Recurrent NeuroblastomaPhase 2NCT01334515
Biological Therapy, Sargramostim, and Isotretinoin in Treating Patients With Relapsed or Refractory Neuroblastoma
A Phase 2 study testing hu14.18-IL2 fusion protein, isotretinoin and sargramostim in people with Recurrent Neuroblastoma, run by Children's Oncology Group at 76 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 year to 30 years
- Conditions the study is for
- Recurrent Neuroblastoma
- What is being tested?
- hu14.18-IL2 fusion protein, isotretinoin and sargramostim
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 76 sitesin 2 countries
- Study dates
- Sep 2011to 30 Sep 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 30 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
76 sites in 2 countries.
76 sites in 2 countries
United States71 sites
Children's Hospital Medical Center of Akron
Akron, Ohio, 44308
University of New Mexico Cancer Center
Albuquerque, New Mexico, 87106
Children's Oncology Group
Arcadia, California, 91006-3776
Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia, 30322
Children's Hospital Colorado
Aurora, Colorado, 80045
Sinai Hospital of Baltimore
Baltimore, Maryland, 21215
Lehigh Valley Hospital - Muhlenberg
Bethlehem, Pennsylvania, 18017
University of Alabama at Birmingham
Birmingham, Alabama, 35294
Dana-Farber Cancer Institute
Boston, Massachusetts, 02115
Roswell Park Cancer Institute
Buffalo, New York, 14263
University of North Carolina
Chapel Hill, North Carolina, 27599
Carolinas Medical Center
Charlotte, North Carolina, 28203
Presbyterian Hospital
Charlotte, North Carolina, 28204
University of Illinois
Chicago, Illinois, 60612
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637-1470
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
Rainbow Babies and Childrens Hospital
Cleveland, Ohio, 44106
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Medical City Dallas Hospital
Dallas, Texas, 75230
The Children's Medical Center of Dayton
Dayton, Ohio, 45404
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Denver, Colorado, 80218
Raymond Blank Children's Hospital
Des Moines, Iowa, 50309
Duke University Medical Center
Durham, North Carolina, 27710
Lee Memorial Health System
Fort Myers, Florida, 33901
Cook Children's Medical Center
Fort Worth, Texas, 76104
Saint Vincent Hospital
Green Bay, Wisconsin, 54301
Connecticut Children's Medical Center
Hartford, Connecticut, 06106
Penn State Hershey Children's Hospital
Hershey, Pennsylvania, 17033
University of Hawaii
Honolulu, Hawaii, 96813
Riley Hospital for Children
Indianapolis, Indiana, 46202
Nemours Children's Clinic - Jacksonville
Jacksonville, Florida, 32207-8426
Bronson Methodist Hospital
Kalamazoo, Michigan, 49007
Kalamazoo Center for Medical Studies
Kalamazoo, Michigan, 49008
University of Kentucky
Lexington, Kentucky, 40536
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205
Loma Linda University Medical Center
Loma Linda, California, 92354
Children's Hospital Los Angeles
Los Angeles, California, 90027
Kosair Children's Hospital
Louisville, Kentucky, 40202
Children's Hospital Central California
Madera, California, 93636-8762
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, 53792
St. Jude Children's Research Hospital
Memphis, Tennessee, 38105
Miami Children's Hospital
Miami, Florida, 33155
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis, Minnesota, 55404
Morristown Memorial Hospital
Morristown, New Jersey, 07962
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37232
Tulane University Health Sciences Center
New Orleans, Louisiana, 70112
Children's Hospital-Main Campus
New Orleans, Louisiana, 70118
Columbia University Medical Center
New York, New York, 10032
Childrens Hospital-King's Daughters
Norfolk, Virginia, 23507
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Childrens Hospital of Orange County
Orange, California, 92868-3874
Florida Hospital
Orlando, Florida, 32803
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Oregon Health and Science University
Portland, Oregon, 97239
Virginia Commonwealth University
Richmond, Virginia, 23298
Mayo Clinic
Rochester, Minnesota, 55905
Primary Children's Medical Center
Salt Lake City, Utah, 84113
Rady Children's Hospital - San Diego
San Diego, California, 92123
University of California San Francisco Medical Center-Parnassus
San Francisco, California, 94143
Seattle Children's Hospital
Seattle, Washington, 98105
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, 57117-5134
Southern Illinois University
