Radiation, Chemotherapy, Vaccine and Anti-MART-1 and Anti-gp100 Cells for Patients With Metastatic Melanoma
Condition: Melanoma; Skin Cancer
MeSH terms: Melanoma
Intervention: MART-1: 26-35(27L) Peptide; Montanide ISA 51 VG; gp100:154-162 Peptide; Radiation; Aldesleukin; Fludarabine; Cyclophosphamide; Anti-gp 100:154 TCR PBL; Anti-MART-1 F5 TCR PBL
Intervention description: Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population).
One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14.; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population).
One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14.; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population).
One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14.; 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute; Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).; Day -6 to -2: Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days; Day -6 to -5: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with mesna15 mg/kg/day over 1 hr X 2 days.; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population).
One mg of either the gp100:154-162 or theMART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population).
One mg of either the gp100:154-162 or theMART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine; Interleukin-2; Monatide (IMS 3015)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Metastatic Melanoma; Tumor Regression; Safety; Immunotherapy

Summary:

      Background:

        -  Melanoma antigen recognized by T-cells (MART-1) and gp100 are two genes found in
           melanoma cells. An experimental procedure developed for treating patients with advanced
           melanoma uses these genes and a type of virus to make special cells called anti-MART-1
           and anti-gp100 cells, which are designed to destroy the patient's tumor. The cells are
           created in the laboratory using the patient's own tumor cells or blood cells.

        -  The procedure also uses one of two vaccines-the anti-MART-1 peptide or the anti-gp100
           peptide-to stimulate cells in the immune system that may increase the effectiveness of
           the anti-MART-1 and anti-gp100 cells. Both vaccines are made from a virus that is
           modified to carry a copy of the MART-1 gene or gp100 gene. The virus cannot cause
           disease in humans.

      Objectives:

      - To evaluate the safety and effectiveness of anti-MART-1 and anti-gp100 cells and peptide
      vaccines for treating patients with advanced melanoma.

      Eligibility:

      - Patients 18 years of age with metastatic melanoma for whom standard treatments, including
      aldesleukin (IL-2) therapy to boost immune response, have not been effective.

      Design:

        -  Participants have an initial evaluation with complete medical history, as well as scans,
           x-rays, and other tests as directed by researchers. Most of the treatments for this
           study will be given on an inpatient basis.

        -  Before the treatment begins, participants will undergo leukapheresis (removal of
           selected blood cells) to obtain cells for preparing the anti-MART-1 and anti-gp100
           cells, and for later stem cell transplantation.

        -  Preinfusion treatment: 5 days of chemotherapy and 2 days of total-body irradiation to
           prepare the immune system for receiving the anti-MART-1 and anti-gp100 cells.

        -  Infusion of cells, followed by IL-2 treatment to improve immune response. IL-2 is given
           as a 15-minute infusion through a vein every 8 hours for a maximum of 15 doses (over 5
           days).

        -  After the cell infusion, participants will be divided into two groups and will receive
           either the gp100 peptide or MART-1 vaccine, given once a week for 3 weeks. Participants
           will also have stem cell transplantation (from previously collected stem cells) to
           promote cell survival.

        -  Periodic follow-up clinic visits after hospital discharge for physical examination,
           review of treatment side effects, laboratory tests and scans every 1 to 6 months.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Metastatic melanoma with measurable disease.

               2. Previously received aldesleukin (IL-2) and have been either non-responders
                  (progressive disease) or have recurred.

               3. Positive for gp100 and melanoma antigen recognized by T-cells (MART-1) (at least
                  1 plus and greater than 5 percent) as assessed by immunohistochemistry (IHC) in
                  the Clinical Laboratory Improvement Amendments (CLIA) approved test in the
                  Laboratory of Pathology, Center for cancer Research (CCR), National Cancer
                  Institute (NCI), National Institutes of Health (NIH).

               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 from the time
                  of enrollment on this study and for up to four months after receiving the
                  preparative regimen.

              10. Must be human leukocyte antigens (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.

             l. Hematology:

               1. Absolute neutrophil count greater than 1000/m^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 anti-CTLA4 (cytotoxic T-lymphocyte antigen
             4) antibody therapy to allow antibody levels to decline, and patients who have
             previously received anti-CTLA4 antibody must have a normal colonoscopy with normal
             colonic biopsies.

        EXCLUSION CRITERIA:

          1. 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.

          2. 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.

          3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
             Disease).

          4. Systemic steroid therapy.

          5. History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          6. History of coronary revascularization

          7. Documented left ventricular ejection fraction (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

        h. Documented forced expiratory volume 1 (FEV1) less 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