Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating Lymphocytes Plus IL-2 Following Non-Myeloablative Lymphocyte Depleting Chemo Regimen Alone or in Conjunction With 12Gy Total Body Irradiation (TBI...

Study Overview
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Brief Summary
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Background: - An experimental treatment for metastatic melanoma involves cell therapy, in which researchers take white blood cells (lymphocytes) from the tumor tissue, grow them in the laboratory in large numbers, and then use the cells to attack the tumor tissue. Before receiving the cells, chemotherapy is needed to temporarily suppress the immune system to improve the chances that the tumor-fighting cells will be able to survive in the body. In some studies of cell therapy, individuals who have received total body irradiation (TBI) in addition to the chemotherapy (in order to increase the length of time that they do not produce white blood cells) seem to have a slightly better response to the treatment, but it is not known if adding radiation to the cell therapy will cause a better response for all individuals. Researchers are interested in comparing cell therapy given with the usual chemotherapy to cell therapy given with the usual chemotherapy and TBI. Objectives: - To compare the effectiveness of cell therapy given with chemotherapy to cell therapy given with chemotherapy and total body irradiation in individuals with metastatic melanoma. Eligibility: - Individuals at least 18 years of age who have been diagnosed with metastatic melanoma. Design: Participants will be screened with a physical examination, medical history, blood tests, and tumor imaging studies. Participants will be divided into two groups: cell therapy with chemotherapy alone (group 1) or cell therapy with chemotherapy plus TBI (group 2). All participants will provide a tumor sample from either surgery or a tumor biopsy for white blood cell collection. Participants will have leukapheresis to collect additional white blood cells for cell growth and future testing, and TBI group participants will also provide stem cells to help them recover after radiation. (TBI participants who cannot provide enough stem cells will be moved to the non-radiation treatment group.) Participants will have chemotherapy with cyclophosphamide (two treatments over 2 days) and fludarabine (five treatments over 5 days) starting 7 days before the cell therapy. Participants in the TBI group will also have TBI for the 3 days immediately before the cell therapy. All participants will receive the white blood cells, followed by high-dose aldesleukin every 8 hours for up to 5 days after the cell infusion to help keep the therapy cells alive and active. Participants will also have injections of filgrastim to stimulate blood cell production, and participants in the TBI group will also receive their stem cells. Participants will take an antibiotic for at least 6 months after treatment to prevent pneumonia, and will be asked to return for regular monitoring and followup visits for at least 5 years to evaluate the tumor s response to treatment.

Detailed Description
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Background: Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine. In a series of consecutive trials using this chemotherapy preparative regimen alone or with 2 Gy or 12 Gy total body irradiation (TBI) objective response rates using RECIST criteria were 49%, 52%, and 72%, respectively. Complete regression rates in these three consecutive trials were 12%, 20%, and 40%, respectively strongly suggesting that the addition of TBI could improve the complete regression rate. Of the 20 complete regressions seen in this trial, 19 are on-going at 37 to 82 months. Because of the complexity of developing selected TIL for use in adoptive transfer, we have recently developed a simplified method for producing TIL that is more applicable to use in outside institutions. Utilizing young TIL cells (sometimes with CD8 purification) in 105 patients, the objective response rate was 34% with a 6.6 % incidence of complete regressions. All patients in this trial received the cyclophosphamide fludarabine regimen alone. Because of the strong suggestion that the addition of TBI to the chemotherapy regimen could increase durable, complete regression rates in patients with metastatic melanoma, we are now attempting to definitively determine whether the addition of TBI to the chemotherapy preparative regimen can improve complete response rates, and overall survival in patients receiving young TIL . Objectives: -To determine, in a prospective randomized trial, the complete response rate and survival of patients with metastatic melanoma receiving ACT using young TIL plus aldesleukin treatment following either a chemotherapy preparative regimen alone, or the same chemotherapy preparative regimen plus TBI. Eligibility: -Patients who are 18 years or older must have: Evaluable metastatic melanoma; Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL; No contraindications to high-dose aldesleukin administration or total body irradiation; No concurrent major medical illnesses or any form of immunodeficiency Design: -Patients with metastatic melanoma will have lesions resected and after TIL growth is established patients with will be prospectively randomized to receive ACT with young TIL plus aldesleukin following either a non-myeloablative chemotherapy preparative regimen or this same regimen plus TBI.

