Clinical Trials /

Lenalidomide and Dinutuximab With or Without Isotretinoin in Treating Younger Patients With Refractory or Recurrent Neuroblastoma

NCT01711554

Description:

This phase I trial studies the side effects and best dose of lenalidomide when given together with dinutuximab with or without isotretinoin in treating younger patients with neuroblastoma that does not respond to treatment or that has come back. Drugs used in chemotherapy, such as lenalidomide and isotretinoin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as dinutuximab, may interfere with the ability of tumor cells to grow and spread. Giving more than one drug (combination chemotherapy) together with dinutuximab therapy may kill more tumor cells.

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Lenalidomide</span> and Dinutuximab With or Without <span class="go-doc-concept go-doc-intervention">Isotretinoin</span> in Treating Younger Patients With Refractory or Recurrent <span class="go-doc-concept go-doc-disease">Neuroblastoma</span>

Title

  • Brief Title: Lenalidomide and Dinutuximab With or Without Isotretinoin in Treating Younger Patients With Refractory or Recurrent Neuroblastoma
  • Official Title: A Phase I Study of Lenalidomide and Anti-GD2 Mab Ch14.18 +/- Isotretinoin in Patients With Refractory/Recurrent Neuroblastoma
  • Clinical Trial IDs

    NCT ID: NCT01711554

    ORG ID: NCI-2012-02011

    NCI ID: NCI-2012-02011

    Trial Conditions

    Recurrent Neuroblastoma

    Trial Interventions

    Drug Synonyms Arms
    Isotretinoin 13-cis retinoic acid, 13-cis-Retinoate, 13-cis-Retinoic Acid, 13-cis-Vitamin A Acid, 13-cRA, Accure, Accutane, Amnesteem, cis-Retinoic Acid, Cistane, Claravis, Isotretinoinum, Isotrex, Isotrexin, Neovitamin A, Neovitamin A Acid, Oratane, Retinoicacid-13-cis, Ro 4-3780, Ro-4-3780, Roaccutan, Roaccutane, Roacutan, Sotret Treatment (lenalidomide, dinutuximab, isotretinoin)
    Lenalidomide CC-5013, CC5013, CDC 501, Revlimid Treatment (lenalidomide, dinutuximab, isotretinoin)

    Trial Purpose

    This phase I trial studies the side effects and best dose of lenalidomide when given
    together with dinutuximab with or without isotretinoin in treating younger patients with
    neuroblastoma that does not respond to treatment or that has come back. Drugs used in
    chemotherapy, such as lenalidomide and isotretinoin, work in different wants to stop the
    growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
    stopping them from spreading. Monoclonal antibodies, such as dinutuximab, may interfere with
    the ability of tumor cells to grow and spread. Giving more than one drug (combination
    chemotherapy) together with dinutuximab therapy may kill more tumor cells.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of
    lenalidomide in combination with fixed doses of ch14.18 (dinutuximab) given intravenously
    (IV) for four days (days 8-11) and isotretinoin given twice each day orally for 14 days
    (days 15-28) and repeated every 28 days to children with refractory or recurrent
    neuroblastoma.

    II. To define the toxicities of lenalidomide administered in combination with ch14.18 and
    isotretinoin.

    III. To describe the differences in immune function modulation between "low" versus "high"
    dose lenalidomide given with ch14.18 and isotretinoin.

    SECONDARY OBJECTIVES:

    I. To determine the pharmacokinetics of lenalidomide given in this combination regimen.

    II. To determine the steady state pharmacokinetics of isotretinoin (day 28, course one)
    given in combination with lenalidomide.

    III. To measure peak and trough levels of ch14.18 in patients receiving lenalidomide and to
    compare to historical controls of patients receiving ch14.18 in combination with interleukin
    2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF).

    IV. To describe the immunological effects of lenalidomide (T cells, natural killer [NK]
    cells, monocytes, cytokines, chemokines) within this three drug regimen.

    V. To define the incidence and titers of human anti-chimeric antibody (HACA) on this
    regimen.

    VI. To describe, within the context of a phase I study, the response rate to lenalidomide
    combined with ch14.18 and isotretinoin in patients with recurrent/refractory neuroblastoma.

