Ganglioneuroblastoma, Nodular, Neuroblastoma
Conditions
Brief summary
This phase II trial studies if dinutuximab, GM-CSF, isotretinoin in combination with irinotecan, and temozolomide (chemo-immunotherapy) can be given safely to patients with high-risk neuroblastoma after Consolidation therapy (which usually consists of two autologous stem cell transplants and radiation) who have not experienced worsening or recurrence of their disease. Dinutuximab represents a kind of cancer therapy called immunotherapy. Unlike chemotherapy and radiation, dinutuximab targets the cancer cells without destroying nearby healthy cells. Sargramostim helps the body produce normal infection-fighting white blood cells. Isotretinoin helps the neuroblastoma cells become more mature. These 3 drugs (standard immunotherapy) are already given to patients with high-risk neuroblastoma after Consolidation because they have been proven to be beneficial in this setting. Chemotherapy drugs, such as irinotecan and temozolomide, 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. They may also affect how well immunotherapy works on neuroblastoma cells. Giving chemo-immunotherapy after intensive therapy may work better in treating patients with high-risk neuroblastoma compared to standard immunotherapy.
Detailed description
PRIMARY OBJECTIVE: I. To determine the feasibility of administering dinutuximab, GM-CSF, and isotretinoin in combination with irinotecan and temozolomide in the frontline Post-Consolidation setting in patients with high-risk neuroblastoma who have undergone Induction and Consolidation therapy with tandem high-dose chemotherapy with stem cell rescue (ASCT). SECONDARY OBJECTIVES: I. To describe the toxicity profile of dinutuximab, GM-CSF, and isotretinoin in combination with irinotecan and temozolomide in the Post-Consolidation setting. II. To describe the event-free survival and overall survival of patients who receive dinutuximab in combination with irinotecan and temozolomide, GM-CSF, and isotretinoin in the Post-Consolidation setting. EXPLORATORY OBJECTIVES: I. To describe the toxicity profiles associated with chemo-immunotherapy in the Post-Consolidation setting according to the type of prior therapy. II. To describe response to chemo-immunotherapy in the Post-Consolidation setting using the revised International Neuroblastoma Risk Classification (INRC) in patients with evaluable or measurable disease at study entry. III. To characterize immune and cytokine profiles in patients receiving Post-Consolidation chemo-immunotherapy. IV. To bank serial blood samples to investigate the relationship between factors related to the tumor, host, and immune environment and clinical outcomes in patients treated with chemo-immunotherapy. OUTLINE: Patients receive temozolomide orally (PO) or via enteral tube daily and irinotecan intravenously (IV) over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim subcutaneously (SC) or IV over 2 hours daily on days 6-12, and isotretinoin PO twice daily (BID) on days 8-21. Patients undergo multigated acquisition scan (MUGA) during screening. Patients also undergo magnetic resonance imaging (MRI), or computed tomography (CT), iobenguane I-123 (123I-MIBG), or fludeoxyglucose F-18-positron emission tomography (FDG-PET), bone marrow (BM) aspiration, and BM biopsy on study. Treatment repeats every 28 days for up to 5 cycles (up to 6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 54, and 60 months.
