Dinutuximab, Sargramostim, and Combination Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma

Study Overview
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Brief Summary
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This phase II pilot trial studies the side effects and how well dinutuximab and sargramostim work when combined with chemotherapy in patients with high-risk neuroblastoma. Immunotherapy with monoclonal antibodies, such as dinutuximab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Sargramostim helps the body produce normal infection-fighting white blood cells. These cells also help the dinutuximab work better. Giving chemotherapy before a stem cell transplant, with drugs such as cisplatin, etoposide, vincristine, doxorubicin, cyclophosphamide, thiotepa, melphalan, etoposide, carboplatin, topotecan, and isotretinoin, helps kill cancer cells that are in the body and helps make room in a patient's bone marrow for new blood-forming cells (stem cells). Giving dinutuximab and sargramostim with combination chemotherapy may work better than combination chemotherapy alone in treating patients with high-risk neuroblastoma.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess the feasibility and tolerability of administering ch14.18 (dinutuximab) and sargramostim (GM-CSF) in combination with a multi-agent chemotherapy regimen during cycles 3-5 of the Induction phase for patients with newly-diagnosed high-risk neuroblastoma. SECONDARY OBJECTIVE: I. To describe the response rates, event-free survival (EFS) and overall survival (OS) for patients receiving the combination of standard Induction chemotherapy and ch14.18 (dinutuximab) followed by tandem transplant, radiation therapy, and post-consolidation immunotherapy. EXPLORATORY OBJECTIVES: I. To describe the clinical relevance of naturally occurring anti-glycan antibodies in patients receiving ch14.18 (dinutuximab). II. To describe the clinical relevance of natural killer (NK) receptor NKp30 isoforms in patients receiving ch14.18 (dinutuximab). III. To describe the association between host factors, including human anti-chimeric antibodies (HACA), and response to protocol therapy. IV. To describe the immune environment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) during and following treatment. V. To describe the association between levels of circulating GD2, and tumor cell GD2 expression with response to therapy. OUTLINE: INDUCTION CYCLES 1-2 (21 days): Patients receive cyclophosphamide intravenously (IV) over 15-30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity. INDUCTION CYCLE 3: Patients receive cisplatin IV over 1 hour on days 1-3, etoposide IV over 2 hours on days 1-3, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim subcutaneously (SC) on day 6 or 7 of a 21-day cycle. INDUCTION CYCLE 4: Patients receive vincristine IV over 1 minute on day 1, doxorubicin IV over 1-15 minutes on days 1-2, cyclophosphamide IV over 1 hour on days 1-2, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC on day 6 or 7 of a 21-day cycle. INDUCTION CYCLE 5: Patients receive cisplatin IV over 1 hour on days 1-3, etoposide IV over 2 hours on days 1-3, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC on day 6 or 7 of a 21-day cycle. Patients may undergo surgery after the fourth or fifth cycle of Induction at the discretion of treating doctor. Patients with stable disease or better tumor response at the end of Induction proceed to Consolidation. Consolidation treatment begins between 4 and 6 weeks from the start date of Induction chemotherapy cycle 5. For patients who have surgical resection delayed until after Induction chemotherapy cycle 5, Consolidation starts within 4 weeks from the date of surgery. CONSOLIDATION #1: 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 undergo autologous stem cell transplant (ASCT) on day 0. CONSOLIDATION #2: Patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide IV over 24 hours on days -7 to -4, and carboplatin IV over 24 hours on days -7 to -4. Patients then undergo ASCT on day 0. RADIATION THERAPY: Beginning 42-80 days following Consolidation #2, patients receive external beam radiation therapy (EBRT) daily for up to 20 days. Patients then receive post-Consolidation therapy starting at least 1 week following radiation therapy. POST-CONSOLIDATION CYCLES 1-5: Patients receive sargramostim SC on days 1-14, dinutuximab IV over 10-20 hours on days 4-7, and isotretinoin orally (PO) twice daily (BID) on days 11-24. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. POST-CONSOLIDATION CYCLE 6: Patients receive isotretinoin PO BID on days 15-28 of a 28-day cycle. After completion of study treatment, patients are followed up at months 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 54, and 60.

Official Title
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A Pilot Induction Regimen Incorporating Chimeric 14.18 Antibody (ch14.18, Dinutuximab) (NSC# 764038) and Sargramostim (GM-CSF) for the Treatment of Newly Diagnosed High-Risk Neuroblastoma

Conditions
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Ganglioneuroblastoma, High Risk Neuroblastoma

