Extraocular Retinoblastoma
Conditions
Brief summary
This phase III trial is studying the side effects and how well giving combination chemotherapy together with autologous stem cell transplant and/or radiation therapy works in treating young patients with extraocular retinoblastoma. Giving chemotherapy before an autologous 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/or bone marrow and stored. More chemotherapy 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. Radiation therapy uses high energy x-rays to kill tumor cells. Giving radiation therapy after combination chemotherapy and/or autologous stem cell transplant may kill any remaining tumor cells.
Detailed description
OBJECTIVES: I. To estimate the proportion of 3 groups of patients with extraocular retinoblastoma (stage 2 and 3: regional extra-ocular disease;, stage 4a: disseminated metastatic disease not involving the central nervous system \[CNS\]; or stage 4b: patients with CNS disease) who achieve long-term event-free survival after treatment with aggressive multimodality therapy compared to historical controls. II. To estimate the response rate to the induction phase of the regimen. III. To evaluate the toxicities associated with this regimen. OUTLINE: INDUCTION CHEMOTHERAPY: Patients receive vincristine intravenously (IV) on days 0, 7, and 14, cisplatin IV over 6 hours on day 0, cyclophosphamide IV over 1 hour and etoposide IV over 1 hour on days 1 and 2, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 3 and continuing until blood counts recover. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of induction chemotherapy, patients with stage 2 or 3 disease who have at least a partial response proceed to radiotherapy. Patients with stage 4a or 4b disease who have at least a partial response proceed to high-dose consolidation chemotherapy and autologous stem cell infusion. STEM CELL HARVESTING (stage 4a or 4b disease only): Peripheral blood stem cells (preferred) or bone marrow cells are collected after at least 1 course of induction chemotherapy. HIGH-DOSE CONSOLIDATION CHEMOTHERAPY (stage 4a or 4b disease only): Patients receive carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3. AUTOLOGOUS STEM CELL INFUSION (stage 4a or 4b disease only): Patients undergo autologous stem cell infusion on day 0. Patients then receive filgrastim subcutaneously (SC) beginning on day 1 and continuing until blood counts recover. RADIOTHERAPY: Patients with stage 2 or 3 disease (orbital and/or regional involvement) undergo radiotherapy to sites that were initially involved beginning within 42 days after the start of course 4 of induction chemotherapy. Patients with stage 4a or 4b disease undergo radiotherapy to sites initially involved based on response beginning approximately 42 days after autologous stem cell infusion. Patients with stage 4a disease who achieve a complete response to induction chemotherapy or with less than 5 mm of residual tumor at the time of planned irradiation, or patients with stage 4b disease who achieve a complete response to induction chemotherapy do not undergo radiotherapy. After completion of study therapy, patients are followed every 3 months for 1 year and then annually thereafter for 9 years.
Interventions
PROCEDUREAutologous Bone Marrow Transplantation
Undergo peripheral blood stem cell or bone marrow transplant
PROCEDUREAutologous Hematopoietic Stem Cell Transplantation
Undergo peripheral blood stem cell or bone marrow transplant
DRUGCarboplatin
Given IV
DRUGCisplatin
Given IV
DRUGCyclophosphamide
Given IV
DRUGEtoposide
Given IV
BIOLOGICALFilgrastim
Given SC
PROCEDUREIn Vitro-Treated Peripheral Blood Stem Cell Transplantation
Undergo peripheral blood stem cell or bone marrow transplant
RADIATIONRadiation Therapy
Undergo radiotherapy
DRUGThiotepa
Given IV
DRUGVincristine Sulfate
Given IV
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 10 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have histologic or cytologic verification of extra-ocular retinoblastoma; extra-ocular disease includes orbital disease, optic nerve involvement at the surgical margin, regional nodal disease, and/or overt distant metastatic disease (at sites such as bone, bone marrow, liver and/or the central nervous system); patients with trilateral retinoblastoma will also be included in this protocol * Patients with a CNS lesion consistent with trilateral or stage 4b disease may be enrolled without tissue confirmation if (1) unequivocal leptomeningeal disease is present on brain or spine magnetic resonance imaging (MRI) scan and/or (2) the primary tumor is at least 2 cm in diameter, predominantly solid, and demonstrates enhancement on the post-gadolinium images; however, even in such cases surgery should be given serious consideration * Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age * No prior chemotherapy or radiotherapy for the extra-ocular retinoblastoma may have been administered prior to entering this study; prior treatment (chemotherapy and/or radiation therapy) for intra-ocular retinoblastoma is permissible * Peripheral absolute neutrophil count (ANC) \>= 750/uL * If the ANC and/or platelet