Clinical Trials /

Study of Gene Modified Immune Cells in Patients With Advanced Melanoma

NCT00910650

Description:

The purpose of this phase 2 study is to find the best way to give this new experimental regimen and determine if it can treat metastatic melanoma in humans. In this phase 2 study, the experimental products are given initially to a group of 8 people. If safe and found to have significant anti-tumor activity, it will be given to up to 14 other people, for a total of 22 people in this study. Physicians watch subjects carefully for any harmful side effects. Although the experimental regimen has been well tested in laboratory and animal studies, and a similar regimen has been given to a group of patients at the National Cancer Institute in Bethesda, MD, the side effects in people cannot be completely known ahead of time. This protocol is offered only to people whose condition cannot be helped by other known treatments. The study procedures will start with the collection of white blood cells through apheresis (a procedure in which blood is drawn from a patient and separated into its components, some of which are retained, such as white blood cells, and the remainder returned by transfusion to the patient). Subjects will be asked to undergo two aphereses, one to make the gene-modified MART-1 TCR CTLs and the dendritic cell vaccines, and a second one after the subject receives the gene modified cells to later study them in the blood. On the day of the first apheresis, subjects will be admitted to the hospital and will receive chemotherapy over the next five days which decreases the risk of rejection of the transferred cells by the subject's immune system and facilitates their expansion and attack of the melanoma lesions. During this time, the gene-modified MART-1 TCR CTLs and the dendritic cells will be manufactured in the laboratory from the apheresis product and will be extensively tested to assure that they express the appropriate TCR and that they do not contain any contaminating bacteria or virus. Then the gene-modified MART-1 TCR CTLs will be given back to the subject through a vein in the arm. It will be followed by vaccination with the dendritic cells under the skin. During the next fourteen days, subjects will also receive interleukin 2 (IL-2), which is a standard treatment for patients with metastatic melanoma. During the next 2 to 3 weeks, subjects will stay in the hospital until the study investigators determine that the subject has fully recovered from all of the procedures, and it is safe for the subject to go home. Chemotherapy frequently causes a decrease in the platelet or red blood cells, and therefore subjects may require platelet and/or red blood cell transfusions.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Study of Gene Modified Immune Cells in Patients With Advanced <span class="go-doc-concept go-doc-disease">Melanoma</span>

Title

  • Brief Title: Study of Gene Modified Immune Cells in Patients With Advanced Melanoma
  • Official Title: Adoptive Transfer of MART-1 F5 TCR Engineered Peripheral Blood Mononuclear Cells (PBMC) After a Nonmyeloablative Conditioning Regimen, With Administration of MART-12635-Pulsed Dendritic Cells and Interleukin-2, in Patients With Advanced Melanoma
  • Clinical Trial IDs

    NCT ID: NCT00910650

    ORG ID: 10-001212

    NCI ID: 08-02-020

    Trial Conditions

    Metastatic Melanoma

    Trial Interventions

    Drug Synonyms Arms
    non-myeloablative conditioning chemotherapy F5 TCR transgenic cells

    Trial Purpose

    The purpose of this phase 2 study is to find the best way to give this new experimental
    regimen and determine if it can treat metastatic melanoma in humans. In this phase 2 study,
    the experimental products are given initially to a group of 8 people. If safe and found to
    have significant anti-tumor activity, it will be given to up to 14 other people, for a total
    of 22 people in this study. Physicians watch subjects carefully for any harmful side
    effects. Although the experimental regimen has been well tested in laboratory and animal
    studies, and a similar regimen has been given to a group of patients at the National Cancer
    Institute in Bethesda, MD, the side effects in people cannot be completely known ahead of
    time. This protocol is offered only to people whose condition cannot be helped by other
    known treatments.

    The study procedures will start with the collection of white blood cells through apheresis
    (a procedure in which blood is drawn from a patient and separated into its components, some
    of which are retained, such as white blood cells, and the remainder returned by transfusion
    to the patient).

