Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Recurrent Neuroblastoma, Regional Neuroblastoma, Stage 4 Neuroblastoma, Stage 4S Neuroblastoma
Conditions
Brief summary
This partially randomized phase III trial studies isotretinoin with dinutuximab, aldesleukin, and sargramostim to see how well it works compared to isotretinoin alone following stem cell transplant in treating patients with neuroblastoma. Drugs used in chemotherapy, such as isotretinoin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as dinutuximab, may block tumor growth in different ways by targeting certain cells. Aldesleukin and sargramostim may stimulate a person's white blood cells to kill cancer cells. It is not yet known if chemotherapy is more effective with or without dinutuximab, aldesleukin, and sargramostim following stem cell transplant in treating neuroblastoma.
Detailed description
PRIMARY OBJECTIVES: I. Determine if monoclonal antibody Ch14.18 (dinutuximab) + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves event free survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-autologous stem cell transplant (ASCT) response of complete response (CR), very good partial response (VGPR), or partial response (PR). SECONDARY OBJECTIVES: I. Determine if monoclonal antibody Ch14.18 + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves overall survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR. II. Determine if immunotherapy + RA improves event free survival and overall survival as compared to RA alone, in the subgroup of high risk International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR. III. Determine the toxicities of the combination of monoclonal antibody Ch14.18 with cytokines. IV. To compare the outcome data of the patients with persistent disease documented by biopsy (Stratum 07) to the historical data for the analogous patients from Children's Cancer Group (CCG)-3981. V. To further describe and refine the event free survival (EFS) and overall survival (OS) estimates and baseline characteristics for subjects receiving Ch14.18 + cytokines + RA, following cessation of the randomized portion of the study. VI. To further describe the safety and toxicity of Ch14.18 + cytokines + RA under the new administration guidelines implemented following cessation of the randomized portion of the study with focus on: a) number of courses delivered per subject; b) number of dose reductions or stoppage (ch14.18 and/or interleukin \[IL\]-2); and c) number of toxic deaths. TERTIARY OBJECTIVES: I. In the subgroup of neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR, determine if there is a difference between the two randomized regimens in reducing the minimal residual disease (MRD) burden as detected by the following parameters: meta-iodobenylguanidine (MIBG) scan, immunocytology (IC) of blood and bone marrow samples, reverse transcriptase-polymerase chain reaction (RT-PCR) for tyrosine hydroxylase, phosphoglycolate phosphatase (PGP) 9.5, and melanoma antigen family A, 1 (MAGE-1) in blood and bone marrow. II. Determine if change from baseline of MRD is associated with event free and overall survival. III. Determine whether tumor biology at diagnosis correlates with event-free and overall survival, for either of the randomized regimens. IV. To explore the relationship between antibody-dependent cellular cytoxicity (ADCC) and EFS. V. To determine a descriptive profile of human anti-chimeric antibody (HACA) during immunotherapy. VI. To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to pharmacogenomic parameters and determine if these levels and/or genetic variations correlate with EFS or systemic toxicity. VII. To determine the potential effect of ch14.18 on cardiac repolarization and to evaluate ch14.18 plasma levels. VIII. To determine if the presence of naturally occurring anti-glycan antibodies correlates with allergic reactions and blood levels of ch14.18. IX. To determine if the genotype of Fc receptor (FcR) and killer cell immunoglobulin-like receptor (Kir)/Kir-ligand correlate with EFS. X. To determine if natural killer cell p30-related protein (NKp30) isoform expression and single nucleotide polymorphism (SNP), and circulating ligand B7-H6 are prognostic of EFS or OS. OUTLINE: Patients stratified with biopsy-confirmed post-ASCT persistent disease who are also enrolled on Children's Oncology Group (COG)-A3973 or COG-ANBL0532 are assigned to treatment Arm II. Patients in the first set of strata are randomized to 1 of 2 treatment arms. ARM I: Beginning on day 56-85 post-ASCT, patients receive isotretinoin orally (PO) twice daily (BID) for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy. (closed to accrual as of 4/16/2009) ARM II: Beginning on day 56-85 post-ASCT, patients receive immunotherapy comprising sargramostim (GM-CSF) subcutaneously (SC) or intravenously (IV) over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy. After completion of study treatment, patients are followed up periodically for 10 years.
