL)
Patients with uveal melanoma will receive the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide followed by infusion of up to 2x10^11 TIL infused intravenously through a central vein catheter and Aldesleukin, administered at a dose of 600,000 IU/kg (based on total body weight) as an intravenous bolus over a 15-minute period approximately every 8 hours beginning within 24 hours of TIL infusion and continuing for up to a maximum of 6 doses.
干预措施: Tumor Infiltrating Lymphocytes (TIL) (Biological)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: Post TIL infusion, up to 24 months (measurements taken at 6 weeks, 12 weeks, 6 months, 9 months, 12 months, 18 months 24 months)
The proportion of patients with response per RECIST for a (minimum) time period. Equation: #patients with CR + #patients with PR / #patients with CR + #patients with PR + #patients with SD + #patients with PD
次要结局
- Overall Survival (OS)(Post TIL infusion up to 24 months (measurements taken at 6 weeks, 12 weeks, 6 months, 9 months, 12 months, 18 months 24 months))
- Duration of Response (DOR)(Up to 24 months)
- Progression Free Survival (PFS)(Post TIL infusion up to 24 months (measurements taken at 6 weeks, 12 weeks, 6 months, 9 months, 12 months, 18 months 24 months))
- Complete Response Rate (CRR)(: Post TIL infusion up to 24 months (measurements taken at 6 weeks, 12 weeks, 6 months, 9 months, 12 months, 18 months 24 months))
- Disease Control Rate (DCR)(Post TIL infusion up to 24 months (measurements taken at 6 weeks, 12 weeks, 6 months, 9 months, 12 months, 18 months 24 months))
研究者
Udai Kammula
Director, Solid Tumor Cell Therapy Program
University of Pittsburgh