Irinotecan Hydrochloride and Temozolomide With Temsirolimus or Dinutuximab in Treating Younger Patients With Refractory or Relapsed Neuroblastoma

Not Recruiting

Trial ID: NCT01767194


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.

Official Title

A Phase II Randomized Trial of Irinotecan/Temozolomide With Temsirolimus (NSC# 683864) or Chimeric 14.18 Antibody (Ch14.18) (NSC# 764038) in Children With Refractory, Relapsed or Progressive Neuroblastoma

Stanford Investigator(s)


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

      - 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

      - 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


biological: Dinutuximab

drug: Irinotecan Hydrochloride

other: Laboratory Biomarker Analysis

biological: Sargramostim

drug: Temozolomide

drug: Temsirolimus

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305

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