Clinical Trials /

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing Human Thyroglobulin to People With Thyroglobulin Expressing Thyroid Cancer

NCT02390739

Description:

Background The NCI Surgery Branch has developed an experimental therapy for treating patient with metastatic thyroid 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. In this protocol, we are modifying the patient s white blood cells with a retrovirus that has the gene for anti-thyroglobulin incorporated in the retrovirus. Objectives: The purpose of this study is to see if these tumor fighting cells (genetically modified cells) that express the receptor for the thyroglobulin molecule on their surface can cause thyroid tumors to shrink and to see if this treatment is safe. Eligibility: <TAB>Adults 18 and older with thyroid cancer that has the thyroglobulin molecule on tumor surfaces Design: <TAB>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 <TAB>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- thyroglobulin cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.} <TAB>Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-thyroglobulin 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:
  • Malignant Thyroid Gland Neoplasm
Recruiting Status:

Withdrawn

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing Human Thyroglobulin to People With Thyroglobulin Expressing <span class="go-doc-concept go-doc-disease">Thyroid Cancer</span>

Title

  • Brief Title: Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing Human Thyroglobulin to People With Thyroglobulin Expressing Thyroid Cancer
  • Official Title: Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing Human Thyroglobulin to Patients With Thyroglobulin Expressing Thyroid Cancer
  • Clinical Trial IDs

    NCT ID: NCT02390739

    ORG ID: 150090

    NCI ID: 15-C-0090

    Trial Conditions

    Metastatic Thyroid Cancer

    Trial Interventions

    Drug Synonyms Arms
    Aldesleukin Single Arm
    Fludarabine Single Arm
    Cyclophosphamide Single Arm

    Trial Purpose

    Background

    The NCI Surgery Branch has developed an experimental therapy for treating patient with
    metastatic thyroid 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. In this protocol, we are
    modifying the patient s white blood cells with a retrovirus that has the gene for
    anti-thyroglobulin incorporated in the retrovirus.

    Objectives:

    The purpose of this study is to see if these tumor fighting cells (genetically modified
    cells) that express the receptor for the thyroglobulin molecule on their surface can cause
    thyroid tumors to shrink and to see if this treatment is safe.

    Eligibility:

    < TAB> Adults 18 and older with thyroid cancer that has the thyroglobulin molecule on tumor
    surfaces

    Design:

    < TAB> 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

    < TAB> 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- thyroglobulin cells.
    {Leukapheresis is a common procedure, which removes only the white blood cells from the
    patient.}

    < TAB> Treatment: Once their cells have grown, the patients will be admitted to the hospital
    for the conditioning chemotherapy, the anti-thyroglobulin 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:

    - We generated a murine T-cell receptor (mTCR) that recognizes human thyroglobulin (hTG)
    in the context of HLA-A0201 and constructed a single retroviral vector that contains
    its alpha and beta chains and will confer hTG recognition to HLA-A0201+ PBL on
    transduction.

    - In co-cultures with HLA-A0201+, hTG+ target cells, anti-TG mTCR transduced T cells
    secrete significant amounts of IFN- >= with high specificity.

    Objectives:

    Primary objectives:

    -To determine the safety of administering PBL transduced with this anti-TG mTCR in concert

    with preparative lymphodepletion and high dose interleukin-2 (IL-2; aldesleukin).

    -Determine if these mTCR-transduced PBL can mediate the regression of TG-expressing tumors.

    Secondary objectives:

    -Determine the in vivo survival of mTCR gene-engineered cells.

    Eligibility:

    Patients who are HLA-A*0201 positive and 18 years of age or older must have

    -Advanced TG-expressing thyroid cancer (including those with bone-only disease) which has
    progressed after surgery (if indicated) and radioiodine ablation

    Patients may not have:

    -Contraindications for high dose aldesleukin administration.

    Design:

    -PBMC obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and

    aldesleukin in order to stimulate T-cell growth.

    - Transduction is initiated by exposure of these cells to retroviral vector supernatant
    containing replication-incompetent virus encoding the anti-TG mTCR.

    - All patients will receive a non-myeloablative lymphocyte depleting preparative regimen
    of

    cyclophosphamide and fludarabine.

    -On day 0 patients will receive their PBL transduced with the anti-TG mTCR and then begin

    high dose aldesleukin.

    -A complete evaluation of evaluable lesions will be conducted approximately 4-6 weeks after

    treatment.

    - The study will be conducted using a Phase I/II optimal design.

    - The objective will be to determine if the combination of high dose aldesleukin,
    lymphocyte

    depleting chemotherapy, and anti-TG mTCR-gene engineered lymphocytes is able to be

    associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest
    20% PR + CR rate (p1=0.20).

    -A total of up to 68 patients may be required; approximately 25 patients in the phase I
    portion of the study and 43 (41, plus an allowance of up to 2 non-evaluable) patients in the
    phase II portion of the study.

    Trial Arms

    Name Type Description Interventions
    Single Arm Experimental All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine followed by antithyroglobulin mTCR PBL and aldesleukin. Aldesleukin, Fludarabine, Cyclophosphamide

    Eligibility Criteria

    - INCLUSION CRITERIA:

    1. Unresectable thyroid cancer expressing TG as assessed by one of the following
    methods: RT-PCR on tumor tissue, or by immunohistochemistry of resected tissue.

    2. Recurrent/metastatic radioiodine refractory disease that has progressed within
    the past 6 months with at least 1 lesion increasing by 0.5cm in diameter or with
    increasing bone metastases.

    3. Confirmation of diagnosis of thyroid cancer by the Laboratory of Pathology of
    the NCI.

    4. PET avid disease with SUV > 5.

    5. Patients must have previously received standard systemic therapy for advanced
    thyroid cancer (to include radioactive iodine for iodine-avid tumors and surgery
    (if indicated)) and have been either non-responders (progressive disease) or
    have recurred.

    6. 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.

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

    8. Willing to sign a durable power of attorney

    9. Able to understand and sign the Informed Consent Document

    10. Clinical performance status of ECOG 0 or 1

    11. Life expectancy of greater than three months

    12. Patients must be HLA-A*0201 positive

    13. 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.

    14. 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.

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

    p. Hematology

    - Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim

    - WBC less than or equal to 3000/mm3

    - Platelet count greater than or equal to 100,000/mm3

    - Hemoglobin greater than 8.0 g/dl

    q. 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 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.

    r. 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.

    EXCLUSION CRITERIA:

    1. Women of child-bearing potential who are pregnant or breastfeeding because of the
    potentially dangerous effects of the treatment on the fetus or infant.

    2. Any form of primary immunodeficiency (such as Severe Combined

    Immunodeficiency Disease).

    3. Active systemic infections (e.g. : requiring anti-infective treatment), coagulation
    disorders or other major medical illnesses of the cardiovascular, respiratory or
    immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive
    pulmonary 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%. Testing is required 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 70 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Determine a safe dose of administration and determine if this approach will result in an objective tumor regression.

    Secondary Outcome Measures

    Trial Keywords

    Immunotherapy

    Gene Therapy

    Metastatic Cancer