Interventions
Given IV
Given IV
Given PO
Correlative studies
Correlative studies
Ancillary studies
Given IV or SC
Sponsors
Study design
Eligibility
Inclusion criteria
* All patients must be diagnosed with neuroblastoma, and categorized as high risk at the time of diagnosis; exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible * All patients must have completed therapy including intensive induction followed by ASCT and radiotherapy to be eligible for ANBL0032; radiotherapy may be waived for patients who either have small adrenal masses which are completely resected up front, or who never have an identifiable primary tumor; examples of such therapies include: * Following treatment per A3973 protocol * Following treatment per Pediatric Oncology Group (POG)-9341/9342 protocol * Following treatment per CCG3891 * Following treatment on New Approaches to Neuroblastoma Therapy (NANT) 2001-02 * Enrollment on or following treatment per ANBL02P1 * Enrollment on or following treatment per ANBL07P1 * Tandem transplant patients are eligible: * Following treatment on or per ANBL0532 * Following treatment per POG 9640 * Following treatment per COG ANBL00P1 * Following treatment per CHP 594/Dana-Farber Cancer Institute (DFCI) 34-DAT * No more than 12 months from the date of starting the first induction chemotherapy after diagnosis to the date of ASCT except for the rare occasions as noted below; for tandem ASCT patients, this will be the date of the FIRST stem cell infusion; exception: for those who are initially diagnosed as non-high risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma, the 12 months restriction should start from the date of induction therapy for high risk neuroblastoma (not from the initial induction therapy for non-high risk disease), to the date of ASCT * At pre-ASCT evaluation patients must meet the International Neuroblastoma Response Criteria (INRC) for CR, VGPR, or PR for primary site, soft tissue metastases and bone metastases; patients who meet those criteria must also meet the protocol specified criteria for bone marrow response as outlined below: * =\< 10% tumor (of total nucleated cellular content) seen on any specimen from a bilateral bone marrow aspirate/biopsy * Patient who have no tumor seen on the prior bone marrow, and then have =\< 10% tumor on any of the bilateral marrow aspirate/biopsy specimens done at pre-ASCT and/or pre-enrollment evaluation will also be eligible (note that per INRC this would have been defined as "overall" response of progressive disease \[PD\]) * Prior to enrollment on ANBL0032, a determination of mandatory disease staging must be performed (tumor imaging studies including computed tomography \[CT\] or magnetic resonance imaging \[MRI\], MIBG scan, and vanillylmandelic acid \[VMA\]/homovanillic acid \[HVA\]; bone marrow aspirates are required but biopsy may be omitted if negative prior to ASCT); this disease assessment is required for eligibility and should be done preferably within 2 weeks, but must be done within a maximum of 4 weeks before enrollment * For those with residual disease before radiotherapy, re-evaluation of irradiated residual tumors is preferably performed at the earliest 5 days after completing radiotherapy; patients with residual disease are eligible; biopsy is not required; patients who have biopsy proven residual disease after ASCT will be enrolled on Stratum 07 * Patients must not have progressive disease at the time of study enrollment except for protocol specified bone marrow response and except for elevations of catecholamines as the only sign of disease in a patient who had normal catecholamines at pre-ASCT evaluation * Patients must be enrolled before treatment begins; the date protocol therapy is projected to start must be no later than ten (10) calendar days after the date of study enrollment; patients should be enrolled preferably between day 56 and day 85 after peripheral blood stem cell (PBSC) infusion (day from 2nd stem cell infusion for tandem transplant); patients must be enrolled no later than day 200 after PBSC infusion; enrollment must occur after completion of radiotherapy, and after completion of tumor assessment post-ASCT and radiotherapy; informed consent should be obtained within 3 weeks pre-ASCT up to the time of registration * Patients must not have received prior anti-disialoganglioside (GD2) antibody therapy * Patients must have a Lansky or Karnofsky performance scale score of \>= 50% and patients must have a life expectancy of \>= 2 months * Total absolute phagocyte count (APC = %neutrophils + %monocytes) X