Clinical Trials /

T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers

NCT02280811

Description:

Background: The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. Researchers want to test this on human papilloma virus (HPV)-associated cancers. Objective: - The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (Anti-HPV E6) can shrink tumors associated with HPV and test the toxicity of this treatment. Eligibility: - Adults age 18-66 with an HPV-16-associated cancer. 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 - Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti HPV E6 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 anti HPV E6 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 take up to 2 days.

Related Conditions:
  • Anal Carcinoma
  • Cervical Carcinoma
  • Oropharyngeal Carcinoma
  • Penile Carcinoma
  • Vaginal Carcinoma
  • Vulvar Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers

Title

  • Brief Title: T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers
  • Official Title: A Phase I/II Study of T Cell Receptor Gene Therapy Targeting HPV-16 E6 for HPV-Associated Cancers
  • Clinical Trial IDs

    NCT ID: NCT02280811

    ORG ID: 150005

    NCI ID: 15-C-0005

    Trial Conditions

    Vaginal Cancer

    Cervical Cancer

    Anal Cancer

    Penile Cancer

    Oropharyngeal Cancer

    Trial Interventions

    Drug Synonyms Arms
    Fludarabine Arm 1
    Cyclophosphamide Arm 1
    Aldesleukin Arm 1

    Trial Purpose

    Background:

    The NCI Surgery Branch has developed an experimental therapy for treating patients with
    cancer that involves taking white blood cells from the patient, growing them in the
    laboratory in large numbers, genetically modifying these specific cells with a type of virus
    (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient.
    This type of therapy is called gene transfer. Researchers want to test this on human
    papilloma virus (HPV)-associated cancers.

    Objective:

    - The purpose of this study is to determine a safe number of these cells to infuse and to
    see if these particular tumor-fighting cells (Anti-HPV E6) can shrink tumors associated with
    HPV and test the toxicity of this treatment.

    Eligibility:

    - Adults age 18-66 with an HPV-16-associated cancer.

    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

    - Leukapheresis: If the patients meet all of the requirements for the study they will
    undergo leukapheresis to obtain white blood cells to make the anti HPV E6 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 anti HPV E6 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 take up to 2 days.

    Detailed Description

    BACKGROUND:

    - Metastatic or refractory/recurrent human papillomavirus (HPV)-16+ cancers (cervical,
    vulvar, vaginal, penile, anal, and oropharyngeal cancers) are incurable and poorly
    palliated by standard therapies.

    - HPV-16+ cancers constitutively express the HPV-16 E6 oncoprotein, which is absent from
    healthy human tissues.

    - Administration of T cell receptor (TCR) gene engineered T cells can induce objective
    tumor responses in certain malignancies.

    - T cells genetically engineered with a TCR targeting HPV-16 E6 (E6 TCR) display specific
    reactivity against HLA-A2+, HPV-16+ target cells.

    OBJECTIVES:

    Primary Objective

    - To determine a safe dose of administration of autologous T cells transduced with an
    anti-HPV-16 E6 TCR and aldesleukin to patients following a nonmyeloablative but
    lymphodepleting preparative regimen.

    - To determine the objective tumor response rate (Complete or Partial Response) and
    duration in patients with metastatic or recurrent/refractory HPV-16+ cancers treated
    with this regimen.

    Secondary Objective(s)

    - To determine the toxicity of this treatment regimen.

    - To study immunologic correlates associated with E6 TCR gene therapy for HPV16+ cancers.

    ELIGIBILITY:

    - Patients greater than or equal to 18 years old and less than or equal to 70 years old
    with metastatic or refractory/recurrent HPV-16+ cancer.

    - Prior first line systemic therapy is required unless the patient declines standard
    treatment.

    - Patients must be HLA-A 02:01-positive.

    DESIGN:

    - Patients will receive a non-myeloablative lymphocyte-depleting preparative regimen of
    cyclophosphamide and fludarabine

    - On day 0 patients will receive transduced lymphocytes and then begin high dose
    aldesleukin

    - The study will begin with a phase I dose escalation. After the MTD cell dose has been
    determined, the patients will be enrolled into the phase II portion of the study.

