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

Status: Recruiting
Phase: Phase 1
DFCI Protocol ID: 12-505

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.

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Suzanne Shusterman, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:

Contacts:

Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

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

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