    Subjects will be asked to undergo two aphereses, one to make the gene-modified MART-1 TCR
    CTLs and the dendritic cell vaccines, and a second one after the subject receives the gene
    modified cells to later study them in the blood.

    On the day of the first apheresis, subjects will be admitted to the hospital and will
    receive chemotherapy over the next five days which decreases the risk of rejection of the
    transferred cells by the subject's immune system and facilitates their expansion and attack
    of the melanoma lesions. During this time, the gene-modified MART-1 TCR CTLs and the
    dendritic cells will be manufactured in the laboratory from the apheresis product and will
    be extensively tested to assure that they express the appropriate TCR and that they do not
    contain any contaminating bacteria or virus. Then the gene-modified MART-1 TCR CTLs will be
    given back to the subject through a vein in the arm. It will be followed by vaccination with
    the dendritic cells under the skin. During the next fourteen days, subjects will also
    receive interleukin 2 (IL-2), which is a standard treatment for patients with metastatic
    melanoma. During the next 2 to 3 weeks, subjects will stay in the hospital until the study
    investigators determine that the subject has fully recovered from all of the procedures, and
    it is safe for the subject to go home. Chemotherapy frequently causes a decrease in the
    platelet or red blood cells, and therefore subjects may require platelet and/or red blood
    cell transfusions.

    Detailed Description

    This is a two-stage phase II clinical trial with the combined primary endpoints to determine
    the safety, feasibility and anti-tumor activity of adoptive transfer of peripheral blood
    mononuclear cells (PBMC) genetically engineered to express the alpha and beta chains of a
    high affinity T cell receptor (TCR) specific for the HLA-A*0201-restricted MART-1 melanoma
    tumor antigen to patients with locally advanced or metastatic melanoma. This gene transfer
    will be facilitated by a retroviral vector pseudotyped with a gibbon ape leukemia virus
    (GaLV) envelope. The two transgenes are linked by a picornavirus 2A sequence. Their
    expression is driven by the retroviral long terminal repeat (LTR).

    Patients with MART-1-positive locally advanced or metastatic melanoma who are
    HLA-A*0201-positive, and HIV, hepatitis B and C seronegative, will receive a
    non-myeloablative but lymphocyte depleting chemotherapy conditioning regimen consisting of
    cyclophosphamide and fludarabine, and then receive the adoptive transfer of autologous PBMC
    transduced with the MSGV1-F5AfT2AB retroviral vector, which expresses a high affinity TCR
    for the MART-1 melanoma antigen (MART-1 F5 TCR). The cell dose will be up to 10^9 autologous
    PBMC transduced with the MSGV1-F5AfT2AB retroviral vector. The transgenic T cells will be
    infused fresh on the day of harvest as done in the last three patients within this protocol,
    prior to which, thawed cryopreserved cells were infused. Following adoptive cell transfer,
    patients will receive MART-1.26-35 peptide-pulsed dendritic cell (DC) vaccines and low dose
    interleukin-2 (IL-2).

    The MART-1 F5 TCR was provided by Dr. Stephen A. Rosenberg from the Surgery Branch, National
    Cancer Institute (NCI). The MART-1 F5 TCR is derived from the DMF5 tumor infiltrating
    lymphocyte (TIL) clone, and was selected from several MART-1-specific TCRs because of its
    high affinity and biological activity. This TCR delivered by the same retroviral vector is
    currently in clinical testing at the Surgery Branch/NCI. Both the NCI clinical trial and the
    trial at UCLA are based on the same retrovirus expressing the MART-1 F5 TCR used to
    transduce whole PBMC and re-infused to patients after a non-myeloablative but
    lymphodepleting chemotherapy conditioning regimen. Major differences between both clinical
    trials include the shorter ex vivo expansion of TCR transduced PBMC, the use of MART-126-35
    peptide pulsed DC and the use of positron imaging tomography (PET) for non-invasive imaging
    of adoptively transferred TCR transgenic cells in the UCLA clinical trial.

