Dinutuximab With Chemotherapy, Surgery and Stem Cell Transplantation for the Treatment of Children With Newly Diagnosed High Risk Neuroblastoma

Study Overview
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Brief Summary
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This phase III trial tests how well adding dinutuximab to induction chemotherapy along with standard of care surgery radiation and stem cell transplantation works for treating children with newly diagnosed high risk neuroblastoma. Dinutuximab is a monoclonal antibody that binds to a molecule called GD2, which is found in greater than normal amounts on some types of cancer cells. This helps cells of the immune system kill the cancer cells. Chemotherapy drugs such as cyclophosphamide, topotecan, cisplatin, etoposide, vincristine, dexrazoxane, doxorubicin, temozolomide, irinotecan and isotretinoin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. During induction, chemotherapy and surgery are used to kill and remove as much tumor as possible. During consolidation, very high doses of chemotherapy are given to kill any remaining cancer cells. This chemotherapy also destroys healthy bone marrow, where blood cells are made. A stem cell transplant is a procedure that helps the body make new healthy blood cells to replace the blood cells that may have been harmed by the cancer and/or chemotherapy. Radiation therapy is also given to the site where the cancer originated (primary site) and to any other areas that are still active at the end of induction.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine if the event-free survival (EFS) of patients with newly diagnosed high-risk neuroblastoma assigned to early chemoimmunotherapy during Induction differs from that of patients who are not assigned to treatment that includes early chemoimmunotherapy. SECONDARY OBJECTIVES: I. To determine if early chemoimmunotherapy during Induction therapy improves end of induction (EOI) response rates and overall survival (OS) for patients with newly diagnosed high-risk neuroblastoma. II. To determine response rates, EFS, and OS following an extended induction regimen with chemoimmunotherapy in patients with progressive disease or a poor response to Induction therapy. III. To compare the toxicities experienced by patients treated with chemoimmunotherapy during induction versus those experienced by patients treated with standard induction and to describe toxicities experienced during extended induction. IV. To determine GD2 expression on tumor tissue and tumor cells in bone marrow and assess for associations with response and outcome. EXPLORATORY OBJECTIVES: I. To describe the association between tumor and host factors and outcomes in patients receiving protocol therapy. II. To evaluate circulating biomarkers and markers of minimal residual disease at baseline and during therapy, and assess for associations with response and outcome. III. To compare patterns of failure between patients treated with and without dinutuximab during induction. IV. To determine the effect of telomere maintenance mechanisms on end of Induction response rates, EFS, and OS. V. To explore the impact of high-risk neuroblastoma (HRNBL) and its therapy, including the addition of dinutuximab to Induction chemotherapy, on functional and quality of life outcomes in patients with HRNBL, as measured by caregiver (parent/legal guardian) and patient questionnaires. VI. To describe the adequacy of diagnostic biopsy specimens, including those obtained by percutaneous core needle biopsy. VII. To explore the associations between family-reported adverse social determinants of health and both clinical outcomes and biology. VIII. To develop and validate deep learning predictors of Induction response based on diagnostic MIBG scans. (Imaging Objective) IX. To compare institutional versus central determination of overall response, individual response components (primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease), and poor end of induction response (PEIR) and good end of induction response (GEIR) determination. (Imaging Objective) X. To describe late toxicities (including impaired organ function, neuropsychiatric toxicity, and incidence of secondary malignancy) in patients treated with dinutuximab during Induction or Extended Induction to late toxicities in patients who have not received dinutuximab during these phases of therapy. XI. To evaluate whether reduced dose radiotherapy to the primary site clinical target volume (CTV) in patients with complete response of the primary site at EOI results in comparable local control relative to historical cohorts. XII. To compare post-transplant complications between treatment arms, and assess for associations with outcome. XIII. To assess for associations between EOI response (including good end of Induction response [GEIR] and poor end of Induction response [PEIR]) and individual response components (primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease) with outcome (EFS and OS). XIV. To describe and compare the changes in image-defined risk factors (IDRFs) between patients treated with and without dinutuximab during Induction and associate with surgical outcomes and local failure rates following primary tumor resection. XV. To bank serial samples of blood, bone marrow, and tumor tissue for future research. OUTLINE: Patients receive induction cycle 1. Patients are then randomized to 1 of 2 arms. INDUCTION CYCLE 1: Patients receive cyclophosphamide intravenously (IV) over 30 minutes and topotecan IV over 30 minutes on days 1-5 in the absence of unacceptable toxicity. ARM A: INDUCTION CYCLES 2-4: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5 of cycle 2 in the absence of unacceptable toxicity. Patients then undergo stem cell harvest via apheresis. Patients then receive cisplatin IV over 4 hours and etoposide IV over 4 hours on days 1-3 of cycle 3 and vincristine IV on day 1 and dexrazoxane IV over 5-15 minutes, doxorubicin over 15 minutes, and cyclophosphamide over 1 hours on days 1-2 of cycle 4 in the absence of unacceptable toxicity. Patients undergo testing to determine response and proceed to surgery followed by induction cycle 5 or extended induction. INDUCTION CYCLE 5: Patients receive cisplatin IV over 4 hours and etoposide IV over 2 hours on days 1-3 in the absence of unacceptable toxicity. Patients with a response to therapy proceed to consolidation. EXTENDED INDUCTION: Patients whose cancer did not respond receive temozolomide orally (PO), via nasogastric tube (NG), or via gastric tube (G-tube) on days 1-5, irinotecan IV over 90 minutes on days 1-5, and dinutuximan IV over 10 hours. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2. Patients then receive stem cell infusion IV on day 0. Between 6 and 10 weeks after stem cell infusion patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide IV over 24 hours on days -7 to -4, and carboplatin over 24 hours on days -7 to -4. Patients receive stem cell infusion IV on day 0. Between day +42 and day +80 after second transplant, patients receive radiation daily for 12 treatments in the absence of disease progression or unacceptable toxicity. POST CONSOLIDATION: Patients receive dinutuximab IV over 10 hours on days 4-7 and isotretinoin PO twice daily (BID) on days 11-24 of each cycle. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive isotretinoin PO BID on days 15-28 for 1 additional cycle. Patients undergo bone marrow aspiration and/or biopsy, computed tomography (CT) scan, magnetic resonance imaging (MRI), iodine-123 meta-iodobenzylguanidine (I-MIBG) scan and fluorodeoxyglucose position emission tomography (FDG-PET) scan throughout the study. ARM B: INDUCTION CYCLES 2-4: Patients receive cyclophosphamide IV over 30 minutes, topotecan IV over 30 minutes on days 1-5, and dinutuximab IV over 10 hours on days 2-5 of cycle 2 in the absence of unacceptable toxicity. Patients then undergo stem cell harvest via apheresis. Patients receive cisplatin IV over 4 hours and etoposide IV over 4 hours on days 1-3 and dinutuximab IV on days 2-5 on cycle 3 and vincristine IV on day 1 and dexrazoxane IV over 5-15 minutes, doxorubicin over 15 minutes, and cyclophosphamide over 1 hours on days 1-2, and dinutuximab IV over 10 hours on days 2-5 of cycle 4 in the absence of unacceptable toxicity. Patients then undergo testing to determine response and proceed to surgery followed by induction cycle 5 or extended induction. INDUCTION CYCLE 5: Patients receive cisplatin IV over 4 hours and etoposide IV over 2 hours on days 1-3 and dinutuximab IV on days 2-5 in the absence of unacceptable toxicity. Patients with a response to therapy proceed to consolidation. EXTENDED INDUCTION: Patients receive temozolomide PO, via NG, or via G-tube on days 1-5, irinotecan IV over 90 minutes on days 1-5, and dinutuximan IV over 10 hours. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity CONSOLIDATION: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2. Patients then receive stem cell infusion IV on day 0. Between 6 and 10 weeks after stem cell infusion patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide IV over 24 hours on days -7 to -4, and carboplatin over 24 hours on days -7 to -4. Patients receive stem cell infusion IV on day 0. Between day +42 and day +80 after second transplant, patients receive radiation daily for 12 treatments in the absence of disease progression or unacceptable toxicity. POST CONSOLIDATION: Patients receive dinutuximab IV over 10 hours on days 4-7 and isotretinoin PO BID on days 11-24 of each cycle. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive isotretinoin PO BID on days 15-28 for 1 additional cycle. Patients undergo bone marrow aspiration and/or biopsy, CT scan, MRI, I-MIBG scan and FGD-PET scan throughout the 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 and then periodically for up to 10 years from enrollment.

