Irinotecan Hydrochloride and Temozolomide With Temsirolimus or Dinutuximab in Treating Younger Patients With Refractory or Relapsed Neuroblastoma
Condition: Ganglioneuroblastoma; Recurrent Neuroblastoma
MeSH terms: Neuroblastoma; Ganglioneuroblastoma
Intervention: Dinutuximab; Irinotecan Hydrochloride; Laboratory Biomarker Analysis; Sargramostim; Temozolomide; Temsirolimus
Intervention description: Given IV; Given IV; Optional correlative studies; Given SC or IV; Given PO; Given IV
Intervention MeSH terms: Sirolimus; Irinotecan; Camptothecin; Temozolomide; Temsirolimus; Dinutuximab; MTOR Inhibitors; Sargramostim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 73.0
Sex: All
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well irinotecan hydrochloride and temozolomide
      with temsirolimus or dinutuximab work in treating younger patients with neuroblastoma that
      has returned or does not respond to treatment. Drugs used in chemotherapy, such as irinotecan
      hydrochloride and temozolomide, 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. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes
      needed for cell growth. Monoclonal antibodies, such as dinutuximab, may find tumor cells and
      help kill them or carry tumor-killing substances to them. It is not yet known whether giving
      irinotecan hydrochloride and temozolomide together with temsirolimus or dinutuximab is more
      effective in treating neuroblastoma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have had histologic verification of neuroblastoma or
             ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with
             elevated urinary catecholamines (i.e., > 2 x upper limit of normal [ULN]), at the time
             of initial diagnosis

          -  For the purposes of this study, aggressive multidrug chemotherapy is defined as
             chemotherapy including 2 or more agents that must include an alkylating agent and a
             platinum-containing compound; patients must have ONE of the following:

               -  First episode of recurrent disease following completion of aggressive multi-drug
                  frontline therapy

               -  First episode of progressive disease during aggressive multi-drug frontline
                  therapy

               -  Primary resistant/refractory disease (less than partial response by INRC)
                  detected at the conclusion of at least 4 cycles of aggressive multidrug induction
                  chemotherapy on or according to a high-risk neuroblastoma protocol (examples
                  include A3973, ANBL0532, ANBL09P1, etc.)

          -  Patients must have at least ONE of the following:

               -  Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT)
                  scan obtained within 3 weeks prior to study entry; measurable is defined as >= 10
                  mm in at least one dimension on spiral/helical CT that is metaiodobenzylguanidine
                  (MIBG) avid or demonstrates increased fludeoxyglucose (FDG) uptake on positron
                  emission tomography (PET) scan

               -  MIBG scan obtained within 3 weeks prior to study entry with positive uptake at a
                  minimum of one site; this site must represent disease recurrence after completion
                  of therapy, progressive disease on therapy, or refractory disease during
                  induction

               -  Patients with resistant/refractory soft tissue disease that is not MIBG avid or
                  does not demonstrate increased FDG uptake on PET scan must undergo biopsy to
                  document the presence of viable neuroblastoma; biopsy is not required for
                  patients who have new site of soft tissue disease (radiographic evidence of
                  disease progression) regardless of whether progression occurs while receiving
                  therapy or after completion of therapy

               -  Note: Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow
                  disease only are NOT eligible for this study

          -  Patients must have a performance status corresponding to Eastern Cooperative Oncology
             Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and
             Lansky for patients =< 16 years of age

          -  Patients must have received frontline therapy (including surgery, chemotherapy,
             autologous stem cell transplant [SCT] +/- MIBG, immunotherapy, radiotherapy, and
             retinoids) but may NOT have received second line chemotherapy for
             resistant/refractory, relapsed disease or progressive disease

          -  At least 14 days must have elapsed since completion of myelosuppressive therapy

          -  At least 7 days must have elapsed since the completion of therapy with a
             non-myelosuppressive biologic agent or retinoid

          -  No interim time prior to study entry is required following prior radiation therapy
             (RT) for non-target lesions; however, patients must not have received radiation for a
             minimum of 4 weeks prior to study entry at the site of any lesion that will be
             identified as a target lesion to measure tumor response; lesions that have been
             previously radiated cannot be used as target lesions unless there is radiographic
             evidence of progression at the site following radiation or a biopsy done following
             radiation shows viable neuroblastoma; palliative radiation is allowed to sites that
             will not be used to measure response during this study

          -  Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell
             infusions as long as hematologic and other eligibility criteria have been met

          -  Patients are eligible >= 6 weeks after therapeutic 131I-MIBG provided that all other
             eligibility criteria are met

