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.
PRIMARY OBJECTIVES: I. To identify a recommended phase 2 dose (RP2D) of iberdomide administered in combination with dinutuximab, cyclophosphamide, topotecan, and GM-CSF in patients with relapsed, refractory, or progressive neuroblastoma previously treated with chemoimmunotherapy. (Phase 1 dose escalation) II. To evaluate whether the addition of iberdomide to dinutuximab, cyclophosphamide, topotecan, and GM-CSF is associated with an improved response rate compared to dinutuximab, cyclophosphamide, topotecan, and GM CSF in patients with refractory, relapsed, or progressive neuroblastoma previously treated with chemoimmunotherapy. (Phase 2 efficacy) SECONDARY OBJECTIVES: I. To evaluate the preliminary response rate of the addition of iberdomide to dinutuximab, cyclophosphamide, topotecan, and GM-CSF in patients with refractory, relapsed, or progressive neuroblastoma previously treated with chemoimmunotherapy. (Phase 1 dose escalation) II. To compare progression-free survival (PFS), overall survival (OS), confirmed response rate, and duration of response (DOR) between patients receiving dinutuximab, cyclophosphamide, topotecan, and GM-CSF with and without the addition of iberdomide. III. To describe the toxicity profile of the combination of dinutuximab, cyclophosphamide, topotecan, and GM-CSF with and without iberdomide. EXPLORATORY OBJECTIVES: I. To characterize the pharmacokinetics and pharmacodynamics of iberdomide in combination with dinutuximab, cyclophosphamide, topotecan, and GM-CSF. II. To characterize the circulating immune profile of patients treated with and without the addition of iberdomide to the dinutuximab, cyclophosphamide, topotecan, and GM-CSF backbone and explore associations with response to therapy. III. To evaluate associations between GD2 levels in tumor cells from patient bone marrow samples and response to therapy. IV. To collect and bank peripheral blood and tumor tissue (archival and fresh tissue from primary tumor resection or relapse, if available) for future biomarker studies. OUTLINE: This is a phase I, dose-escalation study of iberdomide in combination with cyclophosphamide (CPM), topotecan (Topo), dinutuximab (DIN) and sargramostim (GM-CSF) followed by a phase II study. Patients are assigned to 1 of 2 phases. PHASE 1: Patients receive iberdomide orally (PO), via nasogastric (NG)-tube, or via gastric (G)-tube once daily (QD) on days 1-14 or 1-21, cyclophosphamide intravenously (IV) over 15-30 minutes on days 1-5, topotecan IV over 30 minutes on days 1-5, dinutuximab IV over 10 hours on days 2-5, and sargramostim subcutaneously (SC) or IV over 2 hours starting on day 6 or 7 and continuing for a minimum of 7 doses until absolute neutrophil count (ANC) is ≥ 1500/μL after the expected nadir or until day 21 of each cycle. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. PHASE 2: Patients are randomized to 1 of 2 arms. ARM A: Patients receive cyclophosphamide IV over 15-30 minutes on days 1-5, topotecan IV over 30 minutes on days 1-5, dinutuximab IV over 10 hours on days 2-5, and sargramostim SC or IV over 2 hours starting on day 6 or 7 and continuing for a minimum of 7 doses until ANC is ≥ 1500/μL after the expected nadir or until day 21 of each cycle. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive iberdomide PO, via NG-tube, or via G-tube QD on days 1-14 or 1-21, as determined in phase 1, cyclophosphamide IV over 15-30 minutes on days 1-5, topotecan IV over 30 minutes on days 1-5, dinutuximab IV over 10 hours on days 2-5, and sargramostim SC or IV over 2 hours starting on day 6 or 7 and continuing for a minimum of 7 doses until ANC is ≥ 1500/μL after the expected nadir or until day 21 of each cycle. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Additionally, all patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), bone marrow aspiration and biopsy, computed tomography (CT) or magnetic resonance imaging (MRI), and iobenguane I-123 (123I-MIBG) scans or fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) throughout the study. All patients also undergo blood sample collection on study. After completion of study treatment, patients are followed up at 30 days, 3, 6, and 12 months, every 6 months for years 2-3, and then yearly for years 4-5.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
76
Undergo bone marrow aspiration
Undergo bone marrow biopsy
Undergo CT
Given IV
Given IV
Undergo ECHO
Undergo FDG-PET
Given PO, NG-tube, or G-tube
Undergo MRI
Undergo MUGA
Undergo 123I-MIBG scans
Given SC or IV
Given IV
Incidence of therapy-associated dose limiting toxicities (Phase 1)
Graded using Common Terminology Criteria for Adverse Events version 5.0.
Time frame: During cycle 1 (Cycle length = 28 days)
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.
Time frame: Up to the completion of phase 1
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.
Time frame: Post-randomization up through the end of cycle 12 (Cycle length = 28 days)
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.
Time frame: Up to 12 cycles (Cycle length = 28 days)
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.
Time frame: From the time of randomization to the occurrence of relapse, progressive disease, or death, assessed up to 5 years
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.
Time frame: From the time of randomization to death, assessed up to 5 years
Duration of response
The confirmed response rate and duration of response, along with summary statistics, will be calculated in each arm.
Time frame: From randomization to disease progression or death in eligible patients, except those placed off study due to lack of insurance coverage, who achieve a MR or better, assessed up to 5 years
Incidence of grade ≥ 3 toxicities (Phase 2 Arm B)
Toxicities (grade ≥ 3) experienced on Arm B will be descriptively summarized.
Time frame: Up to 5 years post-treatment
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