Springfield, Illinois, 62702
Cardinal Glennon Children's Medical Center
St Louis, Missouri, 63104
Washington University School of Medicine
St Louis, Missouri, 63110
All Children's Hospital
St. Petersburg, Florida, 33701
Overlook Hospital
Summit, New Jersey, 07902
State University of New York Upstate Medical University
Syracuse, New York, 13210
The Toledo Hospital/Toledo Children's Hospital
Toledo, Ohio, 43606
Natalie W Bryant Cancer Center
Tulsa, Oklahoma, 74136
New York Medical College
Valhalla, New York, 10595
Children's National Medical Center
Washington D.C., District of Columbia, 20010
Canada5 sites
Alberta Children's Hospital
Calgary, Alberta, T3B 6A8
The Montreal Children's Hospital of the MUHC
Montreal, Quebec, H3H 1P3
Hospital Sainte-Justine
Montreal, Quebec, H3T 1C5
Hospital for Sick Children
Toronto, Ontario, M5G 1X8
British Columbia Children's Hospital
Vancouver, British Columbia, V6H 3V4
About this study
Official title: Feasibility/Phase II Study of hu14.18-IL2 Immunocytokine + GM-CSF and Isotretinoin in Patients With Relapsed or Refractory Neuroblastoma
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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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.
- 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
- Recurrent Neuroblastoma
- Being tested
- hu14.18-IL2 fusion protein, isotretinoin, sargramostim, laboratory biomarker analysis
- Medical subject headings
- Neuroblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
hu14.18-IL2 fusion proteinBiological
Also called EMD 273063, hu14.18-IL2
Given IV
isotretinoinDrug
Also called 13-CRA, Amnesteem, Cistane, Claravis
Given PO
sargramostimBiological
Also called GM-CSF, Leukine, Prokine
Given SC
laboratory biomarker analysisOther
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| Disease measured by standard radiographic criteria | Experimental | 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. Receives: Biological: hu14.18-IL2 fusion protein; Drug: isotretinoin; Biological: sargramostim; Other: laboratory biomarker analysis |
| Disease evaluable only by I-MIBG or BM histology | Experimental | 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. Receives: Biological: hu14.18-IL2 fusion protein; Drug: isotretinoin; Biological: sargramostim; Other: laboratory biomarker analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Patients With Unacceptable Dose Limiting Toxicities (DLTs)
Test for tolerability and monitor for the occurrence of too many unacceptable DLTs using a two-stage stopping rule: (Stage 1) Accrue 10 patients. If more than 1 experience at least one unacceptable DLT during the first treatment cycle, the regimen will be considered to have unacceptable toxicity, and accrual will be temporarily closed, to review all relevant data and consider modifying the regimen to improve safety. If 1 or no patients have an unacceptable DLT in the first treatment cycle, then continue. (Stage 2) Accrue 20 more patients. If 7 or more experience at least one unacceptable DLT in the first treatment cycle, temporarily close the study for possible dosing-safety modifications. If 6 or fewer have an unacceptable DLT in the first treatment cycle, it is reasonable to assume that the combination therapy is safe.
Measured: Up to 10 courses
Secondary outcomes (1)
Overall Response Evaluated in This Study Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors (RECIST)
Number of patients where best overall response is a complete response (CR)-[disappearance of all target lesions and disappearance of any other measureable disease], a very Good Partial Response (VGPR)- [>90% decrease of the disease measurement for CT/MRI lesions, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size], or partial Response (PR)- [>= 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size], and maintains the response. It is possible that a subject's response to therapy may not occur until after several months of treatment. In order to prevent bias, the maximum duration of time/treatment over which a subject's response is to be assessed for determination of the best overall response is after the completion of up to 10 courses.
Measured: Every two cycles (each cycle lasts 28 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Apr 2011 (estimated)
- Study startSep 2011
- Primary completion31 Dec 2013
- Study completion30 Sep 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Recurrent NeuroblastomaStudies of the same condition, open and under way.
