Immunotherapy Using 41BB Selected Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma
Condition: Melanoma; Skin Cancer
MeSH terms: Melanoma; Skin Neoplasms
Intervention: Aldesleukin; Fludarabine; Cyclophosphamide; 4-1BB Selected Tumor Infiltrating Lymphocytes (TIL)
Intervention description: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).; Fludarabine 25 mg/m^2/day (intravenous piggyback) IVPB daily X 5 days.(The fludarabine will be started approximately 1-2 hours after the cyclophosphamide on Days -5 and -4); Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml 5% dextrose in water (D5W) over 1 hr.; On day 0, cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (one to four days after the last dose of fludarabine).
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Skin Cancer; Metastatic Melanoma; Adoptive Cell Therapy; Immunotherapy; Clinical Response

Summary:

      Background:

      The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy that
      involves taking white blood cells from patients' tumors, growing them in the laboratory in
      large numbers, and then giving the cells back to the patient. These cells are called Tumor
      Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 100
      patients. In this study, we are selecting a specific subset of white blood cells from the
      tumor that we think are the most effective in fighting tumors and will use only these cells
      in making the tumor fighting cells.

      Objective:

      The purpose of this study is to see if these specifically selected tumor fighting cells can
      cause melanoma tumors to shrink and to see if this treatment is safe.

      Eligibility:

      - Adults age 18-70 with metastatic melanoma who have a tumor that can be safely removed.

      Design:

        -  Work up stage: Patients will be seen as an outpatient at the National Institutes of
           Health (NIH) clinical Center and undergo a history and physical examination, scans,
           x-rays, lab tests, and other tests as needed

        -  Surgery: If the patients meet all of the requirements for the study they will undergo
           surgery to remove a tumor that can be used to grow the TIL product.

        -  Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood
           cells. {Leukapheresis is a common procedure, which removes only the white blood cells
           from the patient.}

        -  Treatment: Once their cells have grown, the patients will be admitted to the hospital
           for the conditioning chemotherapy, the tumor infiltrating lymphocytes (TIL) cells and
           aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.

      Follow up: Patients will return to the clinic for a physical exam, review of side effects,
      lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1
      year as long as their tumors are shrinking. Follow up visits take up to 2 days.

      ...
    

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 at least 1 cm in
             diameter that can be surgically removed with minimal morbidity (defined as any
             operation for which expected hospitalization <less than or equal to days).

          2. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of the
             National Cancer Institute (NCI).

          3. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and
             asymptomatic are eligible. Lesions that have been treated with stereotactic
             radiosurgery must be clinically stable for 1 month after treatment for the patient to
             be eligible.

          4. Greater than or equal to 18 years of age and less than or equal to age 70.

          5. Able to understand and sign the Informed Consent Document

          6. Willing to sign a durable power of attorney

          7. Clinical performance status of Easter Cooperative Oncology Group (ECOG) 0 or 1

          8. Oxygen saturation of greater than or equal to 90% on room air

          9. Life expectancy of greater than three months

         10. Patients of both genders must be willing to practice birth control from the time of
             enrollment on this study and for up to four months after treatment.

         11. 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, and seronegative for hepatitis C antibody.
                  If hepatitis C antibody test is positive, then patient 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.

         12. Women of child-bearing potential must have a negative pregnancy test because of the
             potentially dangerous effects of the treatment on the fetus.

         13. Hematology

               -  Absolute neutrophil count greater than 1000/mm^3 without the support of
                  filgrastim

               -  White blood cell (WBC) greater than or equal to 3000/mm^3

               -  Platelet count greater than or equal to 100,000/mm^3

               -  Hemoglobin > 8.0 g/dl

         14. Chemistry:

               -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than
                  or equal to 2.5 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 Gilberts
                  Syndrome who must have a total bilirubin less than 3.0 mg/dl.

         15. 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 must have progressing disease after prior treatment.

             Note: 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 in Section 2.1.1.

         16. 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-associated protein
             4 (CTLA4) antibody therapy at the time the patient receives the preparative regimen to
             allow antibody levels to decline.

        Note: Patients who have previously received ipilimumab and have documented gastrointestinal
        (GI) toxicity must have a normal colonoscopy with normal colonic biopsies.

        EXCLUSION CRITERIA:

          1. Prior treatment with an anti-4-1BB antibody.

          2. Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the treatment on the fetus or infant.

          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. 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).

          6. Concurrent systemic steroid therapy.

          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. Documented left ventricular ejection fraction (LVEF) of less than or equal to 45%,
             testing is required 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