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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.
Full description
PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of sargramostim (GM-CSF) and isotretinoin given in combination with hu14.18-IL-2 (hu14.18-IL2 fusion protein), as a test of feasibility for a future Phase III study.
II. To evaluate the anti-tumor activity of hu14.18-IL2 given in combination with GM-CSF and isotretinoin in patients with recurrent or refractory neuroblastoma with disease measurable by standard radiographic criteria (stratum-1).
III. To evaluate the anti-tumor activity of hu14.18-IL2 given in combination with GM-CSF and isotretinoin in patients with recurrent or refractory neuroblastoma evaluable only by meta iodo benzyl guanidine I 123 (MIBG) scintigraphy and/or bone marrow histology (stratum-2).
SECONDARY OBJECTIVES:
I. To describe the disease burden of stratum-2 patients by semi-quantitative assessment of bone marrow and MIBG scintigraphy and determine whether there is an association between lower disease burden and response to hu14.18-IL2.
II. To assess molecular parameters of response (reverse-transcriptase (RT) polymerase chain reaction (PCR)) for patients meeting complete response (CR) criteria.
III. To evaluate the immunologic activation induced in vivo by hu14.18-IL2. IV. To determine the induction of anti-hu14.18-IL2 antibody by treatment with hu14.18-IL2.
V. To test for associations between tumor response versus immune activation and anti-hu14.18-IL2 activity, and between measurements of toxicity versus immune activation and anti-hu14.18-IL2 activity.
OUTLINE: This is a multicenter study. Patients are stratified according to measurable disease (disease measurable by standard radiographic criteria [stratum-1] vs disease evaluable only by meta iodo benzyl guanidine I 123 (MIBG) and/or bone marrow histology [stratum-2]).
Patients receive sargramostim subcutaneously (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin orally (PO) twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.
After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then yearly for 2 years.
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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:
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-lifetableforeligibility.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:
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
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52 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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