Use of IL-15 After Chemotherapy and Lymphocyte Transfer in Metastatic Melanoma

Study Overview
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Brief Summary
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Background: - Researchers have developed an experimental cancer treatment called cell therapy. White blood cells called lymphocytes are taken from a tumor, grown in large numbers in the lab, and then given back to the patient. Interleukin-15, given to the patient after the cells (now called Young tumor-infiltrating lymphocytes of Young TIL cells) are replaced, helps the cells to grow and boosts the immune system. This process changes your normal cells into cells that are able to recognize your tumor has been studied in the lab. These cells can destroy tumor cells in the test tube, but scientists want to see if they work inside the body. Objectives: -To test the effectiveness of lymphocytes drawn from tumor cells combined with interleukin-15 in treating metastatic melanoma. Eligibility: Patients must be 18 - 66 years of age and have a diagnosis of metastatic melanoma. They will have heart and lung function tests, lab tests, and imaging procedures. Patients may not have conditions such as active systemic infections, blood clotting disorders, or other active major medical illnesses. Patients may not be pregnant or nursing.

Detailed Description
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Background: Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered to the autologous patient along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen. In our analysis of factors that relate to the ability of this treatment to mediate objective responses, we have found a highly significant inverse correlation between reconstitution of cluster of differentiation 4 (CD4)+ forkhead box P3 (Foxp3) + T regulatory cells and the likelihood of achieving an objective response. Interleukin 2 (IL-2) administration has been shown to increase the number of T regulatory cells and in our trials we have found a direct relationship between the number of IL-2 doses and the reconstitution of patients at one week with CD4+ Foxp3 + T regulatory cells. Interleukin 15 (IL-15) is a strong T cell growth factor, but unlike IL-2, IL-15 is not involved in the generation and maintenance of CD4+ Foxp3 + T regulatory cells that can inhibit immune reactions. In pre-clinical adoptive cell transfer studies utilizing a murine melanoma model, the administration of IL-15 following adoptive cell transfer improved anti-tumor effects. Objectives: The primary objective of this trial is to determine the safety, toxicity, and maximum tolerated dose of intravenous recombinant IL-15 administered as a daily intravenous bolus for 10 consecutive days in patients with metastatic melanoma who have received a lymphodepleting chemotherapy regimen and adoptive transfer of tumor infiltrating lymphocytes. An additional primary objective is to determine whether this combination is able to produce a modest number of clinical responses. The secondary objective involves the determination of the level of reconstitution of T regulatory cells in patients who receive cell transfer followed by IL-15 and to determine the pharmacokinetics of IL-15 levels in the serum following intravenous administration. Eligibility: Patients greater than or equal to 18 years old with pathologically confirmed diagnosis of metastatic melanoma. Patients with measurable disease, absolute neutrophil count greater than 1000/mm^3 and platelet count greater than 100,000/mm^3. No serious comorbid conditions such as active systemic infections, coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory or immune systems. Design: Patients with metastatic melanoma will undergo resection to obtain tumor for generation of autologous TIL cultures. Patients will receive a non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of autologous Young TIL. In the phase 1 portion of this study, patients will receive recombinant human IL-15 at doses of 0.25, 0.5, 1 or 2 micrograms per kilogram give intravenously daily for 10 days starting on the day of cell transfer. One patient will be treated at the first dose level, if this patient experiences a dose limiting toxicity (DLT), additional patients will be treated at the dose to confirm that no greater than 1/6 patients have DLT prior to proceeding to the next higher level. If 2 DLTs are encountered in this cohort, the study will be terminated. In all other cohorts, groups of three to six patients will receive recombinant human IL-15. Should a single patient experience a dose limiting toxicity due to the cell transfer at a particular dose level, additional patients will be treated at the dose to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the next higher level. If a level 2 or more DLTs in 3-6 patients has been identified, three additional patients will be accrued at the next-lowest dose, for a total of 6, in order to further characterize the safety of the maximum tolerated dose prior to starting the phase 2 portion. In the phase 2 portion of this study, patients will receive a non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of autologous Young TIL and IL-15 at the maximum tolerated dose (MTD) established in the phase 1 portion. Studies will be performed to determine the reconstitution of patients with T regulatory cells and to determine the pharmacokinetics of IL-15 concentration in serum.