Official Title
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A Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Short-Term Cultured Tumor-Infiltrating Lymphocytes Plus IL-2 Following Either a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Alone or in Conjunction With 12Gy Total Body Irradiation (TBI)

Conditions
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Metastatic Melanoma, Skin Cancer

Intervention / Treatment
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* Drug: Aldesleukin
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: Young TIL
* Radiation: Total Body Irradiation (TBI)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Measurable metastatic melanoma with at least one lesion that is resectable for TIL generation. The lesion must be of at least 1cm in diameter that can be surgically removed with minimal morbidity (defined as any operation for which expected hospitalization less than or equal to 7 days). Patients with 3 or less brain metastases are eligible. Note: If lesions are symptomatic or greater than or equal to 1 cm each, these lesions must have been treated and stable for 3 months for the patient to be eligible. Greater than or equal to 18 years of age and less than or equal to 66 years of age. Willing to practice birth control during treatment and for four months after receiving all protocol related therapy. Life expectancy of greater than three months Willing to sign a durable power of attorney. Able to understand and sign the Informed Consent Document Clinical performance status of ECOG 0 or 1. Hematology: Absolute neutrophil count greater than 1000/mm(3) Hemoglobin greater than 8.0 g/dl Platelet count greater than 100,000/mm(3) j. 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, or hepatitis C antibody or antigen. k. Chemistry: Serum ALT/AST less than three times the upper limit of normal. Calculated creatinine clearance (eGFR) > 50 ml/min. Total bilirubin less than or equal to 2 mg/dl, except in patients with Gilbert s Syndrome who must have a total bilirubin less than 3 mg/dl. l. More than four weeks must have elapsed since any prior systemic therapy at the time of randomization, and patients toxicities must have recovered to a grade 1 or less (except for alopecia or vitiligo). Patients must have stable or progressing disease after prior treatment. 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 inclusion criteria. m. Six weeks must have elapsed since any prior anti-CTLA4 antibody therapy to allow antibody levels to decline. Note: Patients who have previously received ipilimumab or tremelimumab, anti- PD1 or anti-PD-L1 antibodies, and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies. EXCLUSION CRITERIA: Prior cell transfer therapy which included a non-myeloablative or myeloablative chemotherapy regimen. Women of child-bearing potential who are pregnant or breastfeeding because 10 of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Systemic steroid therapy requirement. 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 and AIDS). 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.) History of severe immediate hypersensitivity reaction to any of the agents used in this study. History of coronary revascularization or ischemic symptoms. Any patient known to have an LVEF less than or equal to 45%. In patients > 60 years old, documented LVEF of less than or equal to 45%. 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 Prior radiation therapy that, in the judgment of the radiation oncologist, precludes the administration of total body irradiation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 66 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/ACT<br>Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young TIL + highdose aldesleukin | Drug: Aldesleukin<br>* Arm 1 and Arm 2 - Days 1 to 4: Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) for up to 5 days (maximum 15 doses).<br>Drug: Cyclophosphamide<br>* Arm 1 and Arm 2 - Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 mL D5W with Mesna 15 mg/kg/day X 2 days over 1 hr.<br>Drug: Fludarabine<br>* Arm 1 and Arm 2 - Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days.<br>Biological: Young TIL<br>* Arm 1 and Arm 2 - Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.<br>|
| Experimental: 2/ACT + TBI<br>Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young TIL + highdose aldesleukin + TBI | Drug: Aldesleukin<br>* Arm 1 and Arm 2 - Days 1 to 4: Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) for up to 5 days (maximum 15 doses).<br>Drug: Cyclophosphamide<br>* Arm 1 and Arm 2 - Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 mL D5W with Mesna 15 mg/kg/day X 2 days over 1 hr.<br>Drug: Fludarabine<br>* Arm 1 and Arm 2 - Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days.<br>Biological: Young TIL<br>* Arm 1 and Arm 2 - Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.<br>Radiation: Total Body Irradiation (TBI)<br>* Arm 2 - Days -3 to -1: Ondansetron 0.15 mg/kg IV x 1 dose pre-TBI. Patients will then receive 2 Gy TBI twice a day for 3 days (total dose 12 Gy) using a linear accelerator in Radiation Oncology.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Percentage of patients who have a clinical response to treatment (objective tumor regression) | 6 and 12 weeks after cell infusion, then every 3 months x3, every 6 months x5 years, then per PI discretion | 
| Overall survival | Time to death following the start of treatment | Time to death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Time to disease progression following the start of treatment | Time to progression | 
| Frequency and severity of treatment-related adverse events | Aggregate of all adverse events, as well as their frequency and severity | 30 days after end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Young TIL, Metastatic Melanoma, Immunotherapy, Adoptive Cell Therapy, Skin Cancer