Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma
Condition: Metastatic Melanoma; Skin Cancer
MeSH terms: Melanoma; Skin Neoplasms
Intervention: Cyclophosphamide; Fludarabine; Young Tumor Infiltrating Lymphocytes (TIL)
Intervention description: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr.; Fludarabine 25 mg/m2/day intravenous piggyback (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. On day 0, cells (1x10e9 to 2x10e11) will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Metastatic Melanoma; Adoptive Cell Therapy; Skin Cancer

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 with
           aldesleukin (IL-2) a drug that keeps the white blood cells active. 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. Our prior studies indicate that aldesleukin may not be required for cell
           transfer.

      Objectives:

      - To see if chemotherapy and white blood cell therapy without aldesleukin is a safe and
      effective treatment for metastatic melanoma.

      Eligibility:

      - Individuals at least 18 years of age and less than or equal to 70 years of age with
      metastatic melanoma.

      Design:

        -  Work up stage: Patients will be seen as an outpatient at the National Institute 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 will take up
           to 2 days.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Measurable metastatic melanoma with available autologous tumor infiltrating
             lymphocytes (TIL).

          -  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.

          -  Greater than or equal to 18 years of age and less than or equal to 70 years of age.

          -  Able to understand and sign the Informed Consent Document

          -  Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

          -  Life expectancy of greater than three months

          -  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.

          -  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.

          -  Women of child-bearing potential must have a negative pregnancy test because of the
             potentially dangerous effects of the treatment on the fetus.

          -  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

          -  Chemistry:

          -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than or
             equal to to 2.5 times the upper limit of normal

          -  Serum Creatinine less than or equal to to 1.6 mg/dl

          -  Total bilirubin less than or equal to to 1.5 mg/dl, except in patients with Gilberts
             Syndrome who must have a total bilirubin less than 3.0 mg/dl.

          -  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.

          -  Six weeks must have elapsed since any prior antibody therapy including anti-cytotoxic
             T-lymphocyte antigen 4 (CTLA4) antibody therapy that could affect any anti-cancer
             immune response, 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 colonoscopy with normal
             colonic biopsies.)

          -  Patients must be ineligible to receive interleukin-2 (IL-2) based on evidence that may
             include ischemic heart disease, or arrhythmias, or poor ventricular ejection fraction
             (< 50%), or respiratory compromise (forced expiratory volume in 1 second (FEV1) <
             60%), or clinically significant patient history which in the judgment of the
             investigator would compromise the patients ability to tolerate aldesleukin.

        EXCLUSION CRITERIA:

          -  Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the treatment on the fetus or infant.

          -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
             Disease).

          -  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).

          -  Concurrent systemic steroid therapy.

          -  History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          -  Patients with a ventricular ejection fraction (less than or equal to 30%), or
             respiratory compromise (FEV1 less than or equal to 40%).