count are not adequate, but due to bone marrow metastatic disease, these criteria will be waived * Platelet count \>= 75,000/uL (transfusion independent) * If the ANC and/or platelet count are not adequate, but due to bone marrow metastatic disease, these criteria will be waived * Creatinine clearance OR radioisotope glomerular filtration rate \>= 70 mL/min/1.73 m\^2 or a 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 year of age) * 0.6 mg/dL (1 years to \< 2 years of age) * 0.8 mg/dL (2 years to \< 6 years of age) * 1.0 mg/dL (6 years to \< 10 years of age) * 1.2 mg/dL (10 years to \< 13 years of age) * 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 years 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 glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 2.5 x upper limit of normal (ULN) * 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) for human studies must be met
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | At 1 year | The probability of surviving patients who did not experience events at 1 year following enrollment. An event is defined as relapse, second malignancy, or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate to the Induction Phase of the Regimen | 12 weeks after participant received the first dose | This study used a modified version of the international criteria for neuroblastoma response. The response rate to the induction phase of the regimen and a corresponding 95% confidence interval will be calculated for all strata combined. |
| Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Up to 30 days after completion of study treatment | Grade 3 and higher toxicities will be descriptively summarized. |
Countries
Argentina, Australia, Brazil, Canada, Egypt, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stage 2/3 Patients Patients with orbital disease (including microscopic trans-scleral invasion seen on enucleation pathology), optic nerve margin (+), and/or regional nodal disease, but no other sites of metastases. Stage 2 and 3 patients will receive Induction chemotherapy and External Beam Radiation Therapy, but will not receive Consolidation therapy (High-Dose Chemotherapy with Stem Cell Rescue). | 21 |
| Stage 4a Patients Patients with overt distant metastatic disease (such as bone, bone marrow, and/or liver) but no detectable CNS involvement. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy. | 18 |
| Stage 4b Patients Patients with overt CNS involvement (brain parenchyma, leptomeninges and CSF cytology). Patients with trilateral retinoblastoma will be included. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy. | 21 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 2 |
| Overall Study | Ineligible | 2 | 0 | 1 |
| Overall Study | Lost to Follow-up | 4 | 3 | 3 |
| Overall Study | Physician Decision | 1 | 1 | 3 |
| Overall Study | Progressive disease | 0 | 0 | 3 |
| Overall Study | Refusal of further protocol therapy | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Stage 4a Patients | Stage 4b Patients | Total | Stage 2/3 Patients |
|---|---|---|---|---|
| Age, Continuous | 3.96 years STANDARD_DEVIATION 2.27 | 2.91 years STANDARD_DEVIATION 1.83 | 3.34 years STANDARD_DEVIATION 1.85 | 3.24 years STANDARD_DEVIATION 1.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 8 Participants | 23 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 13 Participants | 36 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 10 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 13 Participants | 6 Participants |
| Race (NIH/OMB) White | 11 Participants | 12 Participants | 34 Participants | 11 Participants |
| Region of Enrollment Argentina | 4 Participants | 2 Participants | 9 Participants | 3 Participants |
| Region of Enrollment Brazil | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Canada | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Chile | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Egypt | 0 Participants | 4 Participants | 7 Participants | 3 Participants |
| Region of Enrollment United States | 14 Participants | 13 Participants | 41 Participants | 14 Participants |
| Sex: Female, Male Female | 9 Participants | 14 Participants | 27 Participants | 4 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 33 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 18 | 5 / 18 | 15 / 19 |
| other Total, other adverse events | 13 / 18 | 12 / 18 | 10 / 19 |
| serious Total, serious adverse events | 1 / 18 | 2 / 18 | 0 / 19 |
Outcome results
Primary
Event-free Survival (EFS)
The probability of surviving patients who did not experience events at 1 year following enrollment. An event is defined as relapse, second malignancy, or death from any cause.
Time frame: At 1 year
Population: Ineligible patients were excluded from analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 2/3 Patients | Event-free Survival (EFS) | 88 Probability |
| Stage 4a Patients | Event-free Survival (EFS) | 83 Probability |
| Stage 4b Patients | Event-free Survival (EFS) | 28 Probability |
Secondary
Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Grade 3 and higher toxicities will be descriptively summarized.