    The primary endpoints will be safety, feasibility and objective tumor response. The phase II
    clinical trial design will have two treatment stages following a Simon optimal two-stage
    clinical phase II clinical trial design 1. The clinical trial will have an initial stage
    with 8 patients followed by a second stage with up to 22 patients.

    Safety will be determined in stage one, and if 3 out of 8 patients have MART-1 F5
    TCR-induced dose limiting toxicities (DLT), then further accrual will not be warranted.
    Feasibility will be also determined in the first stage, and if 3 out of 8 patients cannot
    receive the intended cellular therapies, or if they result in suboptimal TCR transgenic cell
    in vivo persistence, further accrual will not be warranted to the protocol as currently
    designed. Objective tumor responses will be determined by RECIST objective response criteria
    with a design to rule out a 10% response rate as the null hypothesis, and a 35% response
    rate as the alternative hypothesis. With this statistical design, if 2 or more of 8 patients
    in stage one have an objective response, the study will proceed to stage two and accrue a
    total of 22 patients. If 5 or more patients in the overall study have a complete response
    (CR) or partial response (PR), which combined result in the objective response rate, the
    study will be declared positive.

    Secondary study endpoints are transgenic T cell persistence in humans and their ability to
    home to MART-1 positive melanoma metastasis. Analysis will be performed by sampling of
    peripheral blood and tumor deposits for T cell persistence and by non-invasive metabolic
    imaging using PET scans.

    Trial Arms

    Name Type Description Interventions
    F5 TCR transgenic cells Experimental F5 TCR transgenic cell adoptive transfer therapy non-myeloablative conditioning chemotherapy

    Eligibility Criteria

    Inclusion Criteria:

    - Histologically confirmed melanoma that is considered surgically incurable with
    either:

    - Stage IIIc melanoma including locally relapsed, satellite, in-transit lesions or
    bulky draining node metastasis.

    - Stage IV melanoma (M1a, M1b or M1c). At least 1 lesion amenable for outpatient
    biopsies; this should be a cutaneous or palpable metastatic site or a deeper
    site accessible by image-guided biopsy that is deemed safe to access by the
    treating physicians and interventional radiologists. Patients without accessible
    lesions for biopsy but with prior tissue available from metastatic disease would
    be eligible at the investigator's discretion.

    - MART-1 positive melanoma by RT-PCR or IHC.

    - HLA-A*0201 (HLA-A2.1) positivity by molecular subtyping*.

    - Age greater than or equal to 18 years old.

    - Life expectancy greater than 3 months assessed by a study physician.

    - A minimum of one measurable lesion defined as:

    - Meeting the criteria for measurable disease according to Response Evaluation
    Criteria in Solid Tumors (RECIST).

    - Skin lesion(s) selected as non-completely biopsied target lesion(s) that can be
    accurately measured and recorded by color photography with a ruler to document
    the size of the target lesion(s).

    - No restriction based on prior treatments.

    - ECOG performance status (PS) 0 or 1.

    - Adequate bone marrow and hepatic function determined within 30-60 days prior to
    enrollment, defined as:

    - Absolute neutrophil count >= 1.5 x 109 cells/L.

    - Platelets >= 100 x 109/L.

    - Hemoglobin >= 10 g/dL.

    - Aspartate and alanine aminotransferases (AST, ALT) =< 2.5 x ULN (=< 5 x ULN, if
    documented liver metastases are present).

    - Total bilirubin =< 2 x ULN (except patients with documented Gilbert's syndrome).

    - Creatinine < 2 mg/dl (or a glomerular filtration rate > 60).

    - Must be willing and able to accept at least two leukapheresis procedures.

    - Must be willing and able to accept at least two tumor biopsies.

    - Must be willing and able to provide written informed consent.

    - Patients with HLA-A*0205 (HLA-A2.5) positivity by molecular subtyping may be eligible
    if there is demonstration that they can correctly present the MART-126-35 epitope as
    stimulators for IFN-gamma production by MART-1 F5 TCR transgenic cells.