    VII. To summarize, within the context of a phase I study, the event-free survival of
    patients with recurrent/refractory neuroblastoma or in complete response (CR) after
    progressing, and who are treated with lenalidomide combined with ch14.18 and isotretinoin.

    VIII. To determine, within the context of a phase I study, if killer-cell
    immunoglobulin-like receptor (KIR) receptor-ligand mismatch or specific Fc gamma receptor
    (Fc gamma R) alleles are associated with anti-tumor response.

    IX. To quantify neuroblastoma tumor cell "load" using a 5-gene TaqMan Low Density Array
    (TLDA) assay in peripheral blood at study entry, following, with each disease evaluation and
    at end of therapy and bone marrow at study entry, with each response evaluation when bone
    marrow is sampled, and at end of therapy.

    X. To compare the toxicities of this regimen with the historical toxicity data from the
    Children's Oncology Group (COG) ANBL0032 and ANBL0931 studies of ch14.18 with IL-2, GM-CSF
    and isotretinoin.

    XI. To describe the tolerability and ability to give full doses of ch14.18 and lenalidomide
    over extended periods of time, i.e. in courses 6-12.

    OUTLINE: This is a dose-escalation study of lenalidomide.

    Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, dinutuximab IV over
    10 hours on days 8-11, and isotretinoin PO twice daily (BID) on days 15-28 of dose levels
    2-6. Treatment repeats every 28 days for up to 12 courses in the absence of disease
    progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up periodically.

    Trial Arms

    Name Type Description Interventions
    Treatment (lenalidomide, dinutuximab, isotretinoin) Experimental Patients receive lenalidomide PO QD on days 1-21, dinutuximab IV over 10 hours on days 8-11, and isotretinoin PO BID on days 15-28 of dose levels 2-6. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Isotretinoin, 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 high-risk neuroblastoma

    - Patients must have at least ONE of the following:

    - Recurrent/progressive disease at any time prior to enrollment - regardless of
    response to frontline therapy

    - Refractory disease: persistent sites of disease (after less than a partial
    response to frontline therapy, following a minimum of 4 cycles of induction
    therapy) AND patient has never had a relapse/progression

    - Persistent disease: persistent disease after achieving at least a partial
    response to frontline therapy after a minimum of 4 cycles of induction therapy
    and patient has never had a relapse/progression

    - 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):

    - Bone disease

    - At least one metaiodobenzylguanidine (MIBG) avid bone site or diffuse MIBG
    uptake

    - For recurrent/progressive or refractory disease a biopsy is not
    required regardless of number of MIBG avid lesions

    - For persistent disease, if patient has only 1 or 2 MIBG avid lesions
    OR 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 and two weeks
    subsequent to most recent prior therapy; if a patient has 3 or more
    MIBG avid lesions OR a Curie score of >= 3 then no biopsy is required
    for eligibility

    - If a tumor is known to be MIBG non-avid, then a patient must have at least
    one fludeoxyglucose (FDG)-positron emission tomography (PET) avid bone site
    present at the time of enrollment with biopsy confirmation of neuroblastoma
    and/or ganglioneuroblastoma obtained at any time prior to enrollment and
    two weeks subsequent to most recent prior therapy

    - Any amount of neuroblastoma tumor cells in the bone marrow 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 the criteria for a TARGET lesion as
    defined by:

    - 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;
    lesions meeting size criteria will be considered measurable

    - In addition to size, a lesion needs to meet ONE of the following criteria:

    - MIBG avid; for patients with persistent disease only: if a patient has
    only 1 or 2 MIBG avid lesions OR a Curie score of 1-2, then biopsy
    confirmation of neuroblastoma and/or ganglioneuroblastoma in at least
    one site present at time of enrollment (either bone marrow, bone
    and/or soft tissue) is required to be obtained at any time point prior
    to enrollment and at least two weeks subsequent to most recent prior
    therapy; if a patient has 3 or more MIBG avid lesions OR a Curie score
    of >= 3 then no biopsy is required for eligibility

