Chemotherapy, Irradiation, Cell Infusions, and Interleukin-2 to Treat Metastatic Melanoma
Condition: Metastatic Melanoma
MeSH terms: Melanoma
Intervention: Melanoma Reactive TIL; Cyclophosphamide; IL-2; Fludarabine; 1200 total body irradiation (TBI)
Intervention description: 60 mg/kg/ day x 2 days intravenous; 720,000 IU/kg/dose every 8 hours for up to 15 doses; 25 mg/m^2/day intravenous x 5 days; 1200 cGY total body radiation
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Clinical Response; Stage IV Melanoma; Adoptive Cell Therapy; Tumor Infiltrating Lymphocytes; Immunologic Response; Metastatic Melanoma

Summary:

      Background:

        -  In a study in humans with melanoma, patients given total body irradiation to suppress
           the immune system in conjunction with chemotherapy showed a significant clinical
           response.

        -  In previous studies, about one-half of patients given tumor-fighting cells (cells
           created from the patient's tumor cells and grown in the laboratory) showed some
           anti-tumor response.

      Objective: To determine whether tumor-fighting cells taken from a melanoma tumor and grown in
      the lab can more effectively at fight melanoma when the patient's immune system is suppressed
      and cannot attack them.

      Eligibility: Patients 18 years of age or older with metastatic melanoma who have tumor
      reactive cells available.

      Design:

      -Patients are assigned to one of two groups - those having received prior therapy with
      Interleukin-2 (IL-2) and those who have not.

      After five days of injections of filgrastim, a medicine to stimulated the growth of white
      blood cells, patients undergo apheresis or bone marrow harvesting, or both, to collect stem
      cells for later re-infusion. For apheresis, whole blood is collected through a needle in an
      arm vein and circulated through a cell-separating machine where the stem cells are extracted.
      The rest of the blood is returned through the same needle or a needle in the other arm. Bone
      marrow harvesting is done under general anesthesia. Stem cells are collected through a large
      needle inserted into the hipbone.-Patients' immune system cells and bone marrow function are
      eliminated with chemotherapy (7 days) and total body irradiation (3 days) so the patient's
      immune system cells will not fight the tumor-fighting cells they are given in treatment.

        -  1 to 3 days after total body irradiation, patients receive the tumor-fighting cells by
           intravenous (IV) infusion. After the cells are infused, they receive interleukin-2
           (IL-2) infusions every 8 hours for 5 days.

        -  2 days after infusion of the tumor-fighting cells, patients receive the stem cells
           collected earlier by apheresis.

        -  Patients are evaluated 4 to 6 weeks after cell infusion to look for tumor response to
           treatment. Patients whose tumor has not grown return to the National Institutes of
           Health (NIH) every 1 to 3 months for blood tests, scans and x-rays.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Patients must have tumor reactive cells obtained and evaluated while participating in the
        Surgery Branch protocol, "Cell Harvest and Preparation for Surgery Branch Adoptive Cell
        Therapy Protocols" or on another Institutional Review Board (IRB) approved Surgery Branch
        adoptive cell therapy study, i.e. 99-C-0158 or 03-C-0162.

        The first ten patients enrolled must have previously received interleukin-2 (IL-2) and have
        been either non-responders (progressive disease) or have recurred.

        Patients must be greater than or equal to 18 years of age and must have measurable
        metastatic melanoma.

        Patients of both genders must be willing to practice birth control during treatment and for
        four months after receiving the preparative regimen.

        Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, 1.

        Absolute neutrophil count greater than 1000/mm^3 without support of filgrastim.

        Platelet count greater than 100,000/mm^3.

        Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than three 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 mg/dl, except in patients with Gilbert's Syndrome
        who must have a total bilirubin less than 3 mg/dl.

        Must be willing to sign a durable power of attorney.

        Patients must be able to understand and sign the Informed Consent document.

        Patients with resected or stable brain metastases will be eligible.

        Left ventricular ejection fraction (LVEF) greater than or equal to 45%.

        Carbon monoxide diffusing capacity (DLCO) greater than or equal to 60% predicted.

        CELL INFUSION EXCLUSION CRITERIA:

        Less than 30 days has elapsed since any prior systemic therapy at the time the patient
        receives the preparative regimen, or less than six weeks since prior nitrosurea therapy.
        All patients' toxicities must have recovered to a grade 1 or less or as specified in the
        eligibility criteria. 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
        eligibility criteria.

        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.

        Life expectancy of less than three months.

        Systemic steroid therapy required.

        Hemoglobin less than 8 g/dl unable to be corrected with transfusion.

        Any 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 or secondary immunodeficiency. Must have recovered immune competence
        after chemotherapy or radiation therapy as evidenced by normal ANC greater than 1000/mm^3
        and absence of 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.)

        Seropositive 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.)

        Patients with hepatitis B or hepatitis C will be excluded.

        Seronegative for Epstein-Barr virus (EBV).

        Patients who are not willing to complete a durable power of attorney (DPA) will be
        excluded.

        Patients who have received prior preparative regimens with cyclophosphamide and fludarabine
        on prior Surgery Branch adoptive cell therapies will be excluded.

        The following patients will be excluded because of inability to receive high dose IL-2:

        Patients will be excluded if they have a history of electrocardiogram (EKG) abnormalities,
        symptoms of cardiac ischemia or arrhythmias and have a LVEF less than 45% on a cardiac
        stress test (stress thallium, stress multi-gated acquisition scan (MUGA), dobutamine,
        echocardiogram or other stress test).

        Similarly, patients who are 50 years old or greater with an LVEF less than 45% will be
        excluded.

        Patients who have a prolonged history of cigarette smoking or symptoms of respiratory
        dysfunction will be excluded if they have an abnormal pulmonary function test as evidenced
        by a forced expiratory volume 1 (FEV1) less than 60% predicted.