white blood cell (WBC) is at least 1000/uL * Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows: * No greater than 0.4 mg/dL (1 month to \< 6 months) * No greater than 0.5 mg/dL (6 months to \< 1 year) * No greater than 0.6 mg/dL (1 to \< 2 years) * No greater than 0.8 mg/dL (2 to \< 6 years) * No greater than 1.0 mg/dL (6 to \< 10 years) * No greater than 1.2 mg/dL (10 to \< 13 years) * No greater than 1.4 mg/dL (\>= 13 years \[female\]) * No greater than 1.5 mg/dL (13 to \< 16 years \[male\]) * No greater than 1.7 mg/dL (\>= 16 years \[male\]) * Total bilirubin =\< 1.5 x normal * Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 5 x normal * Veno-occlusive disease, if present, should be stable or improving * Shortening fraction of \>= 27% by echocardiogram, or if shortening fraction abnormal, ejection fraction of \>= 55% by gated radionuclide study or echocardiogram; note: the echocardiogram or gated radionuclide study must be performed within 4 weeks prior to enrollment * Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) \> 60% predicted by pulmonary function test; for children who are unable to do pulmonary function tests (PFTs), no evidence of dyspnea at rest and no exercise intolerance should be documented; note: the pulmonary function test must be performed within 4 weeks prior to enrollment * Patients with seizure disorder may be enrolled if on anticonvulsants and well-controlled; central nervous system (CNS) toxicity \< grade 2 * Written informed consent in accordance with institutional and Food and Drug Administration (FDA) guidelines must be obtained from parent or legal guardian * Females of childbearing potential must have a negative pregnancy test; patients of childbearing potential must agree to use an effective birth control method; female patients who are lactating must agree to stop breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | Three years | Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | Three years | Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only for the subgroup of randomized patients with INSS Stage 4 disease. Descriptive comparison of outcome data for patients with persistent disease documented by biopsy to historical data for the analogous patients from CCG-3981. |
| Event-Free Survival (EFS) of Patients From the Non-randomized Portion of the Trial | Three years | EFS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study. |
| Incidence of Toxicities Assessed Using Common Terminology Criteria for Adverse Events Version 4.0 | From enrollment to follow-up | Proportion of patients experiencing at least one Grade 3 or higher toxicity. |
| Number of Courses of Therapy Delivered | Courses 1-6 | Number of courses of therapy delivered for patients randomized to RA + Immunotherapy vs. patients non-randomly assigned to RA + Immunotherapy, excluding patients with persistent disease. |
| Overall Survival (OS) | Three years | Comparison to determine if RA + Immunotherapy improves OS as compared to RA Only. Comparison to determine if RA + Immunotherapy improves OS as compared to RA only and for the subgroup of randomized patients with INSS Stage 4 disease. |
| Overall Survival (OS) of Patients From the Non-randomized Portion of the Trial | Three years | OS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study. |
Countries
Australia, Canada, New Zealand, Puerto Rico, United States
Contacts
Children's Oncology Group
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen A Randomized to Regimen A - RA Only | 116 |
| Regimen B Regimen B - RA + Immunotherapy | 1,333 |
| Total | 1,449 |
Baseline characteristics
| Characteristic | Regimen A | Regimen B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 116 Participants | 1325 Participants | 1441 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 8 Participants | 8 Participants |
| Age, Continuous | 3.22 Years STANDARD_DEVIATION 2.12 | 3.64 Years STANDARD_DEVIATION 2.77 | 3.61 Years STANDARD_DEVIATION 2.73 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 142 Participants | 153 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 99 Participants | 1159 Participants | 1258 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 32 Participants | 38 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 62 Participants | 66 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 153 Participants | 161 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 171 Participants | 184 Participants |
| Race (NIH/OMB) White | 89 Participants | 942 Participants | 1031 Participants |
