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Treatment with Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination with Irinotecan and Temozolomide after Intensive Therapy for People with High-Risk Neuroblastoma (NBL)

Status
Completed
Cancer Type
Neuroblastoma
Neurologocal Tumor
Trial Phase
Phase II
Eligibility
0 - 30 Years, Male and Female
Study Type
Treatment
NCT ID
NCT04385277
Protocol IDs
ANBL19P1 (primary)
NCI-2020-02950
ANBL19P1
Study Sponsor
Children's Oncology Group

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.

Objectives

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. 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 may undergo multigated acquisition scan (MUGA) during screening if applicable. Patients 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.

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.

Eligibility

  1. Patients must be < 31 years of age at the time of enrollment.
  2. 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
  3. 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
  4. 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
  5. 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
  6. Peripheral absolute neutrophil count (ANC) >= 750/uL
  7. Platelet count >= 50,000/uL (transfusion independent for >= 7 days)
  8. 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
  9. Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
  10. 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
  11. Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by echocardiogram or radionuclide angiogram
  12. Absence of dyspnea at rest
  13. If pulmonary function tests (PFTs) are performed, forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) must be > 60%
  14. No clinical evidence of active central nervous system (CNS) disease at the time of study enrollment
  15. Patients with seizure disorder may be enrolled if on non-enzyme-inducing anticonvulsants and well controlled
  16. CNS toxicity from prior therapy =< grade 2
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts... Click here to learn more about clinical trials.
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