Intervention / Treatment
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* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Cyclophosphamide
* Drug: Dexrazoxane
* Biological: Dinutuximab
* Drug: Doxorubicin
* Drug: Etoposide
* Radiation: External Beam Radiation Therapy
* Drug: Isotretinoin
* Drug: Melphalan
* Biological: Sargramostim
* Drug: Thiotepa
* Drug: Topotecan
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be enrolled on ANBL00B1 or APEC14B1 prior to enrollment on ANBL17P1. 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. The following disease groups are eligible: Patients with International Neuroblastoma Risk Group (INRG) stage M disease are eligible if found to have either of the following features: MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features; OR Age > 547 days regardless of biologic features; Patients with INRG stage MS disease with MYCN amplification Patients with INRG stage L2 disease with MYCN amplification Patients > 547 days of age initially diagnosed with INRG stage L1, L2 or MS disease who progress to stage M without prior chemotherapy may enroll within 4 weeks of progression to stage M. Patients >= 365 days of age initially diagnosed with MYCN amplified INRG stage L1 disease who progress to stage M without systemic therapy may enroll within 4 weeks of progression to stage M. Patients initially recognized to have high-risk disease must have had no prior systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing as described). Patients observed or 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 the criteria will also be eligible. Patients who receive localized emergency radiation to sites of life-threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis will be eligible. Creatinine clearance (CrCl) or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/sex as follows: Age 1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL) Age 6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL) Age 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL) Age 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL) Age 6 to < 10 years (male 1 mg/dL, female 1 mg/dL) Age 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL) Age 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL) Age >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL) (within 7 days prior to enrollment). Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment). Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN. For the purposes of this study, ULN for ALT is 45 IU/L (within 7 days prior to enrollment). Shortening fraction of >= 27% by echocardiogram (within 7 days prior to enrollment). Ejection fraction of >= 50% by echocardiogram or radionuclide angiogram (within 7 days prior to enrollment). No known contraindication to peripheral blood stem cell (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. 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. Exclusion Criteria: Patients >18 months of age with INRG stage L2, MYCN non-amplified, regardless of additional biologic features. Patients with bone marrow failure syndromes. Patients that are >= 12 and =< 18 months of age with INRG stage M and all 3 favorable biologic features (i.e., non-amplified MYCN, favorable pathology, and deoxyribonucleic acid [DNA] index > 1) are not eligible. Patients on immunosuppressive medications (e.g. tacrolimus, cyclosporine, corticosteroids for reasons other than prevention/treatment of allergic reactions, adrenal replacement therapy, etc.) are not eligible. Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required 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 during study therapy and for two months after the last dose of ch14.18 (dinutuximab) are not eligible.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)<br>See Detailed Description | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo ASCT<br>* Other names: Stem Cell Transplantation, Autologous;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;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;Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: Teletherapy Radiation;Drug: Isotretinoin<br>* Given PO<br>* Other names: ZENATANE;Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Drug: Topotecan<br>* Given IV<br>* Other names: Topotecan Lactone;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 |
| --- | --- | --- |
| Percentage of Participants With Unacceptable Toxicity | Assessed with National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Assessed by estimation of the combined toxic death and unacceptable toxicity rate during Induction cycles 3-5 together with a 95% confidence interval. | Up to the first 5 cycles of treatment | 
| Percentage of Participants Who Are Feasibility Failure | Feasibility failures were defined as patients that did not receive >= 75% of the planned dinutuximab doses during Induction cycles 3-5. Assessed by estimation of the feasibility failure rate together with a 95% confidence interval. | Up to the first 5 cycles of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Per the revised INRC, response is comprised by responses in 3 components: primary tumor, soft tissue and bone metastases, and bone marrow. Primary and metastatic soft tissue sites were assessed using Response Evaluation Criteria in Solid Tumors and MIBG scans or FDG-PET scans if the tumor was MIBG non-avid. Bone marrow was assessed by histology or immunohistochemistry and cytology or immunocytology. Complete response (CR) - All components meet criteria for CR. Partial response (PR) - PR in at least one component and all other components are either CR, minimal disease (in bone marrow), PR (soft tissue or bone) or not involved (NI; no component with progressive disease (PD). Minor response (MR) - PR or CR in at least one component but at least one other component with stable disease; no component with PD. Stable disease (SD) - Stable disease in one component with no better than SD or NI in any other component; no component with PD. Progressive disease (PD) - Any component with PD. | Up to the first 5 cycles of treatment | 
| Event-free Survival | Per the revised INRC, progressive disease is: 1) > 20% increase in the longest diameter of the primary tumor, taking as reference the smallest sum and ¬> increase of 5 mm in longest dimension, 2) Any new soft tissue lesion detected by CT/MRI that is MIBG avid or FDG-PET avid, 3) Any new soft tissue lesion seen on CT/MRI that is biopsied and found to be neuroblastoma or ganglioneuroblastoma, 4) Any new bone site that is MIBG avid, 5) Any new bone site that is FDG-PET avid and has CT/MRI findings of tumor or is histologically neuroblastoma or ganglioneuroblastoma 6) A metastatic soft tissue site with > 20% increase in longest diameter, taking as reference the smallest sum on study, and with > 5mm in sum of diameters of target soft tissue lesions, 7) A relative MIBG score ¬> 1.2, 8) Bone marrow without tumor infiltration that becomes >5% tumor infiltration, 9) Bone marrow with tumor infiltration that increases by > 2-fold and has > 20% tumor infiltration on reassessment. | Up to 1 year | 
| Overall Survival | Kaplan-Meier method was used to estimate overall survival (OS). OS was defined as the time from study enrollment to death. 1-year OS is provided. | Up to 1 year |