| Region of Enrollment Australia | 3 participants | 89 participants | 92 participants |
| Region of Enrollment Canada | 13 participants | 135 participants | 148 participants |
| Region of Enrollment New Zealand | 0 participants | 17 participants | 17 participants |
| Region of Enrollment United States | 100 participants | 1092 participants | 1192 participants |
| Sex: Female, Male Female | 49 Participants | 534 Participants | 583 Participants |
| Sex: Female, Male Male | 67 Participants | 799 Participants | 866 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| other Total, other adverse events | 92 / 112 | 1,244 / 1,328 |
| serious Total, serious adverse events | 10 / 112 | 785 / 1,328 |
Outcome results
Event-Free Survival (EFS)
Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only
Time frame: Three years
Population: Eligible, randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen A | Event-Free Survival (EFS) | 48.1 Percentage of participants |
| Regimen B | Event-Free Survival (EFS) | 62.9 Percentage of participants |
Event-Free Survival (EFS)
Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only for the subgroup of randomized patients with INSS Stage 4 disease. Descriptive comparison of outcome data for patients with persistent disease documented by biopsy to historical data for the analogous patients from CCG-3981.
Time frame: Three years
Population: Eligible, randomized patients with INSS Stage 4 disease. Eligible patients with persistent disease.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regimen A | Event-Free Survival (EFS) | Randomized patients with INSS Stage 4 disease | 43.2 Percentage of participants |
| Regimen B | Event-Free Survival (EFS) | Randomized patients with INSS Stage 4 disease | 59.7 Percentage of participants |
| Regimen B | Event-Free Survival (EFS) | Eligible patients with persistent disease | 35.1 Percentage of participants |
Event-Free Survival (EFS) of Patients From the Non-randomized Portion of the Trial
EFS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.
Time frame: Three years
Population: Eligible patients non-randomly assigned to Regimen B after halting of randomization, excluding patients with persistent disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen A | Event-Free Survival (EFS) of Patients From the Non-randomized Portion of the Trial | 64.0 Percentage of participants |
Incidence of Toxicities Assessed Using Common Terminology Criteria for Adverse Events Version 4.0
Proportion of patients experiencing at least one Grade 3 or higher toxicity.
Time frame: From enrollment to follow-up
Population: Eligible patients enrolled prior to halting of randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen A | Incidence of Toxicities Assessed Using Common Terminology Criteria for Adverse Events Version 4.0 | 0.64 Proportion |
| Regimen B | Incidence of Toxicities Assessed Using Common Terminology Criteria for Adverse Events Version 4.0 | 0.94 Proportion |
Number of Courses of Therapy Delivered
Number of courses of therapy delivered for patients randomized to RA + Immunotherapy vs. patients non-randomly assigned to RA + Immunotherapy, excluding patients with persistent disease.
Time frame: Courses 1-6
Population: Eligible patients assigned to Regimen B, excluding patients with persistent disease.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Regimen A | Number of Courses of Therapy Delivered | Non-randomly assigned after halting randomization | 6 courses per patient |
| Regimen A | Number of Courses of Therapy Delivered | Randomized to Regimen B - RA + Immunotherapy | 6 courses per patient |
Overall Survival (OS)
Comparison to determine if RA + Immunotherapy improves OS as compared to RA Only. Comparison to determine if RA + Immunotherapy improves OS as compared to RA only and for the subgroup of randomized patients with INSS Stage 4 disease.
Time frame: Three years
Population: Eligible, randomized patients. Eligible, randomized patients with INSS Stage 4 disease.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regimen A | Overall Survival (OS) | Randomized patients | 67.4 Percentage of participants |
| Regimen A | Overall Survival (OS) | Randomized patients with INSS Stage 4 disease | 64.0 Percentage of participants |
| Regimen B | Overall Survival (OS) | Randomized patients | 78.8 Percentage of participants |
| Regimen B | Overall Survival (OS) | Randomized patients with INSS Stage 4 disease | 78.7 Percentage of participants |
Overall Survival (OS) of Patients From the Non-randomized Portion of the Trial
OS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.