          -  Subjects who have previously received anti-GD2 monoclonal antibodies for biologic
             therapy or for tumor imaging are eligible unless they have had progressive disease
             while receiving prior anti-GD2 therapy; subjects who have received autologous marrow
             infusions or autologous stem cell infusions that were purged using monoclonal antibody
             linked to beads, but no other form of anti-GD2 monoclonal antibody, are eligible

          -  Patients must not have received long-acting myeloid growth factors (e.g., Neulasta)
             within 14 days of entry on this study; seven days must have elapsed since
             administration of a short acting myeloid growth factor

          -  Peripheral absolute neutrophil count (ANC) >= 750/uL

          -  Platelet count >= 75,000/uL (transfusion independent)

          -  Patients known to have bone marrow involvement with neuroblastoma are eligible
             provided that minimum ANC and platelet count criteria are met but are not evaluable
             for hematological toxicity

          -  Creatinine clearance or estimated radioisotope glomerular filtration rate (GFR) >= 70
             mL/min/1.73 m^2 or

          -  A serum creatinine =< upper limit of normal (ULN) based on age/gender as follows:

               -  Age 1 month to < 6 months: 0.4 for males, 0.4 for females

               -  Age 6 months to < 1 year: 0.5 for males, 0.5 for females

               -  Age 1 to < 2 years: 0.6 for males, 0.6 for females

               -  Age 2 to < 6 years: 0.8 for males, 0.8 for females

               -  Age 6 to < 10 years: 1 for males, 1 for females

               -  Age 10 to < 13 years: 1.2 for males, 1.2 for females

               -  Age 13 to < 16 years: 1.5 for males, 1.4 for females

               -  Age >= 16 years: 1.7 for males, 1.4 for females

          -  Total bilirubin =< 1.5 x ULN for age AND

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x
             ULN for age (=< 225 U/L); for the purpose of this study, the ULN for SGPT is 45 U/L

          -  Adequate central nervous system function defined as:

               -  Patients with a history of central nervous system (CNS) disease must have no
                  clinical or radiological evidence of CNS disease at the time of study enrollment

               -  Patients with seizure disorders may be enrolled if seizures are well controlled
                  on anticonvulsants

               -  CNS toxicity =< grade 2

          -  Shortening fraction of >= 27% by echocardiogram (ECHO) OR

          -  Ejection fraction >= 50% by ECHO or gated radionuclide study

          -  Adequate coagulation defined as:

               -  Prothrombin time (PT) =< 1.2 x upper limit of normal

          -  Adequate pulmonary function defined as:

               -  No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen
                  requirement, and room air pulse oximetry > 94% if there is a clinical indication
                  for pulse oximetry; normal pulmonary function tests in patients who are capable
                  of cooperating with testing (including diffusion capacity of the lung of carbon
                  monoxide [DLCO]) are required if there is a clinical indication for
                  determination; for patients who do not have respiratory symptoms, full pulmonary
                  function tests (PFTs) are NOT required

        Exclusion Criteria:

          -  Men and women of childbearing potential and their partners must agree to use adequate
             contraception while enrolled on this study; based on the established teratogenic
             potential of alkylating agents, pregnant women will be excluded from this study;
             female patients who are lactating must agree to stop breastfeeding or will otherwise
             be excluded from this study; females of childbearing potential must have a negative
             pregnancy test to be eligible for this study

          -  Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow disease
             only are NOT eligible for this study

          -  Patients must have been off pharmacologic doses of systemic steroids for at least 7
             days prior to enrollment; patients who require or are likely to require pharmacologic
             doses of systemic corticosteroids while receiving treatment on this study are
             ineligible; the only exception is for patients known to require 2 mg/kg or less of
             hydrocortisone (or an equivalent dose of an alternative corticosteroid) as
             premedication for blood product administration in order to avoid allergic transfusion
             reactions; the use of conventional doses of inhaled steroids for the treatment of
             asthma is permitted, as is the use of physiologic doses of steroids for patients with
             known adrenal insufficiency

          -  Patients must not have received enzyme-inducing anticonvulsants including phenytoin,
             phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study
             enrollment; patients receiving non-enzyme inducing anticonvulsants such as gabapentin
             or levetiracetam will be eligible

          -  Patients must not have been diagnosed with myelodysplastic syndrome or with any
             malignancy other than neuroblastoma

          -  Patients with symptoms of congestive heart failure are not eligible

          -  Patients must not have >= grade 2 diarrhea

          -  Patients must not have uncontrolled infection

          -  Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or
             reactions that required discontinuation of the anti-GD2 therapy are not eligible

          -  Patients with a significant intercurrent illness (any ongoing serious medical problem
             unrelated to cancer or its treatment) that is not covered by the detailed exclusion
             criteria and that is expected to interfere with the action of study agents or to
             significantly increase the severity of the toxicities experienced from study treatment
             are not eligible