Clinical Trials /

Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells

NCT02573896

Description:

This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded natural killer (NK) cells when combined with standard dosing of ch14.18 and will assess the feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells with ch14.18, for treatment of children with refractory or recurrent neuroblastoma.

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Immunotherapy</span> of Relapsed Refractory <span class="go-doc-concept go-doc-disease">Neuroblastoma</span> With Expanded NK Cells

Title

  • Brief Title: Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells
  • Official Title: Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells, ch14.18 and Lenalidomide
  • Clinical Trial IDs

    NCT ID: NCT02573896

    ORG ID: NANT 2013-01

    Trial Conditions

    Neuroblastoma

    Trial Interventions

    Drug Synonyms Arms
    Ch14.18 Chimeric Monoclonal Antibody 14.18, MAB Ch 14.18, Unituxin NK cells with Ch14.18 & Lenalidomide
    Lenalidomide NK cells with Ch14.18 & Lenalidomide

    Trial Purpose

    This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded
    natural killer (NK) cells when combined with standard dosing of ch14.18 and will assess the
    feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells
    with ch14.18, for treatment of children with refractory or recurrent neuroblastoma.

    Detailed Description

    This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded
    natural killer (NK) cells when combined with standard dosing of ch14.18 and will assess the
    feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells
    with ch14.18, for treatment of children with refractory or recurrent neuroblastoma.

    Ch14.18 is a chimeric antibody against GD2, which is expressed on a majority of
    neuroblastoma cells. It has been shown to increase EFS and OS in patients with high-risk
    neuroblastoma when given after autologous stem cell transplant in combination with
    subcutaneous GM-CSF and intravenous IL-2, followed by isotretinoin. Lenalidomide has been
    studied in children with solid tumors and can safely be given to patients based on 2 prior
    trials in children. It was also shown to have immunomodulatory effects and is synergistic
    with ch14.18. Lenalidomide is also an oral agent that can be given in the outpatient
    setting. Natural killer cells are lymphocytes of the innate immune system that have the
    ability to recognize and kill malignant cells, including neuroblastoma. Ch14.18 and
    lenalidomide both exert part of their anti-cancer effect through the activation of natural
    killer cells. Patients are being given in combination in NANT 2011-04 where the safety and
    immunomodulatory effect has been established in that study at the dose level proposed in
    this study. Natural killer cells are dysfunctional and low in number in many cancer
    patients, and number and function are further suppressed by chemotherapy and radiation.
    Investigators hypothesize that autologous NK cells can be expanded and activated ex vivo and
    readministered to restore number and function, and in combination with lenalidomide and
    ch14.18 will provide an anti-tumor effect in patients with relapsed or refractory
    neuroblastoma.

    Investigators will determine the feasibility of centralized expansion, cryopreservation, and
    distribution of autologous NK cells. Investigators will then determine the maximum tolerated
    dose by assessing the toxicities of autologous expanded NK cells given with ch14.18; by
    assessing the toxicities, cytokinetics and immunomodulatory effects, Investigators will
    select the recommended Phase II dose of the two-agent combination after dose escalation of
    the NK cells and then adding lenalidomide to the combination to establish the three-agent
    combination.

    Cytokinetics (persistence of infused NK cells) and immune function studies will be required
    for all patients entered on this study. In addition to routine assessment of response,
    quantification of rare tumor cell detection in blood and bone marrow using TLDA will also
    provide another measure of possible anti-tumor efficacy to support the rationale for the
    final schedule chosen.

    Trial Arms

    Name Type Description Interventions
    NK cells with Ch14.18 & Lenalidomide Experimental Patients in this arm will receive a designated dose of NK cells on Day 5 and 17.5 mg/m2/dose of Ch14.18 on Day 1-4. Patients on Dose Level 4 will also receive 25mg/m2/dose of Lenalidomide during Day -6 through 14 of treatment. Ch14.18, Lenalidomide

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have a diagnosis of neuroblastoma either by histologic verification of
    neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased
    urinary catecholamines.

    - Patients must have a history of high-risk neuroblastoma according to COG risk
    classification at the time of study registration. Patients who were initially
    considered low or intermediate-risk, but then reclassified as high-risk are also
    eligible.

    - Patients must have at least ONE of the following:

    1. Recurrent/progressive disease at any time prior to study enrollment

    2. Refractory disease

    3. Persistent disease

    - Patients must have at least ONE of the following (lesions may have received prior
    radiation therapy as long as they meet the other criteria listed below):

    1. For recurrent/progressive or refractory disease, at least one MIBG avid bone
    site.

    2. For persistent disease, If a patient has only 1 or 2 MIBG avid lesions AND a
    Curie Score of 1-2, then biopsy confirmation of neuroblastoma and/or
    ganglioneuroblastoma in at least one site present at the time of enrollment
    (bone marrow, bone, or soft tissue) is required to be obtained at any time point
    prior to enrollment.

    3. FDG-PET avid tumors: A biopsy confirmation of neuroblastoma and/or
    ganglioneuroblastoma is required at any time prior to enrollment OR anatomical
    imaging is required at the time of enrollment consistent with a bone metastasis
    for at least one FDG-avid bone site.