    - Clinical and immunologic response will be evaluated about 4 to 6 weeks after treatment
    and then about every 1-6 months until disease progression

    - Following a dose escalation phase of 9 to 18 patients, initially 21 evaluable patients
    will be enrolled in the phase II portion of the study. If 0 to 1 of the 21 patients
    experiences a clinical response, then no further patients will be enrolled. If 2 or
    more of the first 21 evaluable patients enrolled have a clinical response, then accrual
    will continue until a total of 41 evaluable patients have been enrolled. The accrual
    ceiling will be set at 61 patients. Provided that about 1 patient every 6 weeks will be
    enrolled onto this trial, approximately 4 years may be needed to accrue the maximum
    number of patients.

    Trial Arms

    Name Type Description Interventions
    Arm 1 Experimental patients will receive cyclophosphaide and fludarabinefollowed by infusion of the HPV E6 TCR, followed byhigh dose aldesleukin Fludarabine, Cyclophosphamide, Aldesleukin

    Eligibility Criteria

    -INCLUSION CRITERIA

    1. Measurable metastatic or refractory/recurrent HPV-16+ cancer (determined by in situ
    hybridization (ISH) or a polymerase chain reaction (PCR)-based test).

    2. Patients must be HLA-A 02:01-positive.

    3. All patients must have received prior first line standard therapy or declined
    standard therapy, and have been either non-responders (progressive disease) or have
    recurred.

    4. 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.

    5. Greater than or equal to 18 years of age and less than or equal to 70 years of age.

    6. Able to understand and sign the Informed Consent Document.

    7. Willing to sign durable power of attorney

    8. Clinical performance status of ECOG 0 or 1.

    9. Life expectancy of greater than 3 months.

    10. Patients of both genders must be willing to practice birth control from the time of
    enrollment on this study up to 4 months after treatment. Patients must be willing to
    undergo testing for HPV-16 prior to becoming pregnant.

    11. Women of child bearing potential must have a negative pregnancy test because of the
    potentially dangerous effects of the treatment on the fetus.

    12. 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 are 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 the patient must be tested for
    the presence of antigen by RT-PCR and be HCV RNA negative.

    13. 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 100,000/mm3

    - Hemoglobin greater than 8.0 g/dL

    14. Chemistry:

    - Serum ALT/AST less than or equal to 2.5 times the upper limit of normal

    - Serum creatinine less than or equal to 1.6 mg/dL

    - Total bilirubin less than or equal to to 1.5 mg/dL, except in patients with
    Gilbert s Syndrome who must have a total bilirubin less than 3.0 mg/dL

    15. More than 4 weeks must have elapsed since any prior systemic therapy at the time the
    patient receives the preparative regimen.

    EXCLUSION CRITERIA:

    1. Women of childbearing potential who are pregnant or breastfeeding. There are
    potentially dangerous side effects of the treatment on the fetus or infant.

    2. Active systemic infections (for e.g.: requiring anti-infective treatment),
    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 cyclophosphamide or
    fludarabine.

    7. History of coronary revascularization or ischemic symptoms.

    8. Documented LVEF of less than or equal to 45% tested. The following patients will
    undergo cardiac evaluations

    a. clinically significant atrial and/or ventricular arrhythmias including but not limited
    to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or

    b. age greater than or equal 60 years old

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 70 Years

    Eligible Gender: Both

    Primary Outcome Measures

    To determine the objective tumor response rate and duration in patients with metastatic or recurrent/refractory HPV-16+ cancers treated with autologous T cells expressing the E6 TCR plus aldesleukin following a lymphocyte-depleting preparative r...

    Secondary Outcome Measures

    Trial Keywords

    HPV positive

    Metastatic

    Diet

    Screening

    Risk Factors

    Colorectal adenoma

    Refractory

    Immunotherapy

    Reproductive Cancers