Ganglioneuroblastoma, Stage 1 Neuroblastoma, Stage 2A Neuroblastoma, Stage 2B Neuroblastoma, Stage 2 Neuroblastoma, Stage 3 Neuroblastoma, Stage 4 Neuroblastoma, Stage 4S Neuroblastoma
Conditions
Brief summary
This pilot clinical trial studies busulfan, melphalan, and stem cell transplant after chemotherapy in treating patients with newly diagnosed neuroblastoma that is likely to come back or spread. Giving chemotherapy to the entire body before a stem cell transplant stops the growth of tumor cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy or radiation therapy is given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.
Detailed description
PRIMARY OBJECTIVES: I. To determine if the acute toxicity of an autologous stem cell transplant with a busulfan-melphalan (BuMel) based regimen is tolerable when given as consolidation therapy for high-risk neuroblastoma. EXPLORATORY OBJECTIVES: I. To determine the incidence of non-hematologic organ toxicity (grade 3 and higher) and all cause mortality in patients undergoing autologous stem cell transplant with a BuMel based regimen followed by local radiotherapy for the treatment of high-risk neuroblastoma. II. To describe response rates, event-free survival (EFS), and overall survival (OS) for patients undergoing induction therapy followed by consolidation with myeloablative BuMel preparative regimen and local radiotherapy for the treatment of high-risk neuroblastoma. III. To correlate busulfan pharmacokinetics with non-hematologic toxicity following a BuMel based autologous transplant regimen and event-free survival and overall survival. IV. To determine the feasibility of performing Curie scores in real time, as assessed by central scan committee review of a 123 I-meta-iodobenzylguanidine (MIBG) scan obtained after cycle 4 of induction therapy. V. To examine the concordance between central reviewers and institutional reviewers in performing Curie scoring at diagnosis and after cycle 4 of induction therapy. VI. To determine the feasibility of detecting aberrations in the anaplastic lymphoma kinase (ALK) gene in tumors obtained at the time of diagnosis in patients with high-risk neuroblastoma. VII. To determine the feasibility of performing molecular profiling of neuroblastoma tumors obtained at the time of diagnosis in patients with high-risk neuroblastoma. VIII. To correlate melphalan pharmacokinetics with non-hematologic toxicity following a BuMel based autologous transplant regimen and event-free survival and overall survival. OUTLINE: INDUCTION THERAPY: COURSES 1-2: Patients receive cyclophosphamide intravenously (IV) over 15-30 minutes, topotecan hydrochloride IV over 30 minutes on days 1-5 and filgrastim subcutaneously (SC) or IV once daily (QD) beginning on day 6. Treatment repeats every 3 weeks for 2 courses. COURSES 3 AND 5: Patients receive cisplatin IV over 1 hour on days 1-4 and etoposide IV over 1-2 hours on days 1-3. Treatment repeats every 3 weeks for 2 courses. COURSE 4: Patients receive cyclophosphamide IV over 1-6 hours on days 1-2, vincristine sulfate IV over 1 minute on days 1-3, doxorubicin hydrochloride IV over 24 hours on days 1-3 and mesna IV over 15-30 minutes on days 1-2. Treatment repeats every 3 weeks for 1 course. Treatment continues in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: Beginning 4-8 weeks following the 5th course of induction therapy, patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan IV on day -1. Patients undergo autologous stem cell transplant (ASCT) on day 0 and filgrastim SC or IV beginning on day 0. Some patients also undergo external beam radiation therapy (EBRT) after induction and consolidation. After completion of study treatment, patients are followed up every 3 months for 1 year, and then every 6 months for 4 years.
