Prospective Randomized Comparative Study of Cell Transfer Therapy Using CD8+-Enriched Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Compared to High-Dose Aldesleukin in M...
Condition: Skin Cancer; Melanoma; Metastatic Melanoma
MeSH terms: Melanoma; Skin Neoplasms
Intervention: Aldesleukin; CD8 enriched Young TIL
Intervention description: Aldesleukin 720,000 IU/kg IV over 15 minute every eight hours and continuing for up to 5 days (maximum of 15 doses). Patients will receive one additional cycle of aldesleukin approximately 10-14 days after completion of the first cycle of aldesleukin.; Adoptive Cell Therapy consisting of the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of between 1x10^9 to 2x10^11 CD8+ enriched tumor infiltrating lymphocytes (minimum of 5 x 10^8) and the administration of high-dose aldesleukin.
Intervention MeSH terms: Aldesleukin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Immunotherapy; Metastatic Melanoma; Randomized; Cell Therapy; Skin Cancer; Melanoma

Summary:

      Background:

      - Adoptive cell therapy involves taking white blood cells called lymphocytes from patients'
      tumors, growing them in the laboratory in large numbers, and then giving the cells back to
      the patient to allow the cells to attack the tumor. Because this process is lengthy and
      difficult to perform, researchers have been developing improved means of performing adoptive
      cell therapy. Researchers are now interested in comparing adoptive cell therapy with the
      standard treatment for metastatic melanoma (skin cancer).

      Objectives:

      - To compare the effectiveness of adoptive cell therapy with standard high-dose aldesleukin
      as a treatment for metastatic melanoma.

      Eligibility:

        -  Individuals 18 years of age or older who have been diagnosed with metastatic melanoma
           and have not previously received aldesleukin therapy or cell therapy for their disease.

        -  Participants must have at least one tumor that can be easily removed as part of the
           treatment procedure.

      Design:

        -  Participants will be screened with a full medical history, physical examination, blood
           and urine tests, and imaging scans to evaluate tumor size and treatment options.

        -  Participants will be separated into two groups, in which one group will have adoptive
           cell therapy and one will have aldesleukin treatment.

        -  Adoptive Cell Therapy

             -  Participants will have a tumor sample taken in order to collect white blood cells
                for treatment. Participants whose tumors do not provide sufficient white blood
                cells may be switched to the aldesleukin-only treatment group.

             -  The white blood cells will be grown in the laboratory for several weeks.

             -  Prior to receiving cell therapy, participants will receive chemotherapy for 7 days
                to improve the chances of successful treatment.

             -  Participants will have cell therapy followed by high-dose aldesleukin treatment
                every 8 hours for up to 5 days. This treatment will be followed by 1 to 2 weeks of
                recovery time as an inpatient at the clinical center.

             -  Participants will be evaluated at 12 weeks following the start of the study, every
                2 to 3 months for the first year, every 6 months for the next 5years, and then
                yearly thereafter..

        -  Standard Aldesleukin Treatment

             -  Participants will have high-dose aldesleukin treatment every 8 hours for up to 5
                days (one cycle of treatment), and will have a second cycle of treatment 7 to 10
                days after the first cycle.

             -  If tests show that the tumors have grown, participants will be offered the chance
                to have additional cycles of aldesleukin, or begin a cell therapy treatment.

        -  Participants will be evaluated at 12 weeks following the start of the study, every 2 to
           3 months for the first year, every 6 months for the next 5years, and then yearly
           thereafter.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Measurable metastatic melanoma with at least one lesion that is resectable for
                  tumor infiltrating lymphocytes (TIL) generation. The lesion must be of at least
                  2cm in diameter that can be surgically removed with minimal morbidity (defined as
                  any operation for which expected hospitalization is less than or equal to 7
                  days).

               2. 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.

               3. No prior high-dose aldesleukin therapy at a dose of greater than or equal to
                  600,000 IU/kg.

               4. Greater than or equal to 18 years of age.

               5. Willing to practice birth control during treatment and for four months after
                  receiving all protocol related therapy.

               6. Life expectancy of greater than three months.

               7. Willing to sign a durable power of attorney.

               8. Able to understand and sign the Informed Consent Document.

               9. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

              10. 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

             k. 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 antigen, or hepatitis C antibody or antigen.

             l. Chemistry:

          -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than three
             times the upper limit of normal.

          -  Calculated creatinine clearance estimated glomerular filtration rate(eGFR) > 50
             ml/min.

          -  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.

             m. More than four weeks must have elapsed since any prior systemic therapy at the time
             the time of randomization, and patients' toxicities must have recovered to a grade 1
             or less (except for alopecia or vitiligo). Patients must have stable or progressing
             disease after prior treatment. 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.

             n. Six weeks must have elapsed since any prior anti-CTLA4 antibody therapy to allow
             antibody levels to decline.

             o. Patients who have previously received any cytotoxic T-lymphocyte antigen 4
             (anti-CTLA4) antibody and have documented gastrointestinal (GI) toxicity must have a
             normal colonoscopy with normal colonic biopsies.

        EXCLUSION CRITERIA:

          1. Prior cell transfer therapy which included a non-myeloablative or myeloablative
             chemotherapy regimen.

          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 requirement.

          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 Immunodeficiency 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. In patients > 60 years old, documented LVEF of less than or equal to 45%.

         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