Interventions
PROCEDUREBiospecimen Collection
Correlative studies
PROCEDUREBone Marrow Aspiration
Undergo BM aspiration
PROCEDUREBone Marrow Biopsy
Undergo BM biopsy
PROCEDUREComputed Tomography
Undergo CT
BIOLOGICALDinutuximab
Given IV
PROCEDUREFDG-Positron Emission Tomography
Undergo FDG-PET
RADIATIONIobenguane I-123
Undergo 123I-MIBG
DRUGIrinotecan
Given IV
DRUGIsotretinoin
Given PO
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
PROCEDUREMultigated Acquisition Scan
Undergo MUGA
BIOLOGICALSargramostim
Given SC or IV
DRUGTemozolomide
Given PO or via enteral tube
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 be \< 31 years of age at the time of enrollment. * Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular) (verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites at the time of diagnosis) and have been designated as having high-risk disease based on Children's Oncology Group (COG) risk classification. The following disease groups are eligible: * Patients with International Neuroblastoma Risk Group (INRG) Stage M disease with any of the following features: * MYCN amplification (\> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR * Age \> 547 days at the time of diagnosis regardless of biologic features; OR * Age 365-547 days at the time of diagnosis with tumors with unfavorable histology and/or deoxyribonucleic acid (DNA) index = 1 * Patients with INRG Stage MS disease with MYCN amplification * Patients with INRG Stage L2 disease with either of the following features: * MYCN amplification (\> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR * Age \> 547 days at the time of diagnosis with MYCN non-amplified tumors with unfavorable histology * Note: Patients observed or patients treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high-risk disease but subsequently found to meet criteria will also be eligible * 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 * Prior therapy * All patients must have completed high-risk Induction therapy with 4-6 cycles of chemotherapy * After completion of Induction therapy, patients may have received no more than 4 cycles of bridging chemotherapy or chemo-immunotherapy prior to ASCT * Patients cannot have previously progressed on immunotherapy with dinutuximab or other anti-GD2 monoclonal antibody * All patients must have had undergone surgical resection of their primary tumor as part of frontline therapy. Exceptions to this requirement include patients who had a complete response to Induction chemotherapy, patients with no identifiable primary tumor, and patients for whom the institutional surgical team determined that potential risks outweighed potential benefits of resection * All patients must have undergone tandem high-dose chemotherapy with ASCT as part of Consolidation * Patients must enroll between day +56 and day +200 from the peripheral blood stem cell (PBSC) infusion following the last dose of high-dose chemotherapy during Consolidation * All patients must have undergone external beam radiation therapy. Exceptions to this requirement include patients who had no identifiable primary tumor and no persistent metastatic disease at the end of Induction. For patients who received radiotherapy, at least 7 days must have elapsed between completion of radiotherapy and enrollment on this study * Patients must not have received long-acting myeloid growth factors (e.g., Neulasta) within 14 days of entry on this study. Seven days must have elapsed since administration of a short-acting myeloid growth factor * Peripheral absolute neutrophil count (ANC) \>= 750/uL * Platelet count \>= 50,000/uL (transfusion independent for \>= 7 days) * 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: Maximum Serum Creatinine (mg/dL) * 6 months to \< 1 year: 0.5 (male and female) * 1 to \< 2 years: 0.6 (male and female) * 2 to \< 6 years: 0.8 (male and female) * 6 to \< 10 years: 1 (male and female) * 10 to \< 13 years: 1.2 (male and female) * 13 to \< 16 years: 1.5 (male), 1.4 (female) * \>= 16 years: 1.7 (male), 1.4 (female) * Note: Patients with history of transplant associated-thrombotic microangiopathy (TA-TMA) must have a creatinine clearance or radioisotope GFR at baseline to assess renal function and must meet the above criteria * Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age * Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 5.0 x ULN for age (=\< 225 U/L) * Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L * Shortening fraction of \>= 27% by echocardiogram, or ejection fraction of \>= 50% by echocardiogram or radionuclide angiogram * Absence of dyspnea at rest * If pulmonary function tests (PFTs) are performed, forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) must be \> 60% * No clinical evidence of active central nervous system (CNS) disease at the time of study enrollment * Patients with seizure disorder may be enrolled if on non-enzyme-inducing anticonvulsants and well controlled * CNS toxicity from prior therapy =\< grade 2
Exclusion criteria
