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Biological Therapy, Sargramostim, and Isotretinoin in Treating Patients With Relapsed or Refractory Neuroblastoma

Information source: Children's Oncology Group
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Recurrent Neuroblastoma

Intervention: hu14.18-IL2 fusion protein (Biological); isotretinoin (Drug); sargramostim (Biological); laboratory biomarker analysis (Other)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: Children's Oncology Group

Official(s) and/or principal investigator(s):
Suzanne Shusterman, MD, Principal Investigator, Affiliation: Children's Oncology Group


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.

Clinical Details

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

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Number of Patients With Unacceptable Dose Limiting Toxicities (DLTs)

Secondary outcome: Overall Response Evaluated in This Study Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors (RECIST)

Detailed 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.


Minimum age: 1 Year. Maximum age: 30 Years. Gender(s): Both.


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-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


- 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

Locations and Contacts

University of Alabama at Birmingham, Birmingham, Alabama 35294, United States

Alberta Children's Hospital, Calgary, Alberta T3B 6A8, Canada

University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States

British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada

Children's Oncology Group, Arcadia, California 91006-3776, United States

Loma Linda University Medical Center, Loma Linda, California 92354, United States

Children's Hospital Los Angeles, Los Angeles, California 90027, United States

Children's Hospital Central California, Madera, California 93636-8762, United States

Childrens Hospital of Orange County, Orange, California 92868-3874, United States

Rady Children's Hospital - San Diego, San Diego, California 92123, United States

University of California San Francisco Medical Center-Parnassus, San Francisco, California 94143, United States

Children's Hospital Colorado, Aurora, Colorado 80045, United States

Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center, Denver, Colorado 80218, United States

Connecticut Children's Medical Center, Hartford, Connecticut 06106, United States

Children's National Medical Center, Washington, District of Columbia 20010, United States

Lee Memorial Health System, Fort Myers, Florida 33901, United States

Nemours Children's Clinic - Jacksonville, Jacksonville, Florida 32207-8426, United States

Miami Children's Hospital, Miami, Florida 33155, United States

Florida Hospital, Orlando, Florida 32803, United States

All Children's Hospital, Saint Petersburg, Florida 33701, United States

Children's Healthcare of Atlanta - Egleston, Atlanta, Georgia 30322, United States

University of Hawaii, Honolulu, Hawaii 96813, United States

University of Chicago Comprehensive Cancer Center, Chicago, Illinois 60637-1470, United States

University of Illinois, Chicago, Illinois 60612, United States

Southern Illinois University, Springfield, Illinois 62702, United States

Riley Hospital for Children, Indianapolis, Indiana 46202, United States

Raymond Blank Children's Hospital, Des Moines, Iowa 50309, United States

University of Kentucky, Lexington, Kentucky 40536, United States

Kosair Children's Hospital, Louisville, Kentucky 40202, United States

Children's Hospital-Main Campus, New Orleans, Louisiana 70118, United States

Tulane University Health Sciences Center, New Orleans, Louisiana 70112, United States

Sinai Hospital of Baltimore, Baltimore, Maryland 21215, United States

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States

Bronson Methodist Hospital, Kalamazoo, Michigan 49007, United States

Kalamazoo Center for Medical Studies, Kalamazoo, Michigan 49008, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis, Minneapolis, Minnesota 55404, United States

Mayo Clinic, Rochester, Minnesota 55905, United States

Cardinal Glennon Children's Medical Center, Saint Louis, Missouri 63104, United States

Washington University School of Medicine, Saint Louis, Missouri 63110, United States

Morristown Memorial Hospital, Morristown, New Jersey 07962, United States

Overlook Hospital, Summit, New Jersey 07902, United States

University of New Mexico Cancer Center, Albuquerque, New Mexico 87106, United States

Roswell Park Cancer Institute, Buffalo, New York 14263, United States

Columbia University Medical Center, New York, New York 10032, United States

State University of New York Upstate Medical University, Syracuse, New York 13210, United States

New York Medical College, Valhalla, New York 10595, United States

University of North Carolina, Chapel Hill, North Carolina 27599, United States

Carolinas Medical Center, Charlotte, North Carolina 28203, United States

Presbyterian Hospital, Charlotte, North Carolina 28204, United States

Duke University Medical Center, Durham, North Carolina 27710, United States

Children's Hospital Medical Center of Akron, Akron, Ohio 44308, United States

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, United States

Cleveland Clinic Foundation, Cleveland, Ohio 44195, United States

Rainbow Babies and Childrens Hospital, Cleveland, Ohio 44106, United States

The Children's Medical Center of Dayton, Dayton, Ohio 45404, United States

The Toledo Hospital/Toledo Children's Hospital, Toledo, Ohio 43606, United States

University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States

Natalie W Bryant Cancer Center, Tulsa, Oklahoma 74136, United States

Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

Oregon Health and Science University, Portland, Oregon 97239, United States

Lehigh Valley Hospital - Muhlenberg, Bethlehem, Pennsylvania 18017, United States

Penn State Hershey Children's Hospital, Hershey, Pennsylvania 17033, United States

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States

Hospital Sainte-Justine, Montreal, Quebec H3T 1C5, Canada

The Montreal Children's Hospital of the MUHC, Montreal, Quebec H3H 1P3, Canada

Sanford USD Medical Center - Sioux Falls, Sioux Falls, South Dakota 57117-5134, United States

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, United States

Medical City Dallas Hospital, Dallas, Texas 75230, United States

Cook Children's Medical Center, Fort Worth, Texas 76104, United States

Primary Children's Medical Center, Salt Lake City, Utah 84113, United States

Childrens Hospital-King's Daughters, Norfolk, Virginia 23507, United States

Virginia Commonwealth University, Richmond, Virginia 23298, United States

Seattle Children's Hospital, Seattle, Washington 98105, United States

Saint Vincent Hospital, Green Bay, Wisconsin 54301, United States

University of Wisconsin Hospital and Clinics, Madison, Wisconsin 53792, United States

Additional Information

Starting date: September 2011
Last updated: May 1, 2015

Page last updated: August 23, 2015

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