Dinutuximab, Sargramostim, and Combination Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- 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:
- 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:
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To describe the clinical relevance of naturally occurring anti-glycan antibodies in patients receiving ch14.18 (dinutuximab).
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To describe the clinical relevance of natural killer (NK) receptor NKp30 isoforms in patients receiving ch14.18 (dinutuximab).
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To describe the association between host factors, including human anti-chimeric antibodies (HACA), and response to protocol therapy.
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To describe the immune environment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) during and following treatment.
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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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT) See Detailed Description |
Procedure: Autologous Hematopoietic Stem Cell Transplantation
Undergo ASCT
Other Names:
Drug: Carboplatin
Given IV
Other Names:
Drug: Cisplatin
Given IV
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Dexrazoxane
Given IV
Other Names:
Biological: Dinutuximab
Given IV
Other Names:
Drug: Doxorubicin
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Radiation: External Beam Radiation Therapy
Undergo EBRT
Other Names:
Drug: Isotretinoin
Given PO
Other Names:
Drug: Melphalan
Given IV
Other Names:
Biological: Sargramostim
Given SC
Other Names:
Drug: Thiotepa
Given IV
Other Names:
Drug: Topotecan
Given IV
Other Names:
Drug: Vincristine
Given IV
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence of unacceptable toxicity [Up to the first 5 cycles of treatment]
Assessed with National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Will be assessed by estimation of the combined toxic death and unacceptable toxicity rate during Induction cycles 3-5 together with a 95% confidence interval.
- Proportion of patients who are feasibility "failure" [Up to the first 5 cycles of treatment]
Feasibility "failures" are defined as patients that do not receive >= 75% of the planned dinutuximab doses during Induction cycles 3-5. Will be assessed by estimation of the feasibility "failure" rate together with a 95% confidence interval.
Secondary Outcome Measures
- Response rate [Up to the first 5 cycles of treatment]
Response will be determined using the revised International Neuroblastoma Response Criteria. Response rate will be calculated as the percentage of eligible patients with at least a partial response (PR) or better at the end of Induction. Will be calculated, including placement of a 95% confidence interval on the response rate.
- Event-free survival [Up to 5 years]
Kaplan-Meier method will be used to estimate event-free survival (EFS). EFS is defined as the time from study enrollment to the occurrence of disease relapse or progression, secondary malignancy, or death.
- Overall survival [Up to 5 years]
Kaplan-Meier method will be used to estimate overall survival (OS). OS is defined as the time from study enrollment to death.
Other Outcome Measures
- Incidence of naturally occurring anti-glycan antibodies [Up to 5 years]
Will be calculated, including placement of a 95% CI on the incidence. In addition, anti-glycan levels prior to the start of Induction therapy and prior to the start of post-Consolidation therapy will be compared with Wilcoxon's signed-rank test for paired data.
- Incidence of natural killer (NK) receptor NKp30 isoforms [Up to 5 years]
Will be assessed by calculating the incidence of NK receptor NKp30 isoforms, including placement of a 95% CI on the incidence.
- Response of host factors, including naturally occurring anti-glycan antibodies, KIR/KIR-L genotyping, Fc receptor genotyping, human anti-chimeric antibodies (HACA) [Up to 5 years]
Will be explored with Fisher's exact test for categorical and Wilcoxon rank-sum test for continuous host factors. Both the presence/absence and level of naturally occurring anti-glycan antibodies will be considered. For the KIR/KIR-L analysis, patients will be categorized as either matched or mismatched. Patients will be grouped into one of the three genotype subgroups of Fc receptor genotyping for that analysis. The presence/absence of HACA, anti-idiotype, and pretreatment anti-therapeutic antibodies (PATA)/anti-allotype antibody will be considered for the HACA analysis.
- Immune environment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) [Up to 5 years]
The incidence of NK receptor NKp30 isoforms will be calculated, including placement of a 95% CI on each incidence rate. Summary statistics will also be generated for serum cytokine (IL6, CXCL9) levels and gene expression of circulating immune function cells.
- Levels of circulating GD2 and tumor cell GD2 expression [Up to 5 years]
Will be assessed by exploring the relationship between response to treatment with > PR (response vs. non- response) with circulating GD2 levels, and GD2 tumor cell expression following therapy with a Wilcoxon rank-sum test. Changes from baseline will also be analyzed.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients must be enrolled on ANBL00B1 or APEC14B1 prior to enrollment on ANBL17P1.
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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:
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Patients with International Neuroblastoma Risk Group (INRG) stage M disease are eligible if found to have either of the following features:
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MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features; OR
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Age > 547 days regardless of biologic features;
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Patients with INRG stage MS disease with MYCN amplification
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Patients with INRG stage L2 disease with MYCN amplification
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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.
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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.
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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)
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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).
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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).
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Shortening fraction of >= 27% by echocardiogram (within 7 days prior to enrollment).
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Ejection fraction of >= 50% by echocardiogram or radionuclide angiogram (within 7 days prior to enrollment).
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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.
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All patients and/or their parents or legal guardians must sign a written informed consent.
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All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
Exclusion Criteria:
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Patients >18 months of age with INRG stage L2, MYCN non-amplified, regardless of additional biologic features.
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Patients with bone marrow failure syndromes.
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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.
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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.
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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.
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Lactating females who plan to breastfeed their infants.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital Los Angeles | Los Angeles | California | United States | 90027 |
| 2 | Children's National Medical Center | Washington | District of Columbia | United States | 20010 |
| 3 | Dana-Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
| 4 | NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center | New York | New York | United States | 10032 |
| 5 | Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania | United States | 15224 |
| 6 | Saint Jude Children's Research Hospital | Memphis | Tennessee | United States | 38105 |
| 7 | Primary Children's Hospital | Salt Lake City | Utah | United States | 84113 |
| 8 | The Children's Hospital at Westmead | Westmead | New South Wales | Australia | 2145 |
| 9 | Royal Children's Hospital | Parkville | Victoria | Australia | 3052 |
| 10 | Starship Children's Hospital | Grafton | Auckland | New Zealand | 1145 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Sara M Federico, Children's Oncology Group
Study Documents (Full-Text)
More Information
Publications
None provided.- NCI-2018-03732
- NCI-2018-03732
- ANBL17P1
- ANBL17P1
- U10CA180886