Phase II Study of Metastatic Melanoma With Lymphodepleting Conditioning and Anti-gp100:154-162 TCR Gene Engineered Lymphocytes
Condition: Skin Cancer; Melanoma
MeSH terms: Melanoma; Skin Neoplasms
Intervention: fludarabine phosphate; cyclophosphamide; aldesleukin; autologous anti-gp 100:154-162 T-cell receptor gene-engineered tumor infiltrating lymphocytes; autologous anti-gp 100:154-162 T-cell receptor gene-engineered peripheral blood lymphocytes
Intervention description: 25 mg/m^2/day intravenous piggy back over 30 minutes for 5 days.; 60 mg/kg/day x 2 days intravenous; 720,000 IU/kg intravenously over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).; Patients will receive a minimum of approximately 5 X 10^8 cells and up to 3 x10^11 anti-gp100:154-162 TCR engineered TIL .
The cells are infused intravenously over 20-30 minutes.; Patients will receive a minimum of approximately 5 X 10^8 cells and up to 3 x10^11 anti-gp100:154-162 TCR engineered PBL.
The cells are infused intravenously over 20-30 minutes.
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine; Fludarabine phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 21.0
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, human leukocyte antigen (HLA-A*0201) derived from
           the gp100 protein. A retroviral vector was constructed that can deliver the TCR to
           cells.

        -  This gene-engineered cell is over 10 times more reactive with melanoma cells than is the
           melanoma antigen recognized by T-cells (MART-1) TCR that resulted in tumor shrinkage for
           two patients with metastatic melanoma.

      Objectives:

        -  To determine whether an anti-melanoma protein receptor 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-gp100 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-gp100. Patients receive an IV infusion of the treated cells
           containing anti-gp100 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 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 aldesleukin (IL-2) and have been either
                  non-responders (progressive disease) or have recurred.

               3. Positive for gp100 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.

                  h Life expectancy of greater than three months.

             i. Patients of both genders must be willing to practice birth control for four months
             after receiving the preparative regimen.

             j. Must be human leukocyte antigen (HLA-A 0201) positive

             k. 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.

             l. Hematology:

               1. Absolute neutrophil count greater than 1000/mm^3.

               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 than
                  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. Women of child-bearing potential must have a negative pregnancy test because of the
             potentially dangerous effects of the preparative chemotherapy on the fetus.

             o. 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).

             p. Six weeks must have elapsed since prior cytotoxic T-lymphocyte antigen 4
             (anti-CTLA4) antibody therapy to allow antibody levels to decline, and patients who
             have previously received must have a normal colonoscopy with normal colonic biopsies.

        EXCLUSION CRITERIA:

          1. Patients with reactive TIL (interferon (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.

          9. Documented left ventricular ejection faction (LVEF) of less than 45 percent in
             patients with:

        a. Clinically significant atrial and/or ventricular arrhythmias including but not limited
        to: atrial fibrillation, ventricular tachycardia, 2 degree or 3 degree heart block.

        b. Age greater than or equal to 60 years old.

        j. Documented forced expiratory volume 1 (FEV1) greater than or equal to 60 percent
        predicted for patients with:

          1. A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2
             years).

          2. Symptoms of respiratory distress.