Biological Therapy, Sargramostim, and Isotretinoin in Treating Patients With Relapsed or Refractory Neuroblastoma
Condition: Recurrent Neuroblastoma
MeSH terms: Neuroblastoma
Intervention: hu14.18-IL2 fusion protein; isotretinoin; sargramostim; laboratory biomarker analysis
Intervention description: Given IV; Given PO; Given SC; Correlative studies
Intervention MeSH terms: Isotretinoin; Sargramostim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 52.0
Sex: All
Minimum age: 1 Year
Maximum age: 30 Years
Healthy volunteers: No

Summary:

      This phase II trial is studying how well hu14.18-interleukin-2 (IL2) fusion protein works
      when given together with sargramostim and isotretinoin in treating patients with relapsed or
      refractory neuroblastoma. Biological therapy, such as hu14.18-IL2 fusion protein, and
      sargramostim work in different ways to stimulate the immune system and stop tumor cells from
      growing. Drugs used in chemotherapy, such as isotretinoin, work in different ways to stop the
      growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving
      hu14.18-IL2 fusion protein together with sargramostim and isotretinoin may kill more tumor
      cells.
    

Eligibility criteria:

        Inclusion Criteria:

          -  The target tumor is limited to neuroblastoma; patients must have had histologic
             verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow
             with increased urinary catecholamines at the time of initial diagnosis

          -  Patients must have resistant/refractory or recurrent neuroblastoma

          -  Tumor imaging and bone marrow evaluation for histologic analysis of marrow tumor cell
             quantity must be obtained within 3 weeks (21 days) prior to enrollment onto study and
             patients must have one of the following:

               -  Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT)
                  scan, or x-ray defined as minimum of 20 mm in at least one dimension; measurable
                  is defined as minimum of 20 mm in at least one dimension; for patients who are in
                  first response (i.e., those patients with persistent sites of tumor after
                  frontline therapy, but who have never relapsed), a biopsy of a lesion or bone
                  marrow must demonstrate viable neuroblastoma following completion of therapy; if
                  the lesion was irradiated, the biopsy must be done at least 4 weeks after
                  radiation is completed

               -  Meta iodo benzyl guanidine I 123 (MIBG) scan with positive uptake at minimum of
                  one site; for patients in first response, a biopsy of site must demonstrate
                  viable tumor; if lesion was radiated, biopsy must be done at least 4 weeks after
                  radiation completed

               -  Bone marrow with tumor cells seen on routine morphology (not by neuron specific
                  enolase (NSE) staining only) of bilateral aspirate and/or biopsy on one bone
                  marrow sample

          -  Patients must have a performance status of 0, 1 or 2; use Karnofsky >= 50% for
             patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age

          -  Patients must have a life expectancy of ≥ 8 weeks

          -  Patients must have fully recovered from the acute toxic effects of all prior
             chemotherapy, immunotherapy, or radiotherapy prior to entering this study

          -  Myelosuppressive chemotherapy: Must not have received within 3 weeks of entry onto
             this study (4 weeks if prior nitrosourea).

          -  Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with
             a non-myelosuppressive biologic agent; for agents that have known adverse events
             occurring beyond 7 days after administration, this period must be extended beyond the
             time during which adverse events are known to occur; for information on half-lives of
             these agents, refer to the table provided in the following link:
             https://members.childrensoncologygroup.org/_files/disc/dvl/Half-lifetableforeligibilit
             y.pdf

          -  External beam radiation therapy (XRT): >= 2 wks for local palliative XRT (small port);
             >= 6 months must have elapsed if prior craniospinal XRT or if >= 50% radiation of
             pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation

          -  Autologous stem cell transplant (ASCT): Patients are eligible > 56 days after
             autologous stem cell infusion following myeloablative therapy; patients receiving an
             autologous stem cell infusion to support non-myeloablative therapy (including
             131I-MIBG given as a single agent) are eligible at any time as long as they meet the
             hematologic and other organ function criteria for eligibility; patients who have
             received an allogenic stem cell transplant are excluded

          -  radioactive iodine (131 I) MIBG therapy: Patients are eligible > 6 weeks after
             therapeutic 131I-MIBG