    Exclusion Criteria

    - Previously known hypersensitivity to any of the agents used in this study.

    - Received systemic treatment for cancer, including immunotherapy, within one month
    prior to initiation of dosing within this protocol. However, cell harvesting by
    leukapheresis may be performed before one month from prior therapy if the study
    investigators consider that it will not have a detrimental impact on the generation
    of the two cell therapies in this protocol.

    - History of, or significant evidence of risk for, chronic inflammatory or autoimmune
    disease (eg, Addison's disease, multiple sclerosis, Graves disease, Hashimoto's
    thyroiditis, inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic
    lupus erythematosus, hypophysitis, pituitary disorders, etc.). Patients will be
    eligible if prior autoimmune disease is not deemed to be active (e.g. fibrotic damage
    of the thyroid after thyroiditis or its treatment, with stable thyroid hormone
    replacement therapy). Vitiligo will not be a basis for exclusion.

    - History of inflammatory bowel disease, celiac disease, or other chronic
    gastrointestinal conditions associated with diarrhea or bleeding, or current acute
    colitis of any origin.

    - Potential requirement for systemic corticosteroids or concurrent immunosuppressive
    drugs based on prior history or received systemic steroids within the last 4 weeks
    prior to enrollment (inhaled or topical steroids at standard doses are allowed).

    - HIV seropositivity or other congenital or acquired immune deficiency state, which
    would increase the risk of opportunistic infections and other complications during
    chemotherapy-induced lymphodepletion. If there is a positive result in the infectious
    disease testing that was not previously known, the patient will be referred to their
    primary physician and/or infectious disease specialist.

    - Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would
    increase the likelihood of hepatic toxicities from the chemotherapy conditioning
    regimen and supportive treatments. If there is a positive result in the infectious
    disease testing that was not previously known, the patient will be referred to their
    primary physician and/or infectious disease specialist.

    - Dementia or significantly altered mental status that would prohibit the understanding
    or rendering of informed consent and compliance with the requirements of this
    protocol.

    - Clinically active brain metastases. Radiological documentation of absence of active
    brain metastases at screening is required for all patients. Prior evidence of brain
    metastasis successfully treated with surgery or radiation therapy will not be
    exclusion for participation as long as they are deemed under control at the time of
    study enrollment.

    - Pregnancy or breast-feeding. Female patients must be surgically sterile or be
    postmenopausal for two years, or must agree to use effective contraception during the
    period of treatment and 6 months after. All female patients with reproductive
    potential must have a negative pregnancy test (serum/urine) within 14 days from
    starting the conditioning chemotherapy. The definition of effective contraception
    will be based on the judgment of the study investigators.

    - Since IL-2 is administered following cell infusion:

    - Patients will be excluded if they have a history of clinically significant ECG
    abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left
    ventricular ejection fraction (LVEF) < 45% on a cardiac stress test (stress
    thallium, stress MUGA, dobutamine echocardiogram, or other stress test).

    - Similarly, patients who are 50 years old with a baseline LVEF < 45% will be
    excluded.

    - Patients with ECG results of any conduction delays (PR interval >200ms, QTC >
    480ms), sinus bradycardia (resting heart rate <50 beats per minute), sinus
    tachycardia (HR>120 beats per minute) will be evaluated by a cardiologist prior
    to starting the trial. Patients with any arrhythmias, including atrial
    fibrillation/atrila flutter, excessive ectopy (defined as >20 PVCs per minute),
    ventricular tachycardia, 3rd degree heart block will be excluded from the study
    unless cleared by a cardiologist.

    - Patients with pulmonary function test abnormalities as evidenced by a FEV1/FVC<
    70% of predicted for normality will be excluded.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Response rate: The two-stage phase II study design includes response rate by RECIST criteria as the primary endpoint.

    Secondary Outcome Measures

    Other key measures that will be used to evaluate the intervention(s) or, for observational studies, that are a focus of the study.

    Trial Keywords

    Adoptive transfer therapy

    Dendritic cell vaccines