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...

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 Gray (Gy) or 12 Gy total body irradiation (TBI) objective response rates using Response Evaluation Criteria in Solid Tumors (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 cluster of differentiation 8 (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 adoptive cell transfer (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.

• INCLUSION CRITERIA:

• Measurable metastatic melanoma with at least one lesion that is resectable for tumor infiltrating lymphocytes (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 eastern Cooperative Oncology Group (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 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, or hepatitis C antibody or antigen.

k. Chemistry:

• Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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 patient's 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-cytotoxic T-lymphocyte associated protein 4 (CTLA4) antibody therapy to allow antibody levels to decline.

Note: Patients who have previously received ipilimumab or tremelimumab, anti-programmed cell death protein 1 (PD1) or anti-programmed cell death ligand 1 (PD-L1) antibodies and have documented gastrointestinal (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 acquired immunodeficiency syndrome (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 a 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 forced expiratory volume in one second (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.