Clinical Trials /

T Cell Receptor Immunotherapy Targeting MAGE-A3 for Patients With Metastatic Cancer Who Are HLA-A*01 Positive

NCT02153905

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. In this protocol, we are modifying the patients white blood cells with a retrovirus that has the gene for anti-MAGE-A3 incorporated in the retrovirus. 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-MAGE A3 cells) cause tumors to shrink and to be certain the treatment is safe Eligibility: - Adults age 18-66 with cancer expressing the MAGE-A3 molecule. 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 MAGE-A3 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 MAGE-A3 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:
  • Cancer
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

T Cell Receptor <span class="go-doc-concept go-doc-intervention">Immunotherapy</span> Targeting MAGE-A3 for Patients With Metastatic <span class="go-doc-concept go-doc-disease">Cancer</span> Who Are HLA-A*01 Positive

Title

  • Brief Title: T Cell Receptor Immunotherapy Targeting MAGE-A3 for Patients With Metastatic Cancer Who Are HLA-A*01 Positive
  • Official Title: Phase I-II Study of the Treatment of Metastatic Cancer That Expresses MAGE-A3 Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3 HLA-A*01 Restricted TCR-Gene Engineered Lymphocytes and Aldesleukin
  • Clinical Trial IDs

    NCT ID: NCT02153905

    ORG ID: 140110

    NCI ID: 14-C-0110

    Trial Conditions

    Metastatic Cancer

    Metastatic Melanoma

    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 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. In this protocol, we are modifying the patient
    s white blood cells with a retrovirus that has the gene for anti-MAGE-A3 incorporated in the
    retrovirus.

    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-MAGE A3 cells) cause tumors to shrink and to
    be certain the treatment is safe

    Eligibility:

    - Adults age 18-66 with cancer expressing the MAGE-A3 molecule.

    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 MAGE-A3 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 MAGE-A3 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 have constructed a single retroviral vector that contains both alpha and beta chains
    of a T cell receptor (TCR) that recognizes the HLA-A 01 restricted MAGE-A3 tumor
    antigen, which can be used to mediate genetic transfer of this TCR with high
    efficiency.

    - In co-cultures with HLA-A 01 and MAGE-A3 double positive tumors, the anti-MAGE-A3- A 01
    restricted (anti-MAGE-A3-01) TCR transduced T cells secreted significant amounts of
    IFN- >= with high specificity.

    Objectives:

    Primary objectives:

    - Determine a safe dose of administration of autologous T cells transduced with an anti-
    MAGE-A3 HLA-A 01-restricted TCR (MAGE-A3-01) TCR and aldesleukin to patients following
    a nonmyeloablative but lymphoid depleting preparative regimen.

    - Determine if this approach will result in objective tumor regression in patients with
    metastatic cancer expressing MAGE-A3.

    - Determine the toxicity profile of this treatment regimen.

    Secondary Objective:

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

    Eligibility:

    Patients who are HLA-A 01 positive and 18 years of age or older must have:

    - Metastatic cancer whose tumors express the MAGE-A3 antigen;

    - Previously received and have been a non-responder to or recurred following at least one
    first line treatment for metastatic disease;

    Patients may not have:

    - Contraindications for high dose aldesleukin administration.

    Design:

    - PBMC obtained by leukapheresis will be transduced with the retroviral vector
    supernatant encoding the anti-MAGE-A3 HLA-A 01-restricted TCR.

    - The study will begin with a phase I dose escalation. After the MTD cell dose has been
    determined, patients will be enrolled into the phase 2 portion of the trial at the MTD
    established during the phase I portion of the study. In the phase 2 portion, patients
    will be entered into two cohorts: cohort 1 will include patients with metastatic
    melanoma; cohort 2 will include patients with renal cancer and other types of
    metastatic cancer.

    - Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen
    consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex
    vivo tumor reactive, TCR gene-transduced PBMC plus IV aldesleukin.

    - Patients will undergo complete evaluation of tumor response every 1-6 months until off
    study criteria are met.

    - For each of the 2 strata evaluated in the phase 2 portion, the study will be conducted
    using a phase II optimal design where initially 21 evaluable patients will be enrolled.
    For each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a
    clinical response, then no further patients will be enrolled but 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 in that stratum.

    - For both strata, the objective will be to determine if the treatment regimen is able to
    be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of
    a modes 20% PR + CR rate (p1=0.20).

    - In order to complete the dose escalation phase and both phase 2 cohorts, a total of up
    to 20+82=102 patients may be required (20 + 2 strata with a maximum of 41 apiece). Up
    to 6 patients enrolled at the MTD will count towards the accrual in the appropriate
    phase 2 strata if they are evaluable for response and if they would be fully eligible
    for enrollment in the phase 2 portion of the trial. Provided that about 4-5 patients
    per month will be able to be enrolled onto this trial, approximately 2 to 3 years may
    be needed to accrue the maximum number of required patients.

    Trial Arms

    Name Type Description Interventions
    Single Arm Experimental Patients will receive lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine, followed by cells and high dose aldesleukin Aldesleukin, Fludarabine, Cyclophosphamide

    Eligibility Criteria

    - INCLUSION CRITERIA:

    1. Metastatic or locally advanced refractory/recurrent cancer that expresses
    MAGE-A3 as assessed by one of the following methods: RT-PCR on tumor tissue
    defined as 30,000 copies of MAGE-A3 per 106 GAPDH copies, or by
    immunohistochemistry of resected tissue defined as 10% or greater of tumor cells
    being 2-3+ for MAGE-A3, or serum antibody reactive with MAGE-A3. Metastatic
    cancer diagnosis will be confirmed by the Laboratory of Pathology at the NCI.

    2. Patients must have previously received prior first line standard therapy (or
    effective salvage chemotherapy regimens) for their disease, if known to be
    effective for that disease, and have been either non-responders (progressive
    disease) or have recurred.

    3. Patients must be HLA-A*01 positive.

    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. Willing to sign a durable power of attorney

    7. Clinical performance status of ECOG 0 or 1

    8. Life expectancy of greater than three months

    9. 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.

    10. 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.

    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. 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 to 100,000/mm3

    - Hemoglobin > 8.0 g/dl

    13. 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.

    14. 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). Patients must have progressing disease after prior treatment.

    15. Six weeks must have elapsed from the time of any antibody therapy that could
    affect an anti cancer immune response, including anti-CTLA4 antibody therapy, at
    the time the patient receives the preparative regimen to allow antibody levels
    to decline.

    Note: Patients who have previously received ipilimumab and have documented GI toxicity
    must have a normal colonoscopy with normal colonic biopsies.

    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. 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 any cardiac events including coronary revascularization or ischemic
    symptoms.

    8. Documented LVEF of less than or equal to 45%; testing is required in patients who
    are:

    -- Age greater than or equal to 60 years old

    9. Patients with CNS metastases or symptomatic CNS involvement (including cranial
    neuropathies or mass lesions).

    10. Patients presenting with lesions that may harbor an occult infectious source.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 70 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Determine safety and objective response rate of administration of autologous T cells transduced with an anti- MAGE-A3 HLA-A*01-restricted TCR (MAGE-A3-01) TCR and aldesleukin

    Secondary Outcome Measures

    Trial Keywords

    Metastatic Melanoma

    Renal Cancer

    Metastatic Cancer

    Adoptive Cell Therapy