    - FDG-PET avid (only if tumor is known to be MIBG non-avid); these
    patients must have had a biopsy confirming neuroblastoma and/or
    ganglioneuroblastoma in at least one FDG-PET avid site present at the
    time of enrollment done prior to enrollment and at least two weeks
    subsequent to the most recent prior therapy

    - Non-avid lesion (both MIBG and FDG-PET non-avid); these patients must
    have had a biopsy confirming neuroblastoma and/or ganglioneuroblastoma
    in at least one non-avid lesion present at the time of enrollment done
    prior to enrollment and at least two weeks subsequent to the most
    recent prior therapy

    - Patients with prior progressive disease who do not meet criteria above, are eligible
    as long as they have not been off treatment for > 3 months prior to enrollment on
    NANT 2011-04

    - Patients must have a life expectancy of at least 6 weeks

    - Lansky (=< 16 years) or Karnofsky (> 16 years) score of at least 50

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

    - Patients must not have received the therapies indicated below for the specified time
    period prior to the first day of administration of protocol therapy on this study

    - Myelosuppressive chemotherapy: must have received last dose at least 2 weeks
    prior to protocol therapy; this includes cytotoxic agents given on a low dose
    metronomic regimen

    - Biologic (anti-neoplastic agent) (includes retinoids): must have received last
    dose at least 7 days prior to protocol therapy

    - Monoclonal antibodies: must have received last dose at least 7 days or 3
    half-lives, whichever is longer, prior to protocol therapy

    - Radiation:

    - Patients must not have received radiation (small port) for a minimum of two
    weeks prior to protocol therapy

    - Except for patients with a history of progressive disease, patients whose only
    site(s) of disease have been radiated are eligible if at least one lesion meets
    at least one of the criteria listed in sites of disease above

    - A minimum of 12 weeks prior to start of protocol therapy is required following
    large field radiation therapy (i.e. total body irradiation, craniospinal, whole
    abdominal, total lung, > 50% marrow space)

    - A minimum of 6 weeks must have elapsed prior to start of protocol therapy for
    other substantial bone marrow radiation

    - Stem Cell Transplant (SCT):

    - Patients are eligible 6 weeks after date of autologous stem cell infusion
    following myeloablative therapy (timed from first day of protocol therapy)

    - Patients are not eligible post allogeneic stem cell transplant

    - Patients who have received an autologous stem cell infusion to support
    non-myeloablative therapy (such as 131 iodine [I]-MIBG) are eligible at any time
    as long as they meet the other criteria for eligibility

    - A minimum of 6 weeks must have elapsed after 131I-MIBG therapy prior to start of
    protocol therapy

    - Prior anti-disialoganglioside (GD2) antibody, isotretinoin, or lenalidomide therapy:

    - Patients who have received prior anti-GD2 antibody therapy are eligible if they
    did not have tumor relapse/progression while receiving this therapy

    - Patients who have received either isotretinoin or lenalidomide are eligible, but
    not if they have received the two agents concomitantly

    - All cytokines or hematopoietic growth factors must be discontinued a minimum of 7
    days prior to protocol therapy

    - Patients must not be receiving any other anti-cancer agents or radiotherapy at the
    time of study entry or while on study

    - Absolute phagocyte count (APC = neutrophils and monocytes): >= 1000/mm^3

    - Absolute neutrophil count: >= 750/mm^3

    - Platelet count: >= 50,000/mm^3, transfusion independent (no platelet transfusions
    within 1 week)

    - Hemoglobin >= 8.0 (may transfuse)

    - Patients with known bone marrow metastatic disease will be eligible for study as long
    as they meet hematologic function criteria; patients with marrow disease are not
    evaluable for hematologic toxicity

    - Age-adjusted serum creatinine =< 1.5 x normal for age or creatinine clearance or
    glomerular filtration rate (GFR) >= 60 cc/min/1.73 m^2

