Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Ocular Melanoma

Study Overview
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Brief Summary
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Background: - The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 200 patients with melanoma. This study will use chemotherapy to prepare the immune system before this white blood cell treatment. After receiving the cells, the drug aldesleukin (IL-2) may be given to help the cells stay alive longer. Objectives: - To see if chemotherapy and white blood cell therapy is a safe and effective treatment for advanced ocular melanoma. Eligibility: - Individuals at least greater than or equal to 16 years to less than or equal to 75 years who have advanced ocular melanoma. Design: Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed. Surgery: If the patients meet all of the requirements for the study they will undergo surgery to remove a tumor that can be used to grow the TIL product. Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.} Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.

Detailed Description
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Background: Metastatic ocular melanoma (OM) carries a poor prognosis with estimated survival of 4-6 months. There are no known effective systemic therapies. Metastatic OM is classified as an orphan disease and there are currently few clinical trial options for these patients. Thus, novel systemic approaches are desperately needed. Administration of autologous tumor infiltrating lymphocytes (TIL) generated from resected metastatic cutaneous melanoma can induce objective long-term tumor responses. Minimally invasive, safe, and effective surgical approaches have been developed in the Surgery Branch to procure liver tumor tissue for TIL generation. Objectives: To determine whether autologous Young TIL infused with or without the administration of high-dose aldesleukin may result in clinical tumor regression in patients with metastatic ocular melanoma receiving a non-myeloablative lymphoid depleting preparative regimen. To study immunologic correlates associated with Young TIL therapy for ocular melanoma. To determine the toxicity of this treatment regimen. Eligibility: Patients with metastatic ocular melanoma who are greater than or equal to 16 years of age, and are physically able to tolerate non-myeloablative chemotherapy. Patients who can tolerate high-dose aldesleukin will receive it following cell infusion; those who cannot tolerate high-dose aldesleukin due to medical comorbidities or refuse high dose aldesleukin will receive cell infusion without aldesleukin. There is no requirement for prior systemic therapies, given the lack of known effective systemic treatments for metastatic OM. Design: Patients will undergo biopsy or resection to obtain tumor for generation of autologous TIL cultures and autologous cancer cell lines. All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine. On day 0 patients will receive between 1x10^9 to 2x10^11 young TIL and then begin high dose aldesleukin (720,000 IU/kg intravenous (IV) every 8 hours for up to 15 doses) or no aldesleukin if they are not medically eligible to receive it. A complete evaluation of evaluable lesions will be conducted 4-6 weeks after the last dose of aldesleukin in the aldesleukin arm and 4-6 weeks after the cell administration in the no aldesleukin arm. Patients will be enrolled into two cohorts. The cohort receiving high-dose aldesleukin (cohort A) will be conducted using a small optimal two-stage Phase II design, initially 19 patients will be enrolled, and if 4 or more of the first 19 patients have a clinical response (partial response (PR) or complete response (CR), accrual will continue to 33 patients, targeting a 35% goal for objective response. For the cohort that will not receive aldesleukin (cohort B), the study will be conducted as a Minimax two-stage phase II trial. Initially 12 evaluable patients will be enrolled to this cohort, and if 1 or more the first 12 have a response, then accrual would continue until a total of 21 patients, targeting a 20% goal for objective response.

Official Title
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Phase II Study in Patients With Metastatic Ocular Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of Autologous Tumor-Infiltrating Lymphocytes With or Without High Dose Aldesleukin

Conditions
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Metastatic Ocular Melanoma, Metastatic Uveal Melanoma

Intervention / Treatment
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* Drug: Aldesleukin
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: Young Tumor Infiltrating Lymphocytes (TIL)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Measurable metastatic ocular melanoma. Confirmation of diagnosis of metastatic ocular melanoma by the Laboratory of Pathology of the National Cancer Institute (NCI). 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 16 years of age and less than or equal to age 75. Able to understand and sign the Informed Consent Document Willing to sign a durable power of attorney Clinical performance status of Eastern Cooperative Oncology Group (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 human immunodeficiency virus (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 reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (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/mm^3 without the support of filgrastim White blood cell (WBC) greater than or equal to 3000/mm^3 Platelet count greater than or equal 100,000/mm^3 Hemoglobin > 8.0 g/dl Chemistry: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than or equal to 3.5 times the upper limit of normal Serum creatinine less than or equal to 1.6 mg/dl Total bilirubin less than or equal 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 grade 1 or less (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 or as specified in the eligibility criteria. EXCLUSION CRITERIA: Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant. Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease. 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). Concurrent systemic steroid therapy. History of severe immediate hypersensitivity reaction to any of the agents used in this study. The following patients will be excluded from the high-dose aldesleukin arm (but may be eligible for cells alone arm): History of coronary revascularization or ischemic symptoms Documented left ventricular ejection fraction (LVEF) of less than or equal to 45%. Testing is required in patients with: Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block Age greater than or equal to 60 years old Clinically significant patient history which in the judgment of the Principal Investigator would compromise the patients ability to tolerate aldesleukin

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cells + high dose aldesleukin<br>Patients receiving cells + high dose aldesleukin | Drug: Aldesleukin<br>* Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses) (only for cohort A).<br>* Other names: Interleukin-2;Drug: Cyclophosphamide<br>* Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Fludarabine 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.<br>* Other names: Fludara;Biological: Young Tumor Infiltrating Lymphocytes (TIL)<br>* Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of young TIL and high dose aldesleukin (Cohort A) or no aldesleukin (Cohort B). On day 0,cells (1x10e9 to 2x10e11) will be infused intravenously on the Patient Care Unit over 20-30 minutes.<br>|
| Experimental: cells and no high dose aldesleukin<br>Patients receiving cells and no high dose aldesleukin | Drug: Cyclophosphamide<br>* Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Fludarabine 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.<br>* Other names: Fludara;Biological: Young Tumor Infiltrating Lymphocytes (TIL)<br>* Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of young TIL and high dose aldesleukin (Cohort A) or no aldesleukin (Cohort B). On day 0,cells (1x10e9 to 2x10e11) will be infused intravenously on the Patient Care Unit over 20-30 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Ocular Melanoma Treated With Young Tumor Infiltrating Lymphocytes (TIL) With or Without High Dose Aldesleukin With an Objective Response Rate of (Complete Response (CR) + Partial Response (PR)) | Objective response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. | approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0) | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | 46 months and 12 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic, Ocular Melanoma, Autologous Tumor-Infiltrating Lymphocytes, Uveal Melanoma, Adoptive Cell Therapy