Official Title
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A Phase I/II Study of IL-15 Administration Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen and Autologous Lymphocyte Transfer in Metastatic Melanoma

Conditions
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Metastatic Melanoma, Skin Cancer

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: Tumor Infiltrating Lymphocytes
* Drug: IL-15


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Measurable metastatic melanoma with available autologous tumor infiltrating lymphocyte (TIL). 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 age 66. Able to understand and sign the Informed Consent Document 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 preparative regimen. 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 ribonucleic acid (HCV RNA) negative. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus. Hematology: Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim. White blood cell (WBC) (> 3000/mm^3). Platelet count greater than 100,000/mm^3. Hemoglobin greater than 8.0 g/dl. Chemistry: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 2.5 times the upper limit of normal. Serum creatinine less than or equal to 1.6 mg/dl. Total bilirubin less than or equal to 1.5 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. Six weeks must have elapsed from the time of any antibody therapy that could affect an anti cancer immune response, including anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody therapy, at the time the patient receives the preparative regimen to allow antibody levels to decline. Patients who have previously received any anti-CTLA4 antibody and have documented gastrointestinal (GI) toxicity must have a normal colonoscopy with normal colonic biopsies. 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 major medical illnesses of the cardiovascular, respiratory or immune system, 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. Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%. In patients > 60 years old, documented LVEF of less than or equal to 45%. Documented LVEF of less than or equal to 45% tested 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 or. age greater than or equal to 60 years old. Documented forced expiratory volume 1 (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.

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: IL-15 following Young TIL (0.25 mcg)<br>0.25 mcg/kg/day x 10 | Drug: Cyclophosphamide<br>* 60 mg/m^2, intravenous (IV) (in the vein) x 2 days<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days (days -5 to -1)<br>* Other names: Fludara;Biological: Tumor Infiltrating Lymphocytes<br>* IV over 30 minutes on day 0<br>* Other names: TIL;Drug: IL-15<br>* IV over 30 minutes, daily for 10 days, starting 3-4 hours after the TIL infusion. (day 0 to day 9). Doses will be increased every 3-6 patients.<br>* Other names: Interleukin 15;|
| Experimental: IL-15 following Young TIL (0.50 mcg)<br>0.50 mcg/kg/day x 10 | Drug: Cyclophosphamide<br>* 60 mg/m^2, intravenous (IV) (in the vein) x 2 days<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days (days -5 to -1)<br>* Other names: Fludara;Biological: Tumor Infiltrating Lymphocytes<br>* IV over 30 minutes on day 0<br>* Other names: TIL;Drug: IL-15<br>* IV over 30 minutes, daily for 10 days, starting 3-4 hours after the TIL infusion. (day 0 to day 9). Doses will be increased every 3-6 patients.<br>* Other names: Interleukin 15;|
| Experimental: IL-15 Following Young TIL (1 mcg)<br>1 mcg/kg/day x 10 | Drug: Cyclophosphamide<br>* 60 mg/m^2, intravenous (IV) (in the vein) x 2 days<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days (days -5 to -1)<br>* Other names: Fludara;Biological: Tumor Infiltrating Lymphocytes<br>* IV over 30 minutes on day 0<br>* Other names: TIL;Drug: IL-15<br>* IV over 30 minutes, daily for 10 days, starting 3-4 hours after the TIL infusion. (day 0 to day 9). Doses will be increased every 3-6 patients.<br>* Other names: Interleukin 15;|
| Experimental: IL-15 Following Young TIL (2 mcg)<br>2 mcg/kg/day x 10 | Drug: Cyclophosphamide<br>* 60 mg/m^2, intravenous (IV) (in the vein) x 2 days<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days (days -5 to -1)<br>* Other names: Fludara;Biological: Tumor Infiltrating Lymphocytes<br>* IV over 30 minutes on day 0<br>* Other names: TIL;Drug: IL-15<br>* IV over 30 minutes, daily for 10 days, starting 3-4 hours after the TIL infusion. (day 0 to day 9). Doses will be increased every 3-6 patients.<br>* Other names: Interleukin 15;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Maximum Tolerated Dose (MTD) of Intravenous Recombinant IL-15 as a Daily Intravenous Bolus for 10 Consecutive Days in Patients With Metastatic Melanoma Who Have Received a Lymphodepleting Chemotherapy and ACT TIL. | Intravenous recombinant IL-15 as a daily intravenous bolus for 10 consecutive days in patients with metastatic melanoma who have received a lymphodepleting chemotherapy and ACT TIL with dose escalation (i.e., dose level 1: 0.25 mcg, dose level 2: 0.50 mcg, dose level 3: 1 mcg, and dose level 4: 2 mcg) to further characterize the safety of the MTD prior to starting the phase 2 portion. | 2 years | 
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 8 months, 9 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Cell Therapy, IL-15 Cytokine, Melanoma, Metastatic Melanoma, Skin Cancer