Official Title
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A Phase 3 Study of Dinutuximab Added to Intensive Multimodal Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma

Conditions
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Neuroblastoma, Ganglioneuroblastoma

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Aspiration
* Procedure: Bone Marrow Biopsy
* Procedure: Bone Scan
* Drug: Carboplatin
* Drug: Cisplatin
* Procedure: Computed Tomography
* Drug: Cyclophosphamide
* Drug: Dexrazoxane
* Biological: Dinutuximab
* Drug: Doxorubicin
* Drug: Etoposide
* Procedure: FDG-Positron Emission Tomography and Computed Tomography Scan
* Procedure: Hematopoietic Cell Transplantation
* Drug: Irinotecan
* Drug: Isotretinoin
* Procedure: Leukapheresis
* Procedure: Magnetic Resonance Imaging
* Drug: Melphalan
* Radiation: Radiation Therapy
* Other: Survey Administration
* Drug: Temozolomide
* Drug: Thiotepa
* Drug: Topotecan
* Procedure: Tumor Resection
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be enrolled on APEC14B1 and have consented to testing through the Molecular Characterization Initiative (MCI), prior to enrollment on ANBL2131 ≤ 30 years at the time of initial diagnosis with high-risk disease Must have a diagnosis of neuroblastoma (NBL) or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamines Newly diagnosed, high risk neuroblastoma (HRNBL) defined as one of the following: Any age with International Neuroblastoma Risk Group (INRG) Stage L2, MS, or M and MYCN amplification Age ≥ 547 days and INRG stage M regardless of biologic features (clinical MYCN testing not required prior to enrollment) Any age initially diagnosed with INRG Stage L1 MYCN amplified NBL who have progressed to stage M without systemic chemotherapy Age ≥ 547 days of age initially diagnosed with INRG Stage L1, L2, or MS who have progressed to stage M without systemic chemotherapy (clinical MYCN testing not required prior to enrollment) Patients must have a BSA ≥ 0.25 m^2 No prior anti-cancer therapy except as outlined below: Patients initially recognized to have high-risk disease treated with topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing, and with consent Patients observed or treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (eg, as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high-risk disease but subsequently found to meet the criteria Patients who received localized emergency radiation to sites of life threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis Human immunodeficiency virus (HIV) -infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial A serum creatinine based on age/sex derived from the Schwartz formula for estimating glomerular filtration rate (GFR) utilizing child length and stature data published by the CDC or a 24-hour urine creatinine clearance ≥ 70 mL/min/1.73 m^2 or a GFR ≥ 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method or direct small molecule clearance method (iothalamate or other molecule per institutional standard) Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age Serum glutamic pyruvic transaminase (SGPT) (Alanine aminotransferase [ALT]) ≤ 10 x ULN* 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 Ability to tolerate Peripheral Blood Stem Cell (PBSC) Collection: No known contraindication to PBSC collection. Examples of contraindications might be a weight or size less than the collecting institution finds feasible, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure Exclusion Criteria: Patients who are 365-546 days of age with INRG Stage M and MYCN non amplified NBL, irrespective of additional biologic features Patients ≥ 547 days of age with INRG Stage L2, MYCN non-amplified NBL, regardless of additional biologic features Patients with known bone marrow failure syndromes Patients on chronic immunosuppressive medications (eg, tacrolimus, cyclosporine, corticosteroids) for reasons other than prevention/treatment of allergic reactions and adrenal replacement therapy are not eligible. Topical and inhaled corticosteroids are acceptable Patients with a primary immunodeficiency syndrome who require ongoing immune globulin replacement therapy Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required prior to enrollment for female patients of childbearing potential Lactating females who plan to breastfeed their infants Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation 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) requirements for human studies must be met

Ages Eligible for Study
