Drosophila-generated CTL
Condition: Metastatic Cutaneous Melanoma
MeSH terms: Melanoma
Intervention: fludarabine; cyclophosphamide; Drosophila-peptide pulsed Melanoma-reactive autologous CD8+ PBL; Aldesleukin
Intervention description: Fludarabine 25 mg/m^2 x 5 days; Cyclophosphamide 60 mg/kg intravenous (IV) x 2 days; Up to 1x10e10 CTL-05 cells; Aldesleukin 125,000 IU/kg/dose as a daily subcutaneous injection
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Skin Cancer; Malignancy; Immunotherapy; Melanoma Peptides; Melanoma; Metastatic Melanoma

Summary:

      Background:

        -  Recent cancer treatment studies have shown that altering a cancer patient's own white
           blood cells may help the immune system fight the cancer. In all of these studies,
           participants donate their own white blood cells through a procedure called
           leukapheresis, and the cells are altered in the laboratory and given back to the
           participants. After the cells are given, the patients receive aldesleukin (IL-2) to help
           the tumor fighting cells stay alive longer. For individuals with metastatic melanoma,
           pieces of melanoma proteins may be added to the collected white blood cells to help the
           immune system recognize and attack the cancer cells.

        -  Researchers are interested in testing a new process in which cells from fruit flies
           (Drosophila) are used to help the melanoma proteins attach to the white blood cells. The
           fruit fly cells die off shortly after the proteins are introduced to the white blood
           cells. Researchers are also interested in determining whether IL-2 treatment is
           necessary after this new cancer treatment process.

      Objectives:

        -  To test the safety and effectiveness of modified white blood cells (Drosophila-generated
           CTL) as a treatment for metastatic melanoma that has not responded to standard
           treatments.

        -  To determine whether IL-2 treatment improves the effectiveness of Drosophila-generated
           cytolytic T lymphocytes (CTL).

      Eligibility:

      - Individuals at least 18 years of age who have been diagnosed with metastatic melanoma that
      has not responded to previous IL-2 treatment.

      Design:

        -  Participants will be screened with a physical examination and medical history, tumor
           imaging studies, and heart and lung function tests.

        -  Prior to treatment, participants will have an intravenous catheter inserted into the
           chest to administer the study drugs.

        -  Participants will have leukapheresis to provide white blood cells for laboratory
           modification.

        -  Seven days before the start of the treatment, participants will be admitted to the
           hospital to have chemotherapy with cyclophosphamide and fludarabine. These drugs will
           suppress the immune system to improve the effects of the treatment.

        -  One to four days after the last dose of chemotherapy, participants will receive the
           modified cells. Participants in the group that will receive IL-2 will begin to receive
           the treatment 24 hours after the cell infusion, every day for 5 days. All participants
           will receive filgrastim injections to help the body produce more white blood cells.

        -  Participants will recover in the hospital for about 7 to 12 days after the cell infusion
           or the last dose of IL-2. Participants will continue to receive medications and provide
           blood and tumor samples for testing.

        -  Participants will have regular followup visits to assess the effects of the treatment.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Metastatic cutaneous melanoma with measurable disease by Response Evaluation
                  Criteria in Solid Tumors (RECIST) criteria

               2. Previously received high dose-aldesleukin and have been either non-responders
                  (progressive disease) or have recurred.

               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. Greater than or equal to 18 years of age.

               5. Able to understand and sign the Informed Consent Document

               6. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

               7. Life expectancy of greater than three months.

               8. Patients of both genders must be willing to practice a highly effective method of
                  birth control during and for four months following treatment

               9. Patients must be HLA-A*0201 positive

              10. 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.

              11. Hematology:

                    1. Absolute neutrophil count greater than 1000/mm^3 without the support of
                       filgrastim.

                    2. White blood cell (WBC) (> 3000/mm^3).

                    3. Platelet count greater than 100,000/mm^3.

                    4. Hemoglobin greater than 8.0 g/dl.

              12. 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.

              13. 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 hypothyroidism, alopecia, or
                  vitiligo).

              14. Six weeks must have elapsed since prior anti-CTLA4 antibody therapy to allow
                  antibody levels to decline.

              15. Patients who have previously received anti-CTLA4 antibody must have a normal
                  colonoscopy with normal colonic biopsies.

        EXCLUSION CRITERIA:

          1. Active systemic infections, coagulation disorders or other active major medical
             illnesses.

          2. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
             Disease).

          3. Concurrent 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).

          4. Requirement for systemic steroid therapy

          5. History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          6. History of coronary revascularization or ischemic symptoms

          7. Any patient known to have an left ventricular ejection fraction (LVEF) less than or
             equal to 45%.

          8. Documented LVEF of less than or equal to 45% tested in patients with:

               1. Clinically significant atrial and/or ventricular arrhythmias including but not
                  limited to: atrial fibrillation, ventricular tachycardia, second or third degree
                  heart block

               2. Age greater than or equal to 60 years old

          9. Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted
             tested in patients with:

               1. A prolonged history of cigarette smoking (20 pk/yrs of smoking)

               2. Symptoms of respiratory dysfunction

         10. Pregnant or nursing women