Modified Tumor Infiltrating Lymphocytes for Metastatic Melanoma
Condition: Metastatic Melanoma; Skin Cancer
MeSH terms: Melanoma; Skin Neoplasms
Intervention: Cyclophosphamide; Fludarabine; Aldesleukin; Tumor Infiltrating Lymphocytes
Intervention description: 60 mg/kg/day X 2 days intravenous (IV) over 1 hour on days -7 and -6; 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days (days -5 to -1); 720,000 IU/kg intravenous (IV) over 15 min every 8 hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 5 days (max. 15 doses.); Intravenous (IV) over 30 minutes on day 0
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Immunotherapy; Cell Therapy; Metastatic Cancer; Melanoma; Metastatic Melanoma; Skin Cancer

Summary:

      Background:

      - Tumor infiltrating lymphocytes (TIL) are white blood cells that have been taken from tumor
      tissue. The cells are modified to help them kill tumor cells, then given back to the person
      with cancer. By giving these cells to patients, researchers hope to improve the current
      treatments available for patients with melanoma that has not responded to standard therapies.
      The TIL will be given after treatments that will suppress the immune system. This makes it
      easier for the TIL to attack the cancer cells. The TIL will also be given with aldesleukin
      (IL-2), which is designed to help keep the TIL cells alive in the body.

      Objectives:

      - To study the safety and effectiveness of specially modified tumor infiltrating lymphocytes
      to treat melanoma that has not responded to other treatments.

      Eligibility:

      - Individuals at least 18 years of age who have metastatic melanoma that has not responded to
      other treatments.

      Design:

        -  Participants will be screened with a physical exam and medical history. They will also
           have blood tests and imaging studies.

        -  A piece of tumor will be collected and white blood cells will be separated to make the
           TIL for the treatment.

        -  Participants will take drugs to suppress the immune system for 7 days before the start
           of treatment.

        -  Participants will receive the TIL in a single dose. Then they will receive IL-2 every 8
           hours for up to 15 doses. Participants will remain in the hospital for up to 2 weeks
           after treatment. They will be monitored with frequent blood tests and other studies.

        -  After leaving the hospital, participants will have regular followup visits every 1 to 4
           months for the first year. Then they will return for followup every 3 to 4 months, as
           directed by the study researchers.
    

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 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. Greater than or equal to 18 years of age.

               4. Willing to sign a durable power of attorney

               5. Able to understand and sign the Informed Consent Document

               6. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

               7. Life expectancy of greater than three months.

               8. 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
                  preparative regimen.

               9. Serology:

                    1. Seronegative for human immunodeficiency virus (HIV) antibody. (The
                       experimental treatment being evaluated in this protocol depends on an intact
                       immune system. Patients engineered cells with costimulation enhancement
                       (ECCE) TIL 14 who are HIV seropositive can have decreased immune-competence
                       and thus be less responsive to the experimental treatment and more
                       susceptible to its toxicities.)

                    2. 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.

                    3. Women of child-bearing potential must have a negative pregnancy test because
                       of the potentially dangerous effects of the preparative chemotherapy on the
                       fetus.

              10. Hematology:

                    1. Absolute neutrophil count greater than 1000/mm^3 without the support of
                       filgrastim.

                    2. White blood cell (WBC) (> 3000/mm^3).

                    3. Platelet count greater than 100,000/mm^3.

                    4. Hemoglobin greater than 8.0 g/dl.

              11. Chemistry:

                    1. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less
                       or equal to 2.5 times the upper limit of normal.

                    2. Serum creatinine less than or equal to 1.6 mg/dl.

                    3. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with
                       Gilbert's Syndrome who must have a total bilirubin less than 3.0 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 within the past
                  3 weeks, as long as all toxicities have recovered to grade 1 or less.

              13. Six weeks must have elapsed since any prior anti-cytotoxic T-lymphocyte antigen 4
                  (CTLA4) antibody therapy to allow antibody levels to decline.

              14. Patients who have previously received any anti-CTLA4 antibody and have documented
                  gastrointestinal (GI) toxicity must have a normal colonoscopy with normal colonic
                  biopsies.

        EXCLUSION CRITERIA:

          1. 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.

          2. Systemic steroid therapy required.

          3. Active systemic infections, coagulation disorders or other major medical illnesses of
             the cardiovascular, respiratory or immune system, 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 ECCE TIL 15 have
             decreased immune competence may be less responsive to the experimental treatment and
             more susceptible to its toxicities).

          6. History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          7. History of coronary revascularization or ischemic symptoms

          8. Any patient known to have an left ventricular ejection fraction (LVEF) less than or
             equal to 45%.

          9. 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

         10. 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