Time frame: Three years
Population: Eligible patients non-randomly assigned to Regimen B after halting of randomization, excluding patients with persistent disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen A | Overall Survival (OS) of Patients From the Non-randomized Portion of the Trial | 78.4 Percentage of participants |
Average Level of HACA
The average level of HACA at each collection time point during immunotherapy will be calculated.
Time frame: Up to 10 years
Cardiac Repolarization
In general, descriptive summaries will include n, mean, standard deviation, median, minimum, maximum and 90% confidence intervals for continuous variables, and n and percent for categorical variables. Summaries will present data by assessment time when appropriate.
Time frame: Up to 10 years
Change in MRD
A descriptive analysis of the change from baseline of MRD will be performed. Also, a Wilcoxon rank-sum test will be performed to compare the median change from baseline of MRD between the two treatment arms. A multivariate Cox proportional hazards regression model will test to see if the change in MRD burden is associated with EFS or OS.
Time frame: Baseline to up to 10 years
Change in Tumor Biology
A multivariate Cox proportional hazards regression model will test to see if the dinutuximab serum level, HACA titer, effector cell function, or serum marker for effector cell activation are associated with EFS or OS.
Time frame: Baseline to up to 10 years
Circulating B7-H6 Levels
Kaplan-Meier plots of EFS and OS will be generated after dichotomization using the median value for the cohort. To determine the prognostic value of circulating B7-H6 level, univariate analysis will be performed using a log rank test for EFS and OS. In multivariable analysis of EFS and OS, Cox models will be used to test for the independent prognostic ability of circulating B7-H6 level, adjusting for significant prognostic factors including MYCN status, INSS stage, histology and age at diagnosis.
Time frame: 1 week before first sargramostim injection (day -1 of course 1)
Genotype of FcR
Kaplan-Meier plots of EFS will be generated for the three genotype subgroups of FcR as well as for the three genotype subgroups of Kir/Kir-ligand. In addition, a log rank test comparison will be made in a pairwise fashion of each of the genotypes within FcR and within Kir/Kir-ligand.
Time frame: Up to 10 years
Genotype of Kir/Kir-ligand
Kaplan-Meier plots of EFS will be generated for the three genotype subgroups of FcR as well as for the three genotype subgroups of Kir/Kir-ligand. In addition, a log rank test comparison will be made in a pairwise fashion of each of the genotypes within FcR and within Kir/Kir-ligand.
Time frame: Up to 10 years
Isotretinoin Pharmacokinetic Parameters
To determine if there is a relationship of the peak serum concentration level with EFS, the term for this level will be tested in a Cox proportional hazards model. To determine if there is a relationship of the peak serum concentration level with toxicity rates, Kendall's Tau statistic will be calculated.
Time frame: At 4 hours after administration on day 14 of course 1
Levels of ADCC
Will be descriptively compared.
Time frame: Up to 10 years
NKp30 Isoform Expression and SNP
Kaplan-Meier plots of EFS and OS will be generated after dichotomization using the median value for the cohort. To determine the prognostic value of NKp30 isoform expression and SNP, univariate analysis will be performed using a log rank test for EFS and OS. In multivariable analysis of EFS and OS, Cox models will be used to test for the independent prognostic ability of NKp30 isoform expression and SNP, adjusting for significant prognostic factors including v-MYC myelocytomatosis viral related oncogene, neuroblastoma derived (avian) (MYCN) status, INSS stage, histology and age at diagnosis.
Time frame: 1 week before first sargramostim injection (day -1 of course 1)
Presence of Naturally Occurring Anti-glycan Antibodies
A Fisher's exact test will be performed to determine if the presence of naturally occurring anti-glycan antibodies correlates with allergic reactions. A Wilcoxon test will be performed to determine if the presence of naturally occurring anti-glycan antibodies correlates with blood levels of dinutuximab.
Time frame: Up to 10 years