Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Ocular Melanoma
Condition: Metastatic Ocular Melanoma; Metastatic Uveal Melanoma
MeSH terms: Melanoma
Intervention: Aldesleukin; Cyclophosphamide; Fludarabine; Young Tumor Infiltrating Lymphocytes (TIL)
Intervention description: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses) (only for cohort A).; Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr.; Fludarabine 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.; Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of young TIL and high dose aldesleukin (Cohort A) or no aldesleukin (Cohort B). On day 0,cells (1x10e9 to 2x10e11) will be infused intravenously on the Patient Care Unit over 20-30 minutes.
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine; Interleukin-2
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 16 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Metastatic; Ocular Melanoma; Autologous Tumor-Infiltrating Lymphocytes; Uveal Melanoma; Adoptive Cell Therapy

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 200
      patients with melanoma. This study will use chemotherapy to prepare the immune system before
      this white blood cell treatment. After receiving the cells, the drug aldesleukin (IL-2) may
      be given to help the cells stay alive longer.

      Objectives:

      - To see if chemotherapy and white blood cell therapy is a safe and effective treatment for
      advanced ocular melanoma.

      Eligibility:

      - Individuals at least greater than or equal to 16 years to less than or equal to 75 years
      who have advanced ocular melanoma.

      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 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 ocular melanoma.

               2. Confirmation of diagnosis of metastatic ocular 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. Patients with surgically resected brain metastases are
                  eligible.

               4. Greater than or equal to 16 years of age and less than or equal to age 75.

               5. Able to understand and sign the Informed Consent Document

               6. Willing to sign a durable power of attorney

               7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1

               8. Life expectancy of greater than three months

               9. 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 receiving the
                  treatment.

              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 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 (HCV) ribonucleic acid (RNA)
                       negative.

              11. Women of child-bearing potential must have a negative pregnancy test because of
                  the potentially dangerous effects of the treatment on the fetus.

              12. 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 100,000/mm^3

                    -  Hemoglobin > 8.0 g/dl

              13. Chemistry:

                    -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less
                       than or equal to 3.5 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
                       Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

              14. 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).

        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.

        EXCLUSION CRITERIA:

          1. Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the treatment on the fetus or infant.

          2. 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.

          3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
             Disease).

          4. 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).

          5. Concurrent systemic steroid therapy.

          6. History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          7. The following patients will be excluded from the high-dose aldesleukin arm (but may be
             eligible for cells alone arm):

               1. History of coronary revascularization or ischemic symptoms

               2. 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

               3. Clinically significant patient history which in the judgment of the Principal
                  Investigator would compromise the patients ability to tolerate aldesleukin