Ganglioneuroblastoma, High Risk Neuroblastoma
Conditions
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.
Detailed description
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.
Interventions
BIOLOGICALDinutuximab
Given IV
DRUGDoxorubicin
Given IV
DRUGEtoposide
Given IV
RADIATIONExternal Beam Radiation Therapy
Undergo EBRT
DRUGDexrazoxane
Given IV
PROCEDUREAutologous Hematopoietic Stem Cell Transplantation
Undergo ASCT
DRUGCarboplatin
Given IV
DRUGCisplatin
Given IV
DRUGCyclophosphamide
Given IV
DRUGIsotretinoin
Given PO
DRUGMelphalan
Given IV
BIOLOGICALSargramostim
Given SC
DRUGThiotepa
Given IV
DRUGTopotecan
Given IV
DRUGVincristine
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Unacceptable Toxicity | Up to the first 5 cycles of treatment | 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. |
| Percentage of Participants Who Are Feasibility Failure | Up to the first 5 cycles of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | Up to the first 5 cycles of treatment | 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. |
| Event-free Survival | Up to 1 year | 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. |
| Overall Survival | Up to 1 year | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Naturally Occurring Anti-glycan Antibodies | Up to 5 years | The Incidence of Naturally Occurring Anti-glycan Antibodies was 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 was compared with Wilcoxon's signed-rank test for paired data. |
| 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 | 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 was considered. For the KIR/KIR-L analysis, patients were categorized as either matched or mismatched. Patients were 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 was considered for the HACA analysis. |
| Incidence of Natural Killer (NK) Receptor NKp30 Isoforms | Up to 5 years | Assessed by calculating the incidence of NK receptor NKp30 isoforms, including placement of a 95% CI on the incidence. |
| 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 was calculated, including placement of a 95% CI on each incidence rate. Summary statistics were 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 | 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 were also analyzed. |
Countries
Australia, New Zealand, United States
Participant flow
Recruitment details
Patients with newly diagnosed high-risk Neuroblastoma enrolled between 1/14/2019 and 9/4/2020 across 10 institutions.
Participants by arm
| Arm | Count |
|---|---|
| Treatment(Chemotherapy, Dinutuximab, Sargramostim, ASCT, EBRT) Patients receive 5 cycles of Induction chemotherapy including cyclophosphamide, topotecan, cisplatin, etoposide, dinutuximab, sargramostim, vincristine, and doxorubicin. Patients may undergo surgery after Cycle 4 or 5 of Induction at the discretion of treating doctor. Patients with stable disease or better tumor response at end of Induction proceed to Consolidation. Consolidation treatment begins between 4-6 weeks from the start date of Induction cycle 5. For patients who have surgical resection delayed until after Induction cycle 5, Consolidation starts within 4 weeks from the date of surgery. Patients then undergo 2 cycles of Consolidation including thiotepa, cyclophosphamide, melphalan, etoposide, and carboplatin, followed by Radiation therapy beginning 42-80 days following Consolidation Cycle #2. Patients then receive 6 cycles of post-Consolidation therapy starting at least 1 week following radiation therapy, including sargramostim, dinutuximab, and isotretinoin. | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Disease Progression | 7 |
| Overall Study | Patient/Parent Refusal | 4 |
| Overall Study | Physician Decision | 6 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Treatment(Chemotherapy, Dinutuximab, Sargramostim, ASCT, EBRT) |
|---|---|
| Age, Categorical <=18 years | 42 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 3.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment Australia | 7 participants |
| Region of Enrollment New Zealand | 5 participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 42 |
| other Total, other adverse events | 42 / 42 |
| serious Total, serious adverse events | 14 / 42 |
Outcome results
Primary
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.
Time frame: Up to the first 5 cycles of treatment
Population: All eligible patients who received at least one dose of ch14.18 (dinutuximab) during Induction cycles
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment(Chemotherapy, Dinutuximab, Sargramostim, ASCT, EBRT) | Percentage of Participants Who Are Feasibility Failure | 0.0 Percentage of patients |
Primary
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.
Time frame: Up to the first 5 cycles of treatment
Population: All eligible patients who received at least one dose of ch14.18 (dinutuximab) during Induction cycles
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment(Chemotherapy, Dinutuximab, Sargramostim, ASCT, EBRT) | Percentage of Participants With Unacceptable Toxicity | 0.0 percentage of patients |
Secondary
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.
Time frame: Up to 1 year
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment(Chemotherapy, Dinutuximab, Sargramostim, ASCT, EBRT) | Event-free Survival | 82.6 Percent Probability |
Secondary
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.
Time frame: Up to 1 year
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment(Chemotherapy, Dinutuximab, Sargramostim, ASCT, EBRT) | Overall Survival | 95.0 Percent Probability |
Secondary
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.
Time frame: Up to the first 5 cycles of treatment
Population: All eligible patients. Institutional assessment of end-induction response has been used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment(Chemotherapy, Dinutuximab, Sargramostim, ASCT, EBRT) | Response Rate | 78.6 Percentage of patients |
Other Pre-specified
Immune Environment (Gene Expression; Immune Effector Cells, Activities and Signaling Molecules; Immune Target Expression)
The incidence of NK receptor NKp30 isoforms was calculated, including placement of a 95% CI on each incidence rate. Summary statistics were generated for serum cytokine (IL6, CXCL9) levels and gene expression of circulating immune function cells.
Time frame: Up to 5 years
Other Pre-specified
Incidence of Natural Killer (NK) Receptor NKp30 Isoforms
Assessed by calculating the incidence of NK receptor NKp30 isoforms, including placement of a 95% CI on the incidence.
Time frame: Up to 5 years
Other Pre-specified
Incidence of Naturally Occurring Anti-glycan Antibodies
The Incidence of Naturally Occurring Anti-glycan Antibodies was 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 was compared with Wilcoxon's signed-rank test for paired data.
Time frame: Up to 5 years
Other Pre-specified
Levels of Circulating GD2 and Tumor Cell GD2 Expression
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 were also analyzed.
Time frame: Up to 5 years
Other Pre-specified
Response of Host Factors, Including Naturally Occurring Anti-glycan Antibodies, KIR/KIR-L Genotyping, Fc Receptor Genotyping, Human Anti-chimeric Antibodies (HACA)
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 was considered. For the KIR/KIR-L analysis, patients were categorized as either matched or mismatched. Patients were 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 was considered for the HACA analysis.
Time frame: Up to 5 years