Melanoma Treatment With White Blood Cells That Destroy MART Expressing Tumor Cells
Condition: Metastatic Melanoma; Skin Cancer
MeSH terms: Melanoma; Skin Neoplasms
Intervention: Fludarabine; Cyclophosphamide; Aldesleukin; MART-1 Reactive CD8+ PBL
Intervention description: 25 mg/m^2 IV (in the vein) for 5 days (day -5 to -1); 60 mg/kg IV (in the vein) for days -7 and -6; Only given to patients assigned to high dose (HD) Arm - 720,000 IU/kg intravenous (IV) over 15 minutes, every 8 hrs (+/- 1 hr) for up to 5 days (max 15 doses).-6; Intravenous (IV) over 30 minutes on day 0
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: 5.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Malignant Melanoma; Immunotherapy; Cell Therapy; HLA-A2 Positive; Skin Cancer

Summary:

      Background:

      - Some cancer treatments collect a patient s own blood cells to use as specialized
      cancer-fighting cells. Collected white blood cells known as PBL (peripheral blood
      lymphocytes) can use to isolate special cells that can fight tumors. Before treatment with
      PBL, chemotherapy is given to destroy existing white blood cells so that the new cells can
      survive and attack the tumors. After PBL treatment, aldesleukin is given to help the new
      cells grow. Researchers want to see if special white blood cells that recognize a specific
      protein that is present in melanoma cells (melanoma antigen recognized by T cells (MART)) can
      cause tumors to shrink. These white blood cells will be tested with and without aldesleukin.

      Objectives:

        -  To test the safety and effectiveness of white blood cells that target MART in the
           treatment of melanoma.

        -  To test white blood cells that target MART with and without aldesleukin.

      Eligibility:

      - Individuals at least 18 years of age who have melanoma that has not responded to standard
      treatments.

      Design:

        -  Participants will be screened with a medical history and physical exam. Blood and urine
           samples will be taken. Imaging studies such as x-rays or magnetic resonance imaging
           scans will be performed.

        -  Participants will provide white blood cells through leukapheresis. Researchers will
           attempt to isolate white blood cells that recognize MART

        -  Seven days before the start of treatment, participants will have chemotherapy.

        -  After the last dose of chemotherapy, participants will receive the MART reactive PBL
           cells. Filgrastim doses will also be given to help white blood cell counts return to
           normal. Participants will have frequent blood tests.

        -  Participants who are able to have aldesleukin treatment will start within 24 hours after
           receiving the MART reactive PBL cells. Treatment will continue for up to 5 days.

        -  Participants may have an optional tumor or lymph node biopsy to study the effects of
           treatment.

        -  If the tumor continues to grow after MART PBL treatment, participants may have one more
           round of cell collection and treatment.

        -  Participants will have followup visits for up to 6 months after receiving the MART
           reactive PBL treatment.
    

Eligibility criteria:

        -INCLUSION CRITERIA:

          1. Measurable metastatic melanoma.

          2. Confirmation of diagnosis of metastatic melanoma and positivity for melanoma antigens
             recognized by T cells (MART) confirmed by the Laboratory of Pathology of the National
             Cancer Institute (NCI).

          3. 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.

          4. Patients must be refractory to high dose aldesleukin treatment.

             NOTE: This is not required for patients with non-cutaneous melanoma, patients for whom
             high dose aldesleukin is medically contraindicated or for patients who are unwilling
             to receive high dose aldesleukin.

          5. MART-1:27-35 reactive peripheral blood lymphocytes derived from a leukapheresis.

          6. Human leukocyte antigens (HLA-A) 0201 positive.

          7. Greater than or equal to 18 years of age and less than or equal to age 70.

          8. Both genders must be willing to practice birth control during treatment and for four
             months after receiving the preparative regimen.

          9. Life expectancy of greater than three months.

         10. Willing to sign a durable power of attorney.

         11. Able to understand and sign the Informed Consent Document.

         12. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1 for
             the high-dose aldesleukin cohort or ECOG 0, 1 or 2 for no aldesleukin cohort.

         13. Hematology:

               -  Absolute neutrophil count greater than 1000/mm^3 without support of filgrastim

               -  Normal white blood cell (WBC) (> 3000/mm^3).

               -  Hemoglobin greater than 8.0 g/dl

               -  Platelet count greater than 100,000/mm^3.

         14. 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 or hepatitis C. If hepatitis C antibody test is
                  positive, the patients 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

         15. Chemistry:

               -  Serum alanine aminotransaminase (ALT)/aspartate aminotransaminase (AST) less than
                  less or equal to 3 times the upper limit of normal.

               -  Serum creatinine less than or equal to 1.6 mg/dl.

               -  Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert
                  s Syndrome who must have a total bilirubin less than 3 mg/dl.

         16. More than four weeks must have elapsed since any prior systemic therapy, including
             chemotherapy, immunotherapy, and/or other targeted therapies, 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). Patients may
             have undergone minor surgical procedures within the past 3 weeks, as long as patients
             meet eligibility criteria

         17. 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, so at the time the patient receives the preparative regimen to allow
             antibody levels to decline.

         18. Patients who have previously received ipilimumab and have documented gastrointestinal
             (GI) toxicity must have a normal colonoscopy with normal colonic biopsies.

        NOTE: this is only required for patients who will receive high dose aldesleukin.

        EXCLUSION CRITERIA:

          1. Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the treatment on the fetus or infant.

          2. Systemic steroid therapy required.

          3. 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.

          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. History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          7. The following patients will be excluded from the high-dose aldesleukin arm (but may be
             eligible for cells alone arm):

               1. History of coronary revascularization or ischemic symptoms

               2. Any patient known to have an left ventricular ejection fraction (LVEF) less than
                  or equal to 45 percent.

               3. 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

               4. Documented forced expiratory volume in 1 second (FEV1) less than or equal to 60
                  percent predicted tested in patients with:

                    -  A prolonged history of cigarette smoking (20 pk/yrs of smoking within the
                       past 2 years)

                    -  Symptoms of respiratory dysfunction

               5. Clinically significant patient history which in the judgment of the Principal
                  Investigator would compromise the patients ability to tolerate aldesleukin