          -  Study specific limitations on prior therapy: Subjects who have previously received in
             vivo anti-GD2 monoclonal antibodies for biologic therapy or for tumor imaging, are
             eligible unless they have had progressive disease or a severe allergic reaction while
             receiving prior anti-disialoganglioside (GD2) therapy; subjects who have received
             autologous marrow infusions or autologous stem cell infusions using monoclonal
             antibody linked to beads to purge specimens, but no other form of anti-GD2 monoclonal
             antibody, are eligible

          -  Growth factor(s): Must not have received within 1 week of entry onto this study

          -  Steroids: Patients who require or are likely to require corticosteroid or other
             immunosuppressive drugs for intercurrent disease (any other significant medical
             problem related to or independent from the neuroblastoma or its treatment) while
             tentatively scheduled to be 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
             transfusion in order to avoid allergic transfusion reactions

          -  Peripheral absolute phagocyte count (APC=neutrophils + monocytes) >= 1000/uL

          -  Platelet count ≥ 20,000/μL*

          -  Hemoglobin ≥ 8 g/dL*

          -  Transfusions are permitted to meet these platelet and hemoglobin criteria, if the
             patient is known to have a history of bone marrow involvement with tumor; patients
             with platelet counts < 20,000/uL who are refractory to platelet transfusions are not
             eligible for this study; patients requiring transfusions of platelets or red blood
             cells (RBC) to meet eligibility criteria will not be evaluable for hematologic
             toxicity

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min OR
             serum creatinine based on age/gender as follows:

               -  0.4 mg/dL (1 month to < 6 months of age)

               -  0.5 mg/dL (6 months to < 1 years of age)

               -  0.6 mg/dL (1 to < 2 years of age)

               -  0.8 mg/dL (2 to < 6 years of age)

               -  1.0 mg/dL (6 to < 10 years of age)

               -  1.2 mg/dL (10 to < 13 years of age)

               -  1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

               -  1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)

          -  Total bilirubin =< 1.5 times upper limit of normal (ULN)

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x
             upper limit of normal (ULN) for age

          -  Shortening fraction of >= 27% by echocardiogram

          -  Ejection fraction of >= 55% by gated radionuclide study (interleukin 2 [IL2] is
             associated with capillary leak and, at high doses, pulmonary edema)

          -  Corrected QT (QTC) interval < 450 msec

          -  Due to risk of IL2 associated vascular leak and pulmonary edema, patients must have
             normal respiratory function; this is defined as no evidence of dyspnea at rest, no
             exercise intolerance, and a pulse oximetry > 94% on room air; if pulmonary function
             tests (PFTs) are performed, the forced expiratory volume in 1 second (FEV1)/forced
             vital capacity (FVC) must be greater than 60%

          -  Patients with a history of central nervous system (CNS) disease must have no clinical
             or radiological evidence of CNS disease at the time of protocol enrollment; (it is
             currently unknown whether hu14.18-IL2 penetrates the blood brain barrier to provide
             effective CNS treatment)

          -  Patients with seizure disorders may be enrolled if on anti-convulsants and
             well-controlled

          -  CNS toxicity =< grade 2

        Exclusion Criteria:

          -  Females of childbearing potential must have a negative pregnancy test

          -  Patients of childbearing potential must agree to use an effective birth control method
             (as isotretinoin is known to be teratogenic)

          -  Female patients who are lactating must agree to stop breast-feeding

          -  Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm
             disturbance are not eligible

          -  Patients with symptomatic pleural effusions or ascites (requiring constant or
             intermittent drainage) because IL2 is associated with capillary leak are not eligible

          -  Patients who have had major surgery (i.e., laparotomy or thoracotomy) within the past
             2 weeks are not eligible, due to the capillary leak associated with IL2

          -  Patients with organ allografts (including bone marrow or stem cell) due to the immune
             activating effects of IL2 are not eligible; patients receiving prior autologous bone
             marrow or stem cell re-infusions are eligible

          -  Patients with prior history of ventilator support related to lung injury (lung injury
             such as pneumonia, hemorrhagic pneumonitis, capillary leakage) are excluded

          -  Patients with significant serious intercurrent illnesses (any other ongoing serious
             medical problem unrelated to cancer or its treatment) that is not covered by the
             detailed exclusion criteria and which is expected to interfere with the action of
             hu14.18-IL2 or to significantly increase the severity of the toxicities experienced
             from hu14.18-IL2 treatment are not eligible