This phase I/II trial studies the side effects and best dose of iberdomide when given together with chemoimmunotherapy drugs and to see how well it works in treating patients with neuroblastoma that has come back after a period of improvement (relapsed), that does not respond to treatment (refractory), or that is growing, spreading, or getting worse (progressive) following prior chemoimmunotherapy. Iberdomide is a cereblon-modulating agent. It works by helping the immune system kill tumor cells. Chemoimmunotherapy is chemotherapy combined with immunotherapy. Chemotherapy drugs, such as cyclophosphamide and topotecan, 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. Immunotherapy with dinutuximab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Granulocyte-macrophage colony-stimulating factors (GM-CSF), such as sargramostim, may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Giving iberdomide with chemoimmunotherapy may be safe, tolerable, and/or effective in treating patients with relapsed, refractory, or progressive neuroblastoma following prior chemoimmunotherapy.
Patients must be ≥ 1 year of age and ≤ 30 years of age at the time of study enrollment
Patients must have had histologic verification of neuroblastoma or ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with elevated urinary catecholamines (i.e. > 2 x upper limit of normal [ULN]), at the time of initial diagnosis
Progressive/relapsed or refractory (defined as persistent disease with overall response no better than minor response [MR] to prior therapy per revised International Neuroblastoma Response Criteria [INRC]) neuroblastoma based on the revised INRC
Primary refractory disease
Patients who received allogeneic stem cell therapy will be excluded
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. 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
Patients with untreated CNS disease will be excluded. If the CNS disease has been adequately treated (e.g., surgical resection and radiation; or radiation alone) and there is no evidence of progression in the CNS, then the patient will be eligible
Patients with a history of having to permanently discontinue anti-GD2 therapy or sargarmostim (GM-CSF) due to drug-related toxicity will be excluded
Sequential
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Computed Tomography
Procedure/SurgeryUndergo CT
Cyclophosphamide
DrugGiven IV
Dinutuximab
Biological/VaccineGiven IV
Echocardiography Test
Procedure/SurgeryUndergo ECHO
FDG-Positron Emission Tomography
Procedure/SurgeryUndergo FDG-PET
Iberdomide
DrugGiven PO, NG-tube, or G-tube
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Nuclear Radiology Imaging Procedure
RadiationUndergo 123I-MIBG scans
Sargramostim
Biological/VaccineGiven SC or IV
Topotecan
DrugGiven IV
Incidence of therapy-associated dose limiting toxicities (Phase 1)
Graded using Common Terminology Criteria for Adverse Events version 5.0.
Recommended phase 2 dose (Phase 1)
Will be assessed by determining the recommended phase 2 dose of iberdomide administered in combination with dinutuximab, cyclophosphamide, topotecan, and granulocyte-macrophage colony-stimulating factor (GM-CSF) using the rolling six design.
Proportion of eligible patients who are responders (Phase 2)
Responders are defined as patients who achieve a minor response (MR) or better, per the revised International Neuroblastoma Response Criteria (INRC), as their best overall response at any time post-randomization up through the end of cycle 12. Will be evaluated by Boschloo's test to compare the response rates in the two arms, and the futility monitoring rules. The response rate by the end of 12 cycles as determined by central review will be calculated in each arm, including placement of a 95% confidence interval (CI). If the response rate on Arm B is significantly better, then it will be considered a therapeutic regimen worthy of further testing in patients with high-risk neuroblastoma. In addition, the rate of complete response + partial response by the end of 12 cycles as determined by central review will be calculated in each arm, including placement of a 95% CI, as well as response within each of the INRC components.
Response rate (Phase 1)
The response rate by the end of 12 cycles as determined by the institution will be calculated in the whole cohort, including placement of a 95% CI.
Progression-free survival (Phase 2)
Will be assessed for Phase 2 patients receiving dinutuximab, cyclophosphamide, and topotecan with and without the addition of iberdomide. Kaplan-Meier curves will be generated by arm and compared using log-rank tests.
Overall survival (Phase 2)
Will be assessed for Phase 2 patients receiving dinutuximab, cyclophosphamide, and topotecan with and without the addition of iberdomide. Kaplan-Meier curves will be generated by arm and compared using log-rank tests.
Duration of response
The confirmed response rate and duration of response, along with summary statistics, will be calculated in each arm.
Pharmacokinetic (PK) parameters of iberdomide in combination with dinutuximab, cyclophosphamide, topotecan, and GM-CSF
PK parameters of iberdomide in combination with dinutuximab, cyclophosphamide, topotecan, and GM-CSF at steady state will be performed. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges and standard deviations.
Pharmacodynamic (PD) parameters of iberdomide in combination with dinutuximab, cyclophosphamide, topotecan, and GM-CSF (Phase 1)
PD parameters of iberdomide in combination with dinutuximab, cyclophosphamide, topotecan, and GM-CSF at steady state will be performed. The PD parameters will be summarized with simple summary statistics, including means, medians, ranges and standard deviations.
Immune profiling results (Phase 2)
Immune profiling results will be summarized with descriptive statistics, including describing changes in markers over time. Markers will be correlated with response via a chi-square test.
GD2 levels in tumor cells from bone marrow samples and response
Will correlate GD2 levels in tumor cells from bone marrow samples with response (responder versus non-responder) after 6 cycles using Fisher's exact test for categorical and the Wilcoxon rank-sum test for continuous factors.
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