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

Phase 2

Active, not recruiting

• Conditions: Ganglioneuroblastoma; High Risk Neuroblastoma
• Interventions: 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

• Registration Number: NCT03786783
• Lead Sponsor: National Cancer Institute (NCI)

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. Sargramo...

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:
...

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2018-12-24
• Study First Submitted QC: 2018-12-24
• Study First Posted: 2018-12-26
• Study Start: 2019-03-04
• Primary Completion: 2021-12-31
• Results First Submitted: 2022-12-16
• Results First Submitted QC: 2023-02-14
• Results First Posted: 2023-03-14
• Status Verified: 2024-09
• Last Update Submitted: 2024-09-21
• Last Update Posted: 2024-10-17
• Study Completion: 2025-09-22

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 42

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Thiotepa	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	External Beam Radiation Therapy	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Etoposide	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Isotretinoin	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Autologous Hematopoietic Stem Cell Transplantation	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Dinutuximab	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Melphalan	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Carboplatin	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Dexrazoxane	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Sargramostim	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Topotecan	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Cisplatin	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Cyclophosphamide	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Doxorubicin	See Detailed Description
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)	Vincristine	See Detailed Description

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 neu...
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 immunohist...
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.

Trial Locations

Locations (10)

Saint Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States

Starship Children's Hospital; 🇳🇿 Grafton, Auckland, New Zealand

The Children's Hospital at Westmead; 🇦🇺 Westmead, New South Wales, Australia

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

Children's Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center; 🇺🇸 New York, New York, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

Royal Children's Hospital; 🇦🇺 Parkville, Victoria, Australia

Primary Children's Hospital; 🇺🇸 Salt Lake City, Utah, United States