Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Human Papillomavirus-Associated Cancers

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Brief Title

Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Human Papillomavirus-Associated Cancers

Official Title

A Phase II Study of Lymphodepletion Followed by Autologous Tumor-Infiltrating Lymphocytes and High-Dose Aldesleukin for Human Papillomavirus-Associated Cancers

Brief 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.
    

Detailed Description

      Background:

        -  Metastatic or locally advanced refractory/recurrent human papillomavirus
           (HPV)-associated malignancies (cervical, vulvar, vaginal, penile, anal, and
           oropharyngeal) are incurable and poorly palliated by standard therapies.

        -  Administration of autologous tumor infiltrating lymphocytes (TIL) generated from
           resected metastatic melanoma can induce objective long-term tumor responses.

        -  Young TIL can be generated from HPV-associated tumors.

      Objectives:

        -  To determine if autologous Young TIL infused in conjunction with high dose aldesleukin
           following a non-myeloablative lymphodepleting preparative regimen can mediate tumor
           regression in patients with metastatic or locally advanced refractory/recurrent
           HPV-associated cancer.

        -  To study immunologic correlates associated with Young TIL therapy for HPV-associated
           cancers.

        -  To determine the toxicity of this treatment regimen.

      Eligibility:

      - Patients greater than or equal to 18 years old with a pathologically confirmed diagnosis of
      metastatic or locally advanced refractory/recurrent HIPV-16+ or HPV-18+ human
      papillomavirus-associated cancer.

      Design:

        -  Patients will undergo biopsy or resection to obtain tumor for generation of autologous
           TIL cultures and autologous cancer cell lines.

        -  All patients will receive a non-myeloablative lymphocyte depleting preparative regimen
           of cyclophosphamide (60 mg/kg/day intravenous (IV)) on days -7 and -6 and fludarabine
           (25 mg/m(2)/day IV) on days -5 through -1.

        -  On day 0 patients will receive between 1 times 10 (9) to 2 times 10(11) young TIL and
           then begin high dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).

        -  Clinical and immunologic response will be evaluated about 4-6 weeks after TIL infusion.

        -  Initially, 18 evaluable patients will be enrolled in two cohorts; patients with cervical
           cancer and those with non- cervical cancer. For each cohort, if 0 to 2 of the 18
           patients experience a clinical response, then no further patients will be enrolled. If 3
           or more of the first 18 evaluable patients enrolled have a clinical response, then
           accrual will continue until a total of 35 evaluable patients have been enrolled in each
           cohort. Up to 73 patients may be enrolled over approximately 3-4 years.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of Participants With an Objective Clinical Response

Secondary Outcome

 Number of Patients With Serious and Non-serious Adverse Events

Condition

Cervical Cancer

Intervention

Fludarabine

Study Arms / Comparison Groups

 Cervical
Description:  Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

29

Start Date

April 13, 2012

Completion Date

August 1, 2016

Primary Completion Date

April 9, 2016

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
      

Gender

All

Ages

18 Years - 70 Years

Accepts Healthy Volunteers

No

Contacts

Steven A Rosenberg, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01585428

Organization ID

120116

Secondary IDs

12-C-0116

Responsible Party

Principal Investigator

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Steven A Rosenberg, M.D., Principal Investigator, National Cancer Institute (NCI)


Verification Date

February 2018