Phase II Study of Short-Term Cultured Anti-Tumor Autologous Lymphocytes After Lymphocyte-Depleting Chemotherapy in Metastatic Melanoma
Condition: Melanoma; Malignant Melanoma; Melanoma, Experimental; Experimental Melanomas
MeSH terms: Melanoma; Melanoma, Experimental
Intervention: aldesleukin; therapeutic autologous lymphocytes; Cyclophosphamide; Fludarabine phosphate; Total body irradiation
Intervention description: Given subcutaneously every 8 hours for up to 15 doses, day 0, 720,000 IU/kg; Given as infusion, up to 3 x 10^11 lymphocytes (minimum of 1 x 10^9), day 0; Given intravenously 60 mg/kg/day, day -7 to -6; Given intravenously 25 mg/m^2/day over 15-30 minutes, day -5 to -1; 600 cGy
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine; Fludarabine phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 158.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Clinical Response; Immunotherapy; Cancer; Cytokines; Adoptive Cell Therapy; Melanoma; Skin Cancer; Malignant Melanoma

Summary:

      Background:

        -  Most therapeutic therapies for metastatic melanoma have focused on the ability of T-cell
           lymphocytes to kill cells of tumors.

        -  An adaptive cell transfer therapy has been pioneered, in which cells are grown for a
           short time in the laboratory. The way they are grown may have a better effect in a
           patient's body than do other cells that are cultured for a longer time.

      Objectives:

        -  To determine whether tumor-infiltrating lymphocytes (TIL) 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 human leukocyte antigens (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 TIL cells (called young TIL cells) are 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 young TIL cells. Patients receive an IV infusion of the treated cells,
           followed by infusions the drug aldesleukin-2 (IL-2), 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 computed
           tomography (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. Measurable metastatic melanoma with at least one lesion that is resectable for tumor
             infiltrating lymphocytes (TIL) generation.

          2. Patients with one to three brain metastases are eligible (lesions greater than or
             equal to 1 cm each, or symptomatic lesions must have been treated and stable for 3
             months).

          3. Greater than or equal to 18 years of age .

          4. Willing to practice birth control during treatment and for four months after receiving
             the preparative regimen.

          5. Life expectancy of greater than three months.

          6. Willing to sign a durable power of attorney.

          7. Able to understand and sign the Informed Consent Document.

          8. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

          9. Hematology:

               -  Absolute neutrophil count greater than 1000/mm^3 without support of filgrastim.

               -  Normal white blood cell (WBC) (greater than 3000/ mm^3).

               -  Hemoglobin greater than 8.0 g/dl.

               -  Platelet count greater than 100,000/ mm^3.

         10. 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.

         11. Chemistry: . 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.

         12. 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).
             Patients may have undergone minor surgical procedures with the past 3 weeks, as long
             as all toxicities have recovered to grade 1 or less or as specified in the eligibility
             criteria in Section 2.1.1.

         13. Six weeks must have elapsed since prior MDX-010 (Ipilimumab) therapy to allow antibody
             levels to decline.

         14. Patients who have previously received any anti-CTLA4 (cytotoxic T-lymphocyte antigen
             4) antibody and experienced treatment related colitis must have a normal colonoscopy
             with normal colonic biopsies.

        EXCLUSION CRITERIA:

          1. Prior cell transfer therapy that included non-myeloablative or ablative chemotherapy
             (for cohorts 4 and 5).

          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. Systemic steroid therapy required.

          4. 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.

          5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease
             and Acquired Immune Deficiency Syndrome (AIDS)).

          6. 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.)

          7. History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          8. History of coronary revascularization or ischemic symptoms.

          9. Any patient known to have an left ventricular ejection fraction (LVEF) less than or
             equal to 45%.

         10. Documented LVEF of less than or equal to 45% 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.

         11. Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted
             tested in patients with:

               -  A prolonged history of cigarette smoking

               -  Symptoms of respiratory dysfunction