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Feasibility/Phase II Study of hu14.18-IL2 Immunocytokine + GM-CSF and Isotretinoin in Patients With Relapsed or Refractory Neuroblastoma

Phase 2
1 Year
30 Years
Open (Enrolling)
Recurrent Neuroblastoma

Thank you

Trial Information

Feasibility/Phase II Study of hu14.18-IL2 Immunocytokine + GM-CSF and Isotretinoin in Patients With Relapsed or Refractory Neuroblastoma


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-iodobenzyl guanidine I 123 (MIBG) scintigraphy and/or bone marrow histology


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 polymerase chain
reaction [RT-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 123I-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.

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-iodobenzyl 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:

- 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)

- 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

- 131I-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-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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Incidence of adverse events, utilizing version 4.0 of the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI)

Outcome Time Frame:

Up to 10 courses

Safety Issue:


Principal Investigator

Suzanne Shusterman

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

September 2011

Completion Date:

Related Keywords:

  • Recurrent Neuroblastoma
  • Neuroblastoma



Cleveland Clinic Foundation Cleveland, Ohio  44195
Roswell Park Cancer Institute Buffalo, New York  14263
Mayo Clinic Rochester, Minnesota  55905
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Washington University School of Medicine Saint Louis, Missouri  63110
Medical City Dallas Hospital Dallas, Texas  75230
Sinai Hospital of Baltimore Baltimore, Maryland  21225
Bronson Methodist Hospital Kalamazoo, Michigan  49007
Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838
Morristown Memorial Hospital Morristown, New Jersey  07962-1956
Loma Linda University Medical Center Loma Linda, California  92354
New York Medical College Valhalla, New York  10595
Dana-Farber Cancer Institute Boston, Massachusetts  02115
University of Arkansas for Medical Sciences Little Rock, Arkansas  72205
Children's Hospital Los Angeles Los Angeles, California  90027-0700
Children's National Medical Center Washington, District of Columbia  20010-2970
Miami Children's Hospital Miami, Florida  33155-4069
All Children's Hospital St. Petersburg, Florida  33701
Carolinas Medical Center Charlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma  73104
St. Jude Children's Research Hospital Memphis, Tennessee  38105-2794
Children's Hospital Central California Madera, California  93638-8762
Kosair Children's Hospital Louisville, Kentucky  40202-3830
Children's Hospital Medical Center of Akron Akron, Ohio  44308
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001
Overlook Hospital Summit, New Jersey  07902-0220
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Primary Children's Medical Center Salt Lake City, Utah  84113-1100
Rady Children's Hospital - San Diego San Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis, Minnesota  55404
University of New Mexico Cancer Center Albuquerque, New Mexico  87131-5636
Lehigh Valley Hospital - Muhlenberg Bethlehem, Pennsylvania  18017
Presbyterian Hospital Charlotte, North Carolina  28233-3549
Lee Memorial Health System Fort Myers, Florida  33902
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
Connecticut Children's Medical Center Hartford, Connecticut  06106
University of North Carolina Chapel Hill, North Carolina  27599
Duke University Medical Center Durham, North Carolina  27710
University of Kentucky Lexington, Kentucky  40536-0098
Oregon Health and Science University Portland, Oregon  97201
Tulane University Health Sciences Center New Orleans, Louisiana  70112
Virginia Commonwealth University Richmond, Virginia  
Florida Hospital Orlando, Florida  32803
University of Chicago Comprehensive Cancer Center Chicago, Illinois  60637-1470
Seattle Children's Hospital Seattle, Washington  98105
University of Hawaii Honolulu, Hawaii  96813
Kalamazoo Center for Medical Studies Kalamazoo, Michigan  49008
Columbia University Medical Center New York, New York  10032
State University of New York Upstate Medical University Syracuse, New York  13210
Natalie W Bryant Cancer Center Tulsa, Oklahoma  74136
Saint Vincent Hospital Green Bay, Wisconsin  54301
University of Illinois Chicago, Illinois  60612
Cook Children's Medical Center Fort Worth, Texas  76104
The Children's Medical Center of Dayton Dayton, Ohio  45404
Children's Oncology Group Arcadia, California  91006-3776
Southern Illinois University Springfield, Illinois  62702
Riley Hospital for Children Indianapolis, Indiana  46202
Cardinal Glennon Children's Medical Center St. Louis, Missouri  63104
Childrens Hospital of Orange County Orange, California  92868-3874
Nemours Children's Clinic - Jacksonville Jacksonville, Florida  32207-8426
Children's Healthcare of Atlanta - Egleston Atlanta, Georgia  30322
Rainbow Babies and Childrens Hospital Cleveland, Ohio  44106
Penn State Hershey Children's Hospital Hershey, Pennsylvania  17033
Childrens Hospital-King's Daughters Norfolk, Virginia  23507
Children's Hospital Colorado Aurora, Colorado  80045
University of California San Francisco Medical Center-Parnassus San Francisco, California  94143
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center Denver, Colorado  80218
Raymond Blank Children's Hospital Des Moines, Iowa  50309
Children's Hospital-Main Campus New Orleans, Louisiana  70118
The Toledo Hospital/Toledo Children's Hospital Toledo, Ohio  43606
Sanford USD Medical Center - Sioux Falls Sioux Falls, South Dakota  57117-5134