Time frame: Up to 30 days after completion of study treatment
Population: Three ineligible patients were excluded from this analysis. Two patients who did not receive therapy were also excluded from this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Gastric hemorrhage | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Aspartate aminotransferase increased | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Mucositis oral | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hearing impaired | 11.1 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Acute kidney injury | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Lymphocyte count decreased | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypermagnesemia | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Sepsis | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Lung infection | 16.7 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypertension | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Catheter related infection | 11.1 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Lower gastrointestinal hemorrhage | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypoalbuminemia | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Upper respiratory infection | 11.1 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Infections and infestations - Other, specify | 27.8 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypocalcemia | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Seizure | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypoxia | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypoglycemia | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Dehydration | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypotension | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypokalemia | 27.8 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Anemia | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypophosphatemia | 22.2 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypomagnesemia | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Rectal pain | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hyponatremia | 11.1 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Depressed level of consciousness | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | White blood cell decreased | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Pneumonitis | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Diarrhea | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Skin infection | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Platelet count decreased | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Encephalopathy | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Anorexia | 11.1 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Pharyngeal mucositis | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Enterocolitis | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Vomiting | 11.1 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Peripheral motor neuropathy | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Enterocolitis infectious | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Abdominal pain | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Pain | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Esophagitis | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Sinusitis | 11.1 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Oral pain | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Febrile neutropenia | 55.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Apnea | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Neutrophil count decreased | 5.6 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Fever | 11.1 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Alanine aminotransferase increased | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Nervous system disorders - Other, specify | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | GGT increased | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Sinus tachycardia | 0 percentage of participants |
| Stage 2/3 Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Nausea | 16.7 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Enterocolitis infectious | 11.1 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Abdominal pain | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Acute kidney injury | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Alanine aminotransferase increased | 16.7 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Anemia | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Anorexia | 33.3 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Apnea | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Aspartate aminotransferase increased | 11.1 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Catheter related infection | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Dehydration | 11.1 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Depressed level of consciousness | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Diarrhea | 16.7 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Encephalopathy | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Enterocolitis | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Esophagitis | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Febrile neutropenia | 55.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Fever | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | GGT increased | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Gastric hemorrhage | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hearing impaired | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypermagnesemia | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypertension | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypoalbuminemia | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypocalcemia | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypoglycemia | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypokalemia | 16.7 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypomagnesemia | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hyponatremia | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypophosphatemia | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypotension | 11.1 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypoxia | 2.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Infections and infestations - Other, specify | 33.3 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Lower gastrointestinal hemorrhage | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Lung infection | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Lymphocyte count decreased | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Mucositis oral | 27.8 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Nausea | 11.1 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Nervous system disorders - Other, specify | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Neutrophil count decreased | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Oral pain | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Pain | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Peripheral motor neuropathy | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Pharyngeal mucositis | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Platelet count decreased | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Pneumonitis | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Rectal pain | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Seizure | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Sepsis | 11.1 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Sinus tachycardia | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Sinusitis | 0 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Skin infection | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Upper respiratory infection | 5.6 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Vomiting | 22.2 percentage of participants |
| Stage 4a Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | White blood cell decreased | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | GGT increased | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | White blood cell decreased | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Nausea | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Fever | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Sinus tachycardia | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Nervous system disorders - Other, specify | 10.5 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Febrile neutropenia | 36.8 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Anorexia | 15.8 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Neutrophil count decreased | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Esophagitis | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Vomiting | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Enterocolitis infectious | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Sinusitis | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Pain | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Enterocolitis | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Anemia | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Peripheral motor neuropathy | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Encephalopathy | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Abdominal pain | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Pharyngeal mucositis | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Diarrhea | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Skin infection | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Platelet count decreased | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Depressed level of consciousness | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Alanine aminotransferase increased | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Pneumonitis | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Dehydration | 10.5 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypomagnesemia | 10.5 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Oral pain | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hyponatremia | 15.8 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypokalemia | 21.1 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Rectal pain | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypophosphatemia | 10.5 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypoglycemia | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Catheter related infection | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypotension | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypocalcemia | 10.5 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Upper respiratory infection | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypoxia | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypoalbuminemia | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Seizure | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Infections and infestations - Other, specify | 21.1 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypertension | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Aspartate aminotransferase increased | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Lower gastrointestinal hemorrhage | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hypermagnesemia | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Acute kidney injury | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Lung infection | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Hearing impaired | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Sepsis | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Lymphocyte count decreased | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Gastric hemorrhage | 0 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Apnea | 5.3 percentage of participants |
| Stage 4b Patients | Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Mucositis oral | 5.3 percentage of participants |
Secondary
Response Rate to the Induction Phase of the Regimen
This study used a modified version of the international criteria for neuroblastoma response. The response rate to the induction phase of the regimen and a corresponding 95% confidence interval will be calculated for all strata combined.
Time frame: 12 weeks after participant received the first dose
Population: Ineligible patients were excluded from analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 2/3 Patients | Response Rate to the Induction Phase of the Regimen | 68 percentage of participants |