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Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (SOC treatment)<br>See detailed description | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Bone Scan<br>* Undergo MIBG scan<br>* Other names: Bone Scintigraphy;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Dexrazoxane<br>* Given IV<br>* Other names: Soluble ICRF (L-isomer);Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Procedure: FDG-Positron Emission Tomography and Computed Tomography Scan<br>* Undergo FDG PET<br>* Other names: FDG PET/CT;Procedure: Hematopoietic Cell Transplantation<br>* Undergo stem cell infusion<br>* Other names: Stem Cell Transplantation, NOS;Drug: Irinotecan<br>* Given IV<br>Drug: Isotretinoin<br>* Given PO<br>* Other names: ZENATANE;Procedure: Leukapheresis<br>* Undergo apheresis<br>* Other names: Therapeutic Leukopheresis;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Other: Survey Administration<br>* Ancillary studies<br>Drug: Temozolomide<br>* Given PO or via NG or G tube<br>* Other names: TMZ;Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Drug: Topotecan<br>* Given IV<br>* Other names: Topotecan Lactone;Procedure: Tumor Resection<br>* Undergo tumor resection surgery<br>Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;|
| Experimental: Arm B (Dinutuimab in induction)<br>See detailed description | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Bone Scan<br>* Undergo MIBG scan<br>* Other names: Bone Scintigraphy;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Dexrazoxane<br>* Given IV<br>* Other names: Soluble ICRF (L-isomer);Biological: Dinutuximab<br>* Given IV<br>* Other names: Unituxin;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Procedure: FDG-Positron Emission Tomography and Computed Tomography Scan<br>* Undergo FDG PET<br>* Other names: FDG PET/CT;Procedure: Hematopoietic Cell Transplantation<br>* Undergo stem cell infusion<br>* Other names: Stem Cell Transplantation, NOS;Drug: Irinotecan<br>* Given IV<br>Drug: Isotretinoin<br>* Given PO<br>* Other names: ZENATANE;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Other: Survey Administration<br>* Ancillary studies<br>Drug: Temozolomide<br>* Given PO or via NG or G tube<br>* Other names: TMZ;Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Drug: Topotecan<br>* Given IV<br>* Other names: Topotecan Lactone;Procedure: Tumor Resection<br>* Undergo tumor resection surgery<br>Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival (EFS) | An intent-to-treat log-rank test comparison of EFS starting from the time of randomization between the standard Children's Oncology Group (COG) induction therapy with or without extended Induction (arm A) and induction chemoimmunotherapy (arm B) with or without extended induction arms will be performed. A final analysis two-sided p-value <0.05 will indicate success. In addition, a sensitivity analysis will be performed consisting of a log-rank test comparison of EFS starting from the time of randomization between patients treated without dinutuximab during induction or extended induction (patients on arm A with GEIR) versus patients treated with dinutuximab during Induction (arm B) who do not receive extended induction. | From time of randomization to first episode of disease relapse or progression post-randomization, first occurrence of a second malignancy, or death, whichever occurs first, up to 12 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| End of induction (EOI) response rate | Will be evaluated per the 2017 revised International Neuroblastoma Response Criteria (INRC), with patients categorized as good end of induction response (GEIR) or poor end of induction response (PEIR) and also assigned standard INRC overall EOI response. Will be assessed with an intent-to-treat log-rank test comparison of overall survival (OS) starting from the time of randomization between the standard COG induction therapy with or without extended induction (arm A) and induction chemoimmunotherapy (arm B) with or without extended induction. Depending on the sample size, a chi-square or Fisher's exact test will be used to evaluate the difference in EOI response rates in these two arms. Response will be determined using both the revised INRC and GEIR/PEIR classification. | From randomization to end of extended induction | 
| Overall survival | Response rates at the end of extended Induction (defined as the last complete disease evaluation prior to consolidation or removal from protocol therapy), 3-year EFS with 95% confidence interval (CI), and 3-year OS with 95% CI will be calculated for arm A and arm B patients that receive an extended induction regimen with chemoimmunotherapy due to PD or a PEIR to Induction therapy. Response will be determined using both the revised INRC and GEIR/PEIR classification. | Time to death, up to 12 years | 
| Incidence of adverse events | Common terminology criteria for adverse events (CTCAE) version (v) 5.0 will be used to tabulate grade ≥ 3 non-hematologic and grade ≥ 4 hematologic toxicities. Will be compared with a Fisher's exact/chi-square test. In addition, the rates of grade ≥ 3 non-hematologic and grade ≥ 4 hematologic toxicities experienced during extended induction will be tabulated. | Up to 12 years | 
| GD2 expression | Dinutuximab binding to pre-therapy patient tumor samples will be measured and categorized as high or low. Will evaluate for an association between GD2 binding and event-free survival. | At baseline, end of induction, extended induction, post consolidation, relapse/progression and primary tumor resection |