    - Any amount of neuroblastoma tumor cells in the bone marrow done at the time of study
    enrollment based on routine morphology with or without immunocytochemistry in at
    least one sample from bilateral aspirates and biopsies.

    - At least one soft tissue lesion that meets criteria for a TARGET lesion as defined
    by:

    1. SIZE: Lesion can be accurately measured in at least one dimension with a longest
    diameter 10 mm, or for lymph nodes 15 mm on short axis.

    2. In addition to measurable size, a lesion needs to meet the following criteria:

    1. MIBG avid. For patients with persistent disease only: If a patient has only
    1 or 2 MIBG avid lesions ANDa Curie Score of 1 - 2, then biopsy
    confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one
    site present at time of enrollment is required to be obtained.

    2. MIBG non avid tumors: These patients require a biopsy done at any time
    prior to enrollment confirming neuroblastoma and/or ganglioneuroblastoma in
    at least one soft tissue site (even if FDG-PET avid) present at the time of
    enrollment.

    - At least one non-target soft tissue lesion that is not measurable, but had a biopsy
    positive for neuroblastoma and/or ganglioneuroblastom or is MIBG avid at any time
    prior to enrollment.

    - Patients must have a life expectancy of at least 12 weeks and a Lansky (16 years) or
    Karnofsky (>16 years) score of at least 50.

    - Prior Therapy

    1. Patients must have fully recovered from the acute toxic effects of all prior
    chemotherapy, immunotherapy, or radiotherapy prior to study registration.

    2. Patients must not have received the therapies indicated below after disease
    evaluation or within the specified time period prior to registration on this
    study as follows:

    1. Myelosuppressive chemotherapy: must not have received within 2 weeks prior
    to registration.

    2. Biologic anti-neoplastics- agents not known to be associated with reduced
    platelet or ANC counts (including retinoids): must not have received within
    7 days prior to registration.

    3. Monoclonal antibodies: must have received last dose at least 7 days or 3
    half-lives whichever is longer, but no longer than 30 days (with recovery
    of any associated toxicities), prior to protocol therapy.

    4. Cellular Therapy (e.g. modified T cells, NK cells, dentritic cells etc.):
    must not have received within 3 weeks and resolution of all toxicities.

    5. Radiation: must not have received small port radiation within 7 days prior
    to registration.

    6. Hematopoietic Stem Cell Transplant:

    7. IVIG

    - All patients must have adequate organ function defined as:

    - Hematological Function:

    1. Absolute Phagocyte count (APC= neutrophils and monocytes): 1000/L

    2. Absolute Neutrophil count: 750/L

    3. Absolute Lymphocyte count 500/L

    4. Platelet count: 50,000/L, transfusion independent (no platelet transfusions
    within 1 week)

    5. Hemoglobin 10 g/dL (may transfuse)

    6. Patients with known bone marrow metastatic disease will be eligible for study as
    long as they meet hematologic function criteria above.

    - Renal Function: Age-adjusted serum creatinine to 1.5 x normal for age/gender OR
    creatinine clearance or GFR greater than or equal to 60 cc/min/1.73m2

    - Liver Function: Total bilirubin 1.5 x normal for age, AND SGPT (ALT) 135 and SGOT
    (AST) 3 x upper limit of normal. Sinusoidal obstruction syndrome (SOS) if present,
    must be stable or improving clinically

    - Cardiac Function: Normal ejection fraction documented by either echocardiogram or
    radionuclide MUGA evaluation OR Normal fractional shortening documented by
    echocardiogram

    - Pulmonary Function: No dyspnea at rest, no oxygen requirement.

    - Reproductive Status: All post-menarchal females must have a negative beta-HCG. Males
    and females of reproductive age and childbearing potential must use effective
    contraception for the duration of their participation.

    - Patients with other ongoing serious medical issues must be approved by the study
    chair prior to registration.

    - Patients may not receive any other anti-cancer agents or radiotherapy while on
    protocol therapy.

    - Ability to Swallow Pills

    Exclusion Criteria:

    - Pregnancy: Quantitative Serum B-HCG must be negative in girls who are post-menarchal.

    - Breast feeding women are not eligible.

    - Active or uncontrolled infection

    - CNS metastasis.

    - Hypersensitivity to thalidomide, including history of erythema nodosum if
    characterized by a desquamating rash while taking thalidomide or similar drugs (dose
    level 4 only).

    - Patient declines participation in NANT 2004-05; unless the institution has been
    granted special exemption from mandatory registration on NANT 2004-05 by the NANT
    Operations Center.

    Minimum Eligible Age: 1 Month

    Maximum Eligible Age: 30 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Feasibility of expanding NK cells from neuroblastoma patients and cryopreserving, shipping, and infusing multiple doses of NK cells.

    Determination of the Maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of autologous expanded NK cells

    Secondary Outcome Measures

    Toxicity (Per Patient)

    Evaluation of Clinical Response (Per Patient)

    Trial Keywords

    relapsed refractory neuroblastoma