- More trials run by Children's Oncology GroupThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Oncology Group
- Sponsor type
- Research network
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Suzanne Shusterman, MD, Principal investigator, Children's Oncology Group
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01334515
- Sponsor's protocol ID
- ANBL1021
- Other IDs
- NCI-2011-02672, CDR0000698589, U10CA098543, COG-ANBL1021
- Status last verified
- Oct 2019
- First submitted
- 12 Apr 2011
- Last updated
- 21 Oct 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 21 Oct 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Feasibility/Phase II Study of hu14.18-IL2 Immunocytokine + GM-CSF and Isotretinoin in Patients With Relapsed or Refractory Neuroblastoma
- ClinicalTrials.gov ID
- NCT01334515
- Acronym / sponsor ID
- ANBL1021
- Conditions
- Recurrent Neuroblastoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 52 participants (actual)
- Lead sponsor
- Children's Oncology GroupResearch network
- Collaborators
- National Cancer Institute (NCI)
- Study start
- Sep 2011
- Primary completion
- 31 Dec 2013 (actual)
- Study completion
- 30 Sep 2019 (actual)
- First posted
- 13 Apr 2011 (estimated)
- Results
- Posted 20 Feb 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
PRIMARY OBJECTIVES:
- 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:
- 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.
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Disease measured by standard radiographic criteria | Experimental | Biological: hu14.18-IL2 fusion protein, Drug: isotretinoin, Biological: sargramostim, Other: laboratory biomarker analysisTreatment (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. |
| Disease evaluable only by I-MIBG or BM histology | Experimental | Biological: hu14.18-IL2 fusion protein, Drug: isotretinoin, Biological: sargramostim, Other: laboratory biomarker analysisTreatment (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. |
Who may qualify
- Ages
- 1 year to 30 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (39 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| hu14.18-IL2 fusion proteinAlso: EMD 273063, hu14.18-IL2Given IV | Biological | Disease evaluable only by I-MIBG or BM histology, Disease measured by standard radiographic criteria |
| isotretinoinAlso: 13-CRA, Amnesteem, Cistane, ClaravisGiven PO | Drug | Disease evaluable only by I-MIBG or BM histology, Disease measured by standard radiographic criteria |
| sargramostimAlso: GM-CSF, Leukine, ProkineGiven SC | Biological | Disease evaluable only by I-MIBG or BM histology, Disease measured by standard radiographic criteria |
| laboratory biomarker analysisCorrelative studies | Other | Disease evaluable only by I-MIBG or BM histology, Disease measured by standard radiographic criteria |
Primary outcome
Number of Patients With Unacceptable Dose Limiting Toxicities (DLTs)
Time frame: Up to 10 courses
Test for tolerability and monitor for the occurrence of too many unacceptable DLTs using a two-stage stopping rule: (Stage 1) Accrue 10 patients. If more than 1 experience at least one unacceptable DLT during the first treatment cycle, the regimen will be considered to have unacceptable toxicity, and accrual will be temporarily closed, to review all relevant data and consider modifying the regimen to improve safety. If 1 or no patients have an unacceptable DLT in the first treatment cycle, then continue. (Stage 2) Accrue 20 more patients. If 7 or more experience at least one unacceptable DLT in the first treatment cycle, temporarily close the study for possible dosing-safety modifications. If 6 or fewer have an unacceptable DLT in the first treatment cycle, it is reasonable to assume that the combination therapy is safe.
1 secondary outcome
Overall Response Evaluated in This Study Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors (RECIST)
Time frame: Every two cycles (each cycle lasts 28 days)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Oct 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Suzanne Shusterman, MD principal investigator
Children's Oncology Group
76 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing hu14.18-IL2 fusion protein, isotretinoin and sargramostim in people with Recurrent Neuroblastoma, run by Children's Oncology Group at 76 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 39 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 76 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Feb 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Patients With Unacceptable Dose Limiting Toxicities (DLTs) (time frame: Up to 10 courses). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Oct 2019.