Phase II Study of Metastatic Melanoma With Lymphodepleting Conditioning and Infusion of Anti-MART-1 F5 TCR-Gene-Engineered Lymphocytes
Condition: Melanoma; Skin Cancer
MeSH terms: Melanoma; Skin Neoplasms
Intervention: autologous anti-MART-1 F5 T-cell receptor; Cyclophosphamide; Fludarabine; Aldesleukin; autologous anti-MART-1 F5 T-cell receptor gene-engineered tumor infiltrating lymphocytes
Intervention description: Autologous anti-MART-1 F5 T-cell receptor gene-engineered tumor infiltrating lymphocytes.
A minimum of approximately 5 X 10^8 cells will be given up to 3x10^11 anti-MART-1 F5 TCR engineered TIL or PBL.; Day -7 to -5: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml D5W with mesna 15 mg/kg/day X 2 days over 1 hr; Day -5 to 1: Fludarabine 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days; Day 0: Cells will be infused intravenously (i.v.). Patients will receive up to 3x10e^11 (with a minimum of 5x10e^8 cells) anti-MART-1 F5 TCR engineered TIL or PBL Aldesleukin (based on total body weight) 720,000 IU/kg intravenous (IV) over 15 minute every eight hours beginning within 24 hours of cell infusion
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Refractory; Gene Therapy; HLA-A2 Positive; Stage IV Melanoma; Melanoma; Skin Cancer; Malignant Melanoma

Summary:

      Background:

        -  Human peripheral blood lymphocytes have been engineered to express a T-cell receptor
           (TCR) that recognizes a blood type,HLA-A 0201 (human leukocyte antigen) derived from the
           gp100 protein. A retroviral vector was constructed that can deliver the T-cell receptor
           (TCR) to cells.

        -  Patients' cells will be converted into cells able to recognize and fight melanoma
           tumors.

      Objectives:

        -  To determine whether TCR-engineered lymphocytes can be put in cells removed from
           patients' tumors or blood and then reinfused, with the purpose of shrinking tumors.

        -  To evaluate safety and effectiveness of the treatment.

      Eligibility:

        -  Patients 18 years of age or older with metastatic cancer melanoma (cancer that has
           spread beyond the original site).

        -  Patient's leukocyte antigen type is HLA-A 0201.

      Design:

      -Patients undergo the following procedures:

        -  Leukapheresis (on two occasions). This is a method of collecting large numbers of white
           blood cells. The cells obtained in the first leukapheresis procedure are grown in the
           laboratory, and the anti-MART-1 protein is inserted into the cells using an inactivated
           (harmless) virus in a process called retroviral transduction. Cells collected in the
           second leukapheresis procedure are used to evaluate the effectiveness of the study
           treatment.

        -  Chemotherapy. Patients are given chemotherapy through a vein (intravenously, IV) over 1
           hour for 2 days to suppress the immune system so that the patient's immune cells do not
           interfere with the treatment.

        -  Treatment with anti-melanoma antigen recognized by T-cells (MART)-1. Patients receive an
           intravenous (IV) infusion of the treated cells containing anti-MART-1 protein, followed
           by infusions of a drug called IL-2 (aldesleukin), which helps boost the effectiveness of
           the treated white cells.

        -  Patients are given support medications to prevent complications such as infections.

        -  Patients may undergo a tumor biopsy (removal of a small piece of tumor tissue).

        -  Patients are evaluated with laboratory tests and imaging tests, such as CT (computed
           tomography) scans, 4 to 6 weeks after treatment and then once a month for 3 to 4 months
           to determine the response to treatment.

        -  Patients have blood tests at 3, 6, and 12 months and then annually for 5 years.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Metastatic melanoma with measurable disease

               2. Previously received high dose IL-2 (aldesleukin) and have been either
                  non-responders (progressive disease) or have recurred.

               3. Positive for MART-1 by immunohistochemistry (IHC)

               4. Greater than or equal to 18 years of age.

               5. Willing to sign a durable power of attorney

               6. Able to understand and sign the Informed Consent Document

               7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

               8. Life expectancy of greater than three months.

               9. Patients of both genders must be willing to practice birth control for four
                  months after receiving the preparative regimen.

              10. Patients must be human leukocyte antigen (HLA-A)*0201 positive

              11. Serology:

               1. 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.)

               2. Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen
                  negative.

               3. Women of child-bearing potential must have a negative pregnancy test because of
                  the potentially dangerous effects of the preparative chemotherapy on the fetus.

             l. Hematology:

               1. Absolute neutrophil count greater than 1000/mm^3 without the support of
                  filgrastim.

               2. White blood cell (WBC) (greater than 3000/mm^3).

               3. Platelet count greater than 100,000/ mm^3.

               4. Hemoglobin greater than 8.0 g/dl.

             m. Chemistry:

               1. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or
                  equal to 2.5 times the upper limit of normal.

               2. Serum creatinine less than or equal to 1.6 mg/dl.

               3. 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.

             n. 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).

             o. Six weeks must have elapsed since prior anti-CTLA4 antibody therapy to allow
             antibody levels to decline.

             p. Patients who have previously received anti-CTLA4 antibody must have a normal
             colonoscopy with normal colonic biopsies.

        EXCLUSION CRITERIA:

          1. Patients with reactive TIL (IFN-gamma release greater than 200 pg/mL) available based
             on overnight co-culture assay with autologous tumor or MHC-matched tumor cells.

          2. Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

          3. 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.

          4. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
             Disease).

          5. 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).

          6. Systemic steroid therapy.

          7. History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          8. History of coronary revascularization or ischemic symptoms.

          9. Any patient known to have an left ventricular ejection fraction (LVEF) less than or
             equal to 45 percent.

         10. Documented LVEF of less than or equal to 45 percent 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.

               -  Age greater than or equal to 60 years old.

         11. Documented forced expiratory volume 1 (FEV1) less than or equal to 60 percent
             predicted tested in patients with:

               -  A prolonged history of cigarette smoking (20 pk/yrs of smoking).

               -  Symptoms of respiratory dysfunction.