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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01585428
First received: April 24, 2012
Last updated: April 29, 2015
Last verified: November 2014
  Purpose

Background:

The human papillomavirus (HPV) can cause a number of cancers, including cervical and throat cancers. The 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 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 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.


Condition Intervention Phase
Cervical Cancer
Oropharyngeal Cancer
Vaginal Cancer
Anal Cancer
Penile Cancer
Drug: Fludarabine
Drug: Cycolphosphamide
Biological: Young TIL
Drug: Aldesleukin
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Lymphodepletion Followed by Autologous Tumor-Infiltrating Lymphocytes and High-Dose Aldesleukin for Human Papillomavirus-Associated Cancers

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To determine if autologous Young TIL infused in conjunction with high dose aldesleukin following a nonmyeloablative lymphodepleting preparative regimen can mediate tumor regression in patients with metastatic or locally advanced refractory/recur... [ Time Frame: Approximately 3-4 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 73
Study Start Date: April 2012
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cervical
Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by IV infusion of Young TIL plus high dose IV aldesleukin.
Drug: Fludarabine
Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Cycolphosphamide
Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
Biological: Young TIL
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).
Drug: Aldesleukin
Aldeskeukin 720,000 IU/kg 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).
Experimental: NonCervica
Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by IV infusion of Young TIL plus high dose IV aldesleukin
Drug: Fludarabine
Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Cycolphosphamide
Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
Biological: Young TIL
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).
Drug: Aldesleukin
Aldeskeukin 720,000 IU/kg 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).

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/recurrentHIPV-16+ or HPV-18+ human papillomavirus-associated cancer.
  • Prior platinum-based chemotherapy is required.

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 IV) on days -7 and -6 and fludarabine (25 mg/m2/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 iwth 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.
  Eligibility

Ages Eligible for Study:   18 Years to 66 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Measurable metastatic or locally advanced refractory/recurrent malignancies that are HPV-16 or 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 66.
  5. Able to understand and sign the Informed Consent Document
  6. Clinical performance status of 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 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 RT-PCR and be 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/mm3 without the support of filgrastim
    • WBC greater than or equal to 3000/mm3
    • Platelet count greater than or equal too 100,000/mm3
    • Hemoglobin greater than 8.0 g/dl
  12. Chemistry:

    • Serum ALT/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 arrhythimas, 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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01585428

Contacts
Contact: June Kryk, R.N. (301) 451-1929 ncisbirc@mail.nih.gov
Contact: Steven A Rosenberg, M.D. (301) 496-4164 sar@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    ncisbirc@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01585428     History of Changes
Other Study ID Numbers: 120116, 12-C-0116
Study First Received: April 24, 2012
Last Updated: April 29, 2015
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Immunotherapy
HPV-Associated Cancers
Cervical Cancer
Oropharyngeal Cancer
HPV Infection

Additional relevant MeSH terms:
Oropharyngeal Neoplasms
Uterine Cervical Neoplasms
Vaginal Neoplasms
Genital Diseases, Female
Genital Neoplasms, Female
Head and Neck Neoplasms
Neoplasms
Neoplasms by Site
Otorhinolaryngologic Diseases
Otorhinolaryngologic Neoplasms
Pharyngeal Diseases
Pharyngeal Neoplasms
Stomatognathic Diseases
Urogenital Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Uterine Neoplasms
Vaginal Diseases
Aldesleukin
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Alkylating Agents
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating

ClinicalTrials.gov processed this record on May 03, 2015