Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Human Papillomavirus-Associated Cancers
Condition: Cervical Cancer; Oropharyngeal Cancer; Vaginal Cancer; Anal Cancer; Penile Cancer
MeSH terms: Uterine Cervical Neoplasms; Anus Neoplasms; Oropharyngeal Neoplasms; Vaginal Neoplasms; Penile Neoplasms
Intervention: Fludarabine; Cyclophosphamide; Young TIL; Aldesleukin
Intervention description: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.; Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.; Cells 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).; Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 29.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Immunotherapy; HPV-Associated Cancers; Cervical Cancer; Oropharyngeal Cancer; HPV Infection

Summary:

      Background:

      The human papillomavirus (HPV) can cause a number of cancers, including cervical and throat
      cancers. 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. Researchers want to know if TIL shrink s tumors in people
      with human papilloma virus (HPV)-related cancer. 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 HPV-related cancers to shrink and to see if this treatment is safe.

      Eligibility:

      - Adults age 18-66 with HPV-related cancer 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 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:

          1. Measurable metastatic or locally advanced refractory/recurrent malignancies that are
             human papilloma virus 16 (HPV-16) or human papilloma virus 18 (HPV-18) high HPV
             positive by in situ hybridization (ISH) or polymerase chain reaction (PCR) or any
             cancer from the uterine cervix..

          2. All patients must have received at least one standard chemotherapy or
             chemoradiotherapy.

          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. 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 treatment.

          9. 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.

         10. Women of child bearing potential must have a negative pregnancy test because of the
             potentially dangerous effects of the treatment on the fetus.

         11. 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 too 100,000/mm(3)

               -  Hemoglobin greater than 8.0 g/dl

         12. 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 that 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.

         13. 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 in Section 2.1.1.

         14. More than four weeks must have elapsed since any prior radiation therapy.

        EXCLUSION CRITERIA:

          1. Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the preparative chemotherapy 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. 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 i) clinically
             significant atrial and/or ventricular arrhythmias including but not limited to: atrial
             fibrillation, ventricular tachycardia, second or third degree heart block or ii) age
             greater than or equal 60 years old.

         10. Active Bleeding