    - Age 1 month to < 6 months: 0.4 mg/dL for males and 0.4 mg/dL for females

    - Age 6 months to < 1 year: 0.5 mg/dL for males and 0.5 mg/dL for females

    - Age 1 to < 2 years: 0.6 mg/dL for males and 0.6 mg/dL for females

    - Age 2 to < 6 years: 0.8 mg/dL for males and 0.8 mg/dL for females

    - Age 6 to < 10 years: 1.0 mg/dL for males and 1.0 mg/dL for females

    - Age 10 to < 13 years: 1.2 mg/dL for males and 1.2 mg/dL for females

    - Age 13 to < 16 years: 1.5 mg/dL for males and 1.4 mg/dL for females

    - Age >= 16 years: 1.7 mg/dL for males and 1.4 mg/dL for females

    - =< grade 2 hematuria (criteria applicable only for dose levels that include
    isotretinoin) and =< grade 2 proteinuria

    - Total bilirubin =< 1.5 x upper limit of normal for age

    - Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
    and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])
    =< 3 x upper limit of normal (note that for ALT, the upper limit of normal is defined
    as 45 U/L)

    - Sinusoidal obstruction syndrome (SOS) if present, must be stable or improving
    clinically

    - Cardiac function:

    - Normal ejection fraction (>= 55%) documented by either echocardiogram or
    radionuclide multi gated acquisition scan (MUGA) evaluation; OR

    - Normal fractional shortening (>= 27%) documented by echocardiogram

    - No dyspnea at rest

    - Serum triglyceride =< 300 mg/dL (applicable only for dose levels that include
    isotretinoin) (note that a non-fasting triglyceride value could be obtained, if this
    is > 300 mg/dL then a fasting triglyceride should be obtained and patient will be
    eligible if the fasting level is =< 300 mg/dL)

    - =< grade 2 hypercalcemia (applicable only for dose levels that include cis retinoic
    acid [RA])

    - Skin toxicity =< grade 1

    - All post-menarchal females must have a negative beta-human chorionic gonadotropin
    (HCG); males and females of reproductive age and childbearing potential must use
    effective contraception for the duration of their participation; females of
    childbearing potential (FCBP) must have a negative serum or urine pregnancy test with
    a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior
    to prescribing lenalidomide for cycle 1 and must either commit to continued
    abstinence from heterosexual intercourse or begin TWO acceptable methods of birth
    control, one highly effective method and one additional effective method AT THE SAME
    TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to
    ongoing pregnancy testing; men must agree to use a latex condom during sexual contact
    with a FCBP even if they have had a successful vasectomy

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

    Exclusion Criteria:

    - Quantitative serum b-HCG must be negative in girls who are post-menarchal; males or
    females of reproductive potential may not participate unless they have agreed to use
    an effective contraceptive method; pregnant or breast-feeding women will not be
    entered on this study

    - Breast feeding women are not eligible

    - Patients who have an active or uncontrolled infection are excluded

    - Patients with a paraben allergy cannot take isotretinoin preparations containing this
    compound (i.e. Accutane, Sotret) but are eligible if they can take an alternate
    preparation without paraben; (applicable only for entry onto dose levels receiving
    isotretinoin)

    - Patients with a history of venous or arterial thrombosis personally before the age of
    40 years unless associated with a central line

    - Patients with a history of prior central nervous system (CNS) metastases or skull
    lesions with intracranial extension will be required to have a head computed
    tomography (CT) or magnetic resonance imaging (MRI) at study entry demonstrating no
    active CNS metastases; patients with skull metastases with associated intracranial
    soft tissue masses will remain eligible

    - Inability to swallow lenalidomide capsules whole; capsules of 13-isotretinoin may be
    opened

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

    Minimum Eligible Age: N/A

    Maximum Eligible Age: 21 Years

    Eligible Gender: Both

    Primary Outcome Measures

    MTD defined as the highest dose level tested at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) criteria, version 4.0

    Recommended phase II dose

    Secondary Outcome Measures

    Changes in levels of HACA (or other genotype) and tumor response

    Changes in the levels of T cells, NK cells, monocytes, cytokines, and chemokines

    Changes in TLDA scores

    Event-free survival

    Overall response

    Overall survival

    Pharmacokinetic determinations of lenalidomide

    Trial Keywords