Biological Therapy, Sargramostim, and Isotretinoin in Treating Patients With Relapsed or Refractory Neuroblastoma
NCT ID: NCT01334515
Last Updated: 2019-10-21
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
52 participants
INTERVENTIONAL
2011-09-30
2019-09-30
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Disease measured by standard radiographic criteria
Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (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 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.
hu14.18-IL2 fusion protein
Given IV
isotretinoin
Given PO
sargramostim
Given SC
laboratory biomarker analysis
Correlative studies
Disease evaluable only by I-MIBG or BM histology
Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (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 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.
hu14.18-IL2 fusion protein
Given IV
isotretinoin
Given PO
sargramostim
Given SC
laboratory biomarker analysis
Correlative studies
Interventions
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hu14.18-IL2 fusion protein
Given IV
isotretinoin
Given PO
sargramostim
Given SC
laboratory biomarker analysis
Correlative studies
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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-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:
* 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
* 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
1 Year
30 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
Children's Oncology Group
NETWORK
Responsible Party
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Principal Investigators
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Suzanne Shusterman, MD
Role: PRINCIPAL_INVESTIGATOR
Children's Oncology Group
Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Children's Oncology Group
Arcadia, California, United States
Loma Linda University Medical Center
Loma Linda, California, United States
Children's Hospital Los Angeles
Los Angeles, California, United States
Children's Hospital Central California
Madera, California, United States
Childrens Hospital of Orange County
Orange, California, United States
Rady Children's Hospital - San Diego
San Diego, California, United States
University of California San Francisco Medical Center-Parnassus
San Francisco, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Denver, Colorado, United States
Connecticut Children's Medical Center
Hartford, Connecticut, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Lee Memorial Health System
Fort Myers, Florida, United States
Nemours Children's Clinic - Jacksonville
Jacksonville, Florida, United States
Miami Children's Hospital
Miami, Florida, United States
Florida Hospital
Orlando, Florida, United States
All Children's Hospital
St. Petersburg, Florida, United States
Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia, United States
University of Hawaii
Honolulu, Hawaii, United States
University of Illinois
Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States
Southern Illinois University
Springfield, Illinois, United States
Riley Hospital for Children
Indianapolis, Indiana, United States
Raymond Blank Children's Hospital
Des Moines, Iowa, United States
University of Kentucky
Lexington, Kentucky, United States
Kosair Children's Hospital
Louisville, Kentucky, United States
Tulane University Health Sciences Center
New Orleans, Louisiana, United States
Children's Hospital-Main Campus
New Orleans, Louisiana, United States
Sinai Hospital of Baltimore
Baltimore, Maryland, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Bronson Methodist Hospital
Kalamazoo, Michigan, United States
Kalamazoo Center for Medical Studies
Kalamazoo, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis, Minnesota, United States
Mayo Clinic
Rochester, Minnesota, United States
Cardinal Glennon Children's Medical Center
St Louis, Missouri, United States
Washington University School of Medicine
St Louis, Missouri, United States
Morristown Memorial Hospital
Morristown, New Jersey, United States
Overlook Hospital
Summit, New Jersey, United States
University of New Mexico Cancer Center
Albuquerque, New Mexico, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Columbia University Medical Center
New York, New York, United States
State University of New York Upstate Medical University
Syracuse, New York, United States
New York Medical College
Valhalla, New York, United States
University of North Carolina
Chapel Hill, North Carolina, United States
Carolinas Medical Center
Charlotte, North Carolina, United States
Presbyterian Hospital
Charlotte, North Carolina, United States
Duke University Medical Center
Durham, North Carolina, United States
Children's Hospital Medical Center of Akron
Akron, Ohio, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Rainbow Babies and Childrens Hospital
Cleveland, Ohio, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
The Children's Medical Center of Dayton
Dayton, Ohio, United States
The Toledo Hospital/Toledo Children's Hospital
Toledo, Ohio, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
Natalie W Bryant Cancer Center
Tulsa, Oklahoma, United States
Oregon Health and Science University
Portland, Oregon, United States
Lehigh Valley Hospital - Muhlenberg
Bethlehem, Pennsylvania, United States
Penn State Hershey Children's Hospital
Hershey, Pennsylvania, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
Medical City Dallas Hospital
Dallas, Texas, United States
Cook Children's Medical Center
Fort Worth, Texas, United States
Primary Children's Medical Center
Salt Lake City, Utah, United States
Childrens Hospital-King's Daughters
Norfolk, Virginia, United States
Virginia Commonwealth University
Richmond, Virginia, United States
Seattle Children's Hospital
Seattle, Washington, United States
Saint Vincent Hospital
Green Bay, Wisconsin, United States
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States
Alberta Children's Hospital
Calgary, Alberta, Canada
British Columbia Children's Hospital
Vancouver, British Columbia, Canada
Hospital for Sick Children
Toronto, Ontario, Canada
The Montreal Children's Hospital of the MUHC
Montreal, Quebec, Canada
Hospital Sainte-Justine
Montreal, Quebec, Canada
Countries
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Other Identifiers
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NCI-2011-02672
Identifier Type: REGISTRY
Identifier Source: secondary_id
CDR0000698589
Identifier Type: OTHER
Identifier Source: secondary_id
COG-ANBL1021
Identifier Type: OTHER
Identifier Source: secondary_id
ANBL1021
Identifier Type: -
Identifier Source: org_study_id
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