* Patients must not have had progressive disease (PD) per the revised International Neuroblastoma Risk Criteria (INRC) since the initial diagnosis of high-risk neuroblastoma * Exception: Progressive disease within the first 2 cycles of Induction chemotherapy consisting of cyclophosphamide and topotecan is allowed. Patients with progression subsequent to initial cyclophosphamide and topotecan cycles are excluded * Patients may not have received additional systemic cancer-directed therapy following completion of the last planned high-dose chemotherapy with ASCT prior to enrollment on this trial * Patients may not have received iodine-131 (131I)-metaiodobenzylguanidine (MIBG) therapy at any time prior to enrollment on this trial * Patients who received single (rather than tandem) high-dose chemotherapy with ASCT are excluded * Patients cannot be receiving other ongoing anticancer therapy * Patients who were enrolled onto ANBL1531 AND underwent arm assignment are not eligible. Patients who enrolled onto ANBL1531 who declined second consent may be eligible for ANBL19P1 if all other criteria are met * Patients enrolled onto ANBL17P1 are not eligible * Patients must have been off pharmacologic doses of systemic steroids for at least 7 days prior to enrollment * Patients who require or are likely to require pharmacologic doses of systemic corticosteroids while 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 administration in order to avoid allergic transfusion reactions * Note: The use of conventional doses of inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for patients with known adrenal insufficiency * Patients on any other immunosuppressive medications (e.g., cyclosporine, tacrolimus) are not eligible. However, prior or planned concomitant treatment with eculizumab is permitted (e.g., treatment of TA-TMA) * Patients must not have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study enrollment * Note: Patients receiving non-enzyme inducing anticonvulsants such as gabapentin or levetiracetam are eligible * Patients must not have received drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment * Patients must not have been diagnosed with myelodysplastic syndrome or with any malignancy other than neuroblastoma * Patients with symptoms of congestive heart failure are not eligible * Patients with moderate or large pericardial effusions are not eligible * Patients must not have \>= grade 2 diarrhea * Patients must not have uncontrolled infection * Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or reactions that required discontinuation of the anti-GD2 therapy are not eligible * Patients with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Complete 5 Cycles of Dinutuximab + Chemotherapy Without Progressive Disease (PD) | Within 30 weeks from the date of first treatment | Will be assessed by estimation of the feasibility therapy completion rate together with a 95% Wilson confidence interval (CI). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | From the time of start of protocol therapy to the occurrence of disease relapse or progression, secondary malignancy, or death, assessed at 1 year. | EFS Kaplan-Meier estimates will be generated. |
| Overall Survival (OS) | From the time of start of protocol therapy to death, assessed at 1 year. | OS Kaplan-Meier estimates will be generated. |
Countries
Australia, Canada, New Zealand, United States
Participant flow
Recruitment details
Patients with newly diagnosed high-risk Neuroblastoma enrolled between 12/31/2020 and 6/27/2022 across 22 institutions.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Temozolomide, Irinotecan, Dinutuximab) Patients receive temozolomide PO or via enteral tube daily and irinotecan IV over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim SC or IV over 2 hours daily on days 6-12, and isotretinoin PO BID on days 8-21. Patients undergo MUGA during screening. Treatment repeats every 28 days for up to 5 cycles (up to 6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI, or CT, I23I-MIBG, or FDG-PET, BM aspiration, and BM biopsy on study. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 1 |
| Overall Study | Patient/Parent Refusal | 2 |
| Overall Study | Physician Decision | 2 |
Baseline characteristics
| Characteristic | Treatment (Temozolomide, Irinotecan, Dinutuximab) |
|---|---|
| Age, Categorical <=18 years | 41 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 4.74 years STANDARD_DEVIATION 2.66 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Region of Enrollment Australia | 3 participants |
| Region of Enrollment New Zealand | 4 participants |
| Region of Enrollment United States | 34 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 40 |
| other Total, other adverse events | 34 / 40 |
| serious Total, serious adverse events | 3 / 40 |
Outcome results
Primary
Percentage of Patients Who Complete 5 Cycles of Dinutuximab + Chemotherapy Without Progressive Disease (PD)
Will be assessed by estimation of the feasibility therapy completion rate together with a 95% Wilson confidence interval (CI).
Time frame: Within 30 weeks from the date of first treatment
Population: All eligible patients who receive at least one dose of dinutuximab in combination with irinotecan and temozolomide, GM-CSF, and isotretinoin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Temozolomide, Irinotecan, Dinutuximab) | Percentage of Patients Who Complete 5 Cycles of Dinutuximab + Chemotherapy Without Progressive Disease (PD) | 87.50 Percentage of patients |
Secondary
Event-free Survival (EFS)
EFS Kaplan-Meier estimates will be generated.
Time frame: From the time of start of protocol therapy to the occurrence of disease relapse or progression, secondary malignancy, or death, assessed at 1 year.
Population: All eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Temozolomide, Irinotecan, Dinutuximab) | Event-free Survival (EFS) | 90.0 percentage of participants |
Secondary
Overall Survival (OS)
OS Kaplan-Meier estimates will be generated.
Time frame: From the time of start of protocol therapy to death, assessed at 1 year.
Population: All eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Temozolomide, Irinotecan, Dinutuximab) | Overall Survival (OS) | 97.5 percentage of participants |