Interventions
DRUGVincristine Sulfate
Given IV
PROCEDUREAutologous Hematopoietic Stem Cell Transplantation
Undergo autologous peripheral blood stem cell transplant
DRUGBusulfan
Given IV
DRUGCisplatin
Given IV
DRUGCyclophosphamide
Given IV
DRUGDoxorubicin Hydrochloride
Given IV
DRUGEtoposide
Given IV
RADIATIONExternal Beam Radiation Therapy
Undergo EBRT
BIOLOGICALFilgrastim
Given SC or IV
OTHERLaboratory Biomarker Analysis
Optional correlative studies
DRUGMelphalan
Given IV
DRUGMesna
Given IV
PROCEDUREPeripheral Blood Stem Cell Transplantation
Undergo autologous peripheral blood stem cell transplant
OTHERPharmacological Study
Correlative studies
DRUGTopotecan Hydrochloride
Given IV
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have a diagnosis of neuroblastoma (International Classification of Diseases for Oncology \[ICD-O\] morphology 9500/3) or ganglioneuroblastoma (nodular or intermixed) verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites; patients with the following disease stages at diagnosis are eligible, if they meet the other specified criteria * Patients with newly diagnosed neuroblastoma with International Neuroblastoma Staging System (INSS) stage 4 are eligible with the following: * V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) amplification (\> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or * Age \> 18 months (\> 547 days) regardless of biologic features or * Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features (MYCN amplification, unfavorable pathology and/or deoxyribonucleic acid \[DNA\] index = 1) or any biologic feature that is indeterminate/unsatisfactory/unknown * Patients with newly diagnosed neuroblastoma with INSS stage 3 are eligible with the following: * MYCN amplification (\> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or * Age \> 18 months (\> 547 days) with unfavorable pathology, regardless of MYCN status * Patients with newly diagnosed neuroblastoma with INSS stage 2A/2B with MYCN amplification (\> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features * Patients with newly diagnosed neuroblastoma with INSS stage 4S with MYCN amplification (\> 4-fold increase in MYCN expression signals as compared to reference signals), regardless of additional biologic features * Patients \>= 365 days initially diagnosed with neuroblastoma INSS stage 1, 2, 4S who progressed to a stage 4 without interval chemotherapy; these patients must have been enrolled on ANBL00B1; study enrollment on ANBL12P1 must occur within 4 weeks of progression to stage 4 for INSS stage 1, 2, 4S * Patients must not have had prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCN amplification status and histology * 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: * Age 1 month to \< 6 months: 0.4 mg/dL * Age 6 months to \< 1 year: 0.5 mg/dL * Age 1 to \< 2 years: 0.6 mg/dL * Age 2 to \< 6 years: 0.8 mg/dL * Age 6 to \< 10 years: 1 mg/dL * Age 10 to \< 13 years: 1.2 mg/dL * Age 13 to \< 16 years: 1.5 mg/dL (males), 1.4 mg/dL (females) * Age \>= 16 years: 1.7 mg/dL (males), 1.4 mg/dL (females) * Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age, and * Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 10 x ULN for age * Shortening fraction of \>= 27% by echocardiogram, or * Ejection fraction of \>= 50% by radionuclide evaluation * No known contraindication to peripheral blood stem cell (PBSC) collection; examples of contraindications might be a weight or size less than that determined to be feasible at the collecting institution, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion criteria
* Patients that are 12-18 months of age with INSS stage 4 and all 3 favorable biologic features (ie, nonamplified MYCN, favorable pathology, and DNA index \> 1) are not eligible * Female patients who are pregnant are ineligible * Lactating females are not eligible unless they have agreed not to breastfeed their infants * Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained * Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Tolerability of BuMel Regimen | Up to 28 days post-consolidation therapy, up to 1 year | Number of patients who experience one or more unacceptable toxicities (severe sinusoidal obstruction syndrome \[SOS\] or Grade 4-5 pulmonary toxicity per Common Toxicity Criteria \[CTC\] v.4.0) during the Consolidation phase of therapy. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Non-hematologic Organ Toxicity (Grade 3 and Higher) and All Cause Mortality Graded According to CTC v4.0 | Up to 180 days | Assessed by a descriptive analysis of the incidence of grade 3-5 non-hematologic toxicities (CTC v4.0) and all-cause mortality during consolidation therapy. In addition, a descriptive analysis of late onset grade 4-5 pulmonary and hepatic complications that occur within 180 days of the start of consolidation therapy will be examined, regardless if the patient has proceeded to other therapy (including chimeric antibody) during that 180 day period. |
| Response Rate Determined Using the International Response Criteria | Up to 5 years | — |
| EFS | Up to 5 years | — |
| Overall Survival | Up to 5 years | — |
| Proportion of High-risk Neuroblastoma Patients With MYCN Non-amplified Tumors for Whom Molecular Profiling Results Can be Obtained | Within 8 weeks of diagnosis | — |
| Percentage of Centrally Reviewed Post-course 4 MIBG Scans Reporting a Curie Score Considered to Have Been Determined in Real Time | Up to week 12 (course 4 of induction therapy) | — |
| Percentage of MIBG Scans Receiving Institutionally and Centrally Reviewed and Automated Advanced Assisted Scoring Platform Curie Scores Within 1 Unit of Each Other | Up to week 12 (course 4 of induction therapy) | Cohen's kappa will be calculated to evaluate the concordance in Curie scores between each of the scoring methods at each time point. Up to 160 MIBG scans are expected at diagnosis and up to 144 MIBG scans from the 90% of patients estimated to be MIBG avid are projected post-course 4 of induction therapy, for a total of up to 304 MIBG scans. |
| Proportion of High-risk Neuroblastoma Patients for Whom ALK Status Can be Obtained | Within 6 weeks of diagnosis | — |
| Melphalan Pharmacokinetics and the Combination of Busulfan and Melphalan AUC (Optional) | Within 28 days post-consolidation | A descriptive analysis of the relationship between melphalan pharmacokinetics and the combination of busulfan and melphalan AUC with the occurrence of non-hematologic toxicities within 28 days following completion of consolidation will be assessed. In addition, the association between melphalan exposure levels as measured by the AUC and event-free survival and overall survival will be examined using Cox proportional hazards models. |
| First Dose Area Under the Curve (AUC) and Average Daily AUC for Busulfan | Within 28 days following consolidation | Relationship with occurrence of non-hematologic toxicities assessed by a descriptive analysis. Association between busulfan exposure levels as measured by the area under the curve (AUC) and event-free survival and overall survival will be examined using Cox proportional hazards models. |
Countries
Australia, Canada, New Zealand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Patients Induction with multi-agent chemotherapy followed by Consolidation with BuMel chemotherapy + ASCT + XRT | 150 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
| Overall Study | Enrollment another COG therapeutic trial | 32 |
| Overall Study | Ineligible | 4 |
| Overall Study | Initiation of other non-protocol therapy | 5 |
| Overall Study | Lack of Efficacy | 8 |
| Overall Study | Patient/parent refusal | 7 |
| Overall Study | Physician Decision | 25 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Categorical <=18 years | 149 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 3.1 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 129 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) White | 107 Participants |
| Region of Enrollment Australia | 3 participants |
| Region of Enrollment Canada | 14 participants |
| Region of Enrollment New Zealand | 1 participants |
| Region of Enrollment United States | 132 participants |
| Sex: Female, Male Female | 60 Participants |
| Sex: Female, Male Male | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 82 / 146 |
| serious Total, serious adverse events | 10 / 146 |
Outcome results
Primary
The Tolerability of BuMel Regimen
Number of patients who experience one or more unacceptable toxicities (severe sinusoidal obstruction syndrome \[SOS\] or Grade 4-5 pulmonary toxicity per Common Toxicity Criteria \[CTC\] v.4.0) during the Consolidation phase of therapy.
Time frame: Up to 28 days post-consolidation therapy, up to 1 year
Population: All eligible and evaluable patients who received at least one dose of either busulfan or melphalan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | The Tolerability of BuMel Regimen | 9 participants |
Other Pre-specified
EFS
Time frame: Up to 5 years
Other Pre-specified
First Dose Area Under the Curve (AUC) and Average Daily AUC for Busulfan
Relationship with occurrence of non-hematologic toxicities assessed by a descriptive analysis. Association between busulfan exposure levels as measured by the area under the curve (AUC) and event-free survival and overall survival will be examined using Cox proportional hazards models.
Time frame: Within 28 days following consolidation
Other Pre-specified
Incidence of Non-hematologic Organ Toxicity (Grade 3 and Higher) and All Cause Mortality Graded According to CTC v4.0
Assessed by a descriptive analysis of the incidence of grade 3-5 non-hematologic toxicities (CTC v4.0) and all-cause mortality during consolidation therapy. In addition, a descriptive analysis of late onset grade 4-5 pulmonary and hepatic complications that occur within 180 days of the start of consolidation therapy will be examined, regardless if the patient has proceeded to other therapy (including chimeric antibody) during that 180 day period.
Time frame: Up to 180 days
Other Pre-specified
Melphalan Pharmacokinetics and the Combination of Busulfan and Melphalan AUC (Optional)
A descriptive analysis of the relationship between melphalan pharmacokinetics and the combination of busulfan and melphalan AUC with the occurrence of non-hematologic toxicities within 28 days following completion of consolidation will be assessed. In addition, the association between melphalan exposure levels as measured by the AUC and event-free survival and overall survival will be examined using Cox proportional hazards models.
Time frame: Within 28 days post-consolidation
Other Pre-specified
Overall Survival
Time frame: Up to 5 years
Other Pre-specified
Percentage of Centrally Reviewed Post-course 4 MIBG Scans Reporting a Curie Score Considered to Have Been Determined in Real Time
Time frame: Up to week 12 (course 4 of induction therapy)
Other Pre-specified
Percentage of MIBG Scans Receiving Institutionally and Centrally Reviewed and Automated Advanced Assisted Scoring Platform Curie Scores Within 1 Unit of Each Other
Cohen's kappa will be calculated to evaluate the concordance in Curie scores between each of the scoring methods at each time point. Up to 160 MIBG scans are expected at diagnosis and up to 144 MIBG scans from the 90% of patients estimated to be MIBG avid are projected post-course 4 of induction therapy, for a total of up to 304 MIBG scans.
Time frame: Up to week 12 (course 4 of induction therapy)
Other Pre-specified
Proportion of High-risk Neuroblastoma Patients for Whom ALK Status Can be Obtained
Time frame: Within 6 weeks of diagnosis
Other Pre-specified
Proportion of High-risk Neuroblastoma Patients With MYCN Non-amplified Tumors for Whom Molecular Profiling Results Can be Obtained
Time frame: Within 8 weeks of diagnosis
Other Pre-specified
Response Rate Determined Using the International Response Criteria
Time frame: Up to 5 years