Treatment With Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination With Irinotecan and Temozolomide After Intensive Therapy for People With High-Risk Neuroblastoma (NBL)

NCT ID: NCT04385277

Last Updated: 2025-10-27

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 41 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-12-31
• Study Completion Date: 2027-09-30

Brief Summary

This phase II trial studies if dinutuximab, GM-CSF, isotretinoin in combination with irinotecan, and temozolomide (chemo-immunotherapy) can be given safely to patients with high-risk neuroblastoma after Consolidation therapy (which usually consists of two autologous stem cell transplants and radiation) who have not experienced worsening or recurrence of their disease. Dinutuximab represents a kind of cancer therapy called immunotherapy. Unlike chemotherapy and radiation, dinutuximab targets the cancer cells without destroying nearby healthy cells. Sargramostim helps the body produce normal infection-fighting white blood cells. Isotretinoin helps the neuroblastoma cells become more mature. These 3 drugs (standard immunotherapy) are already given to patients with high-risk neuroblastoma after Consolidation because they have been proven to be beneficial in this setting. Chemotherapy drugs, such as irinotecan and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. They may also affect how well immunotherapy works on neuroblastoma cells. Giving chemo-immunotherapy after intensive therapy may work better in treating patients with high-risk neuroblastoma compared to standard immunotherapy.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the feasibility of administering dinutuximab, GM-CSF, and isotretinoin in combination with irinotecan and temozolomide in the frontline Post-Consolidation setting in patients with high-risk neuroblastoma who have undergone Induction and Consolidation therapy with tandem high-dose chemotherapy with stem cell rescue (ASCT).

SECONDARY OBJECTIVES:

I. To describe the toxicity profile of dinutuximab, GM-CSF, and isotretinoin in combination with irinotecan and temozolomide in the Post-Consolidation setting.

II. To describe the event-free survival and overall survival of patients who receive dinutuximab in combination with irinotecan and temozolomide, GM-CSF, and isotretinoin in the Post-Consolidation setting.

EXPLORATORY OBJECTIVES:

I. To describe the toxicity profiles associated with chemo-immunotherapy in the Post-Consolidation setting according to the type of prior therapy.

II. To describe response to chemo-immunotherapy in the Post-Consolidation setting using the revised International Neuroblastoma Risk Classification (INRC) in patients with evaluable or measurable disease at study entry.

III. To characterize immune and cytokine profiles in patients receiving Post-Consolidation chemo-immunotherapy.

IV. To bank serial blood samples to investigate the relationship between factors related to the tumor, host, and immune environment and clinical outcomes in patients treated with chemo-immunotherapy.

OUTLINE:

Patients receive temozolomide orally (PO) or via enteral tube daily and irinotecan intravenously (IV) over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim subcutaneously (SC) or IV over 2 hours daily on days 6-12, and isotretinoin PO twice daily (BID) on days 8-21. Patients undergo multigated acquisition scan (MUGA) during screening. Patients also undergo magnetic resonance imaging (MRI), or computed tomography (CT), iobenguane I-123 (123I-MIBG), or fludeoxyglucose F-18-positron emission tomography (FDG-PET), bone marrow (BM) aspiration, and BM biopsy on study. Treatment repeats every 28 days for up to 5 cycles (up to 6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity.

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.

Conditions

Ganglioneuroblastoma, Nodular; Neuroblastoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (temozolomide, irinotecan, dinutuximab)

Patients receive temozolomide PO or via enteral tube daily and irinotecan IV over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim SC or IV over 2 hours daily on days 6-12, and isotretinoin PO BID on days 8-21. Patients undergo MUGA during screening. Patients also undergo MRI, or CT, I23I-MIBG, or FDG-PET, BM aspiration, and BM biopsy on study. Treatment repeats every 28 days for up to 5 cycles (up to 6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Biospecimen Collection

Intervention Type: PROCEDURE

Correlative studies

Bone Marrow Aspiration

Intervention Type: PROCEDURE

Undergo BM aspiration

Bone Marrow Biopsy

Intervention Type: PROCEDURE

Undergo BM biopsy

Computed Tomography

Intervention Type: PROCEDURE

Undergo CT

Dinutuximab

Intervention Type: BIOLOGICAL

Given IV

FDG-Positron Emission Tomography

Intervention Type: PROCEDURE

Undergo FDG-PET

Iobenguane I-123

Intervention Type: RADIATION

Undergo 123I-MIBG

Irinotecan

Intervention Type: DRUG

Given IV

Isotretinoin

Intervention Type: DRUG

Given PO

Magnetic Resonance Imaging

Intervention Type: PROCEDURE

Undergo MRI

Multigated Acquisition Scan

Intervention Type: PROCEDURE

Undergo MUGA

Sargramostim

Intervention Type: BIOLOGICAL

Given SC or IV

Temozolomide

Intervention Type: DRUG

Given PO or via enteral tube

Interventions

Biospecimen Collection

Correlative studies

Intervention Type: PROCEDURE

Bone Marrow Aspiration

Undergo BM aspiration

Intervention Type: PROCEDURE

Bone Marrow Biopsy

Undergo BM biopsy

Intervention Type: PROCEDURE

Computed Tomography

Undergo CT

Intervention Type: PROCEDURE

Dinutuximab

Given IV

Intervention Type: BIOLOGICAL

FDG-Positron Emission Tomography

Undergo FDG-PET

Intervention Type: PROCEDURE

Iobenguane I-123

Undergo 123I-MIBG

Intervention Type: RADIATION

Irinotecan

Given IV

Intervention Type: DRUG

Isotretinoin

Given PO

Intervention Type: DRUG

Magnetic Resonance Imaging

Undergo MRI

Intervention Type: PROCEDURE

Multigated Acquisition Scan

Undergo MUGA

Intervention Type: PROCEDURE

Sargramostim

Given SC or IV

Intervention Type: BIOLOGICAL

Temozolomide

Given PO or via enteral tube

Intervention Type: DRUG

Other Intervention Names

Biological Sample Collection; Biospecimen Collected; Specimen Collection; Biopsy of Bone Marrow; Biopsy, Bone Marrow; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized axial tomography (procedure); Computerized Tomography; CT; CT Scan; tomography; Ch 14.18UTC; Ch14.18; Dinutuximab Beta; MOAB Ch14.18; monoclonal antibody Ch14.18; Qarziba; Unituxin; FDG; FDG-PET; FDG-PET Imaging; AdreView; iobenguane I 123; 13-cis retinoic acid; 13-cis-Retinoate; 13-cis-Retinoic Acid; 13-cis-Vitamin A Acid; 13-cRA; Absorica; Accure; Accutane; Amnesteem; cis-Retinoic Acid; Cistane; Claravis; Isotretinoinum; Isotrex; Isotrexin; Myorisan; Neovitamin A; Neovitamin A Acid; Oratane; Retinoicacid-13-cis; Ro 4-3780; Ro-4-3780; Roaccutan; Roaccutane; Roacutan; Sotret; ZENATANE; Magnetic Resonance; Magnetic resonance imaging (procedure); Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; Gated Heart Pool Scan; MUGA; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; 23-L-Leucinecolony-Stimulating Factor 2; DRG-0012; Leukine; Prokine; rhu GM-CFS; Sagramostim; Sargramostatin; CCRG-81045; Gliotem; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Methazolastone; RP-46161; SCH 52365; Temcad; Temizole; Temodal; Temodar; Temomedac; TMZ

Eligibility Criteria

Inclusion Criteria

• Patients must be < 31 years of age at the time of enrollment.
• 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 at the time of diagnosis) and have been designated as having high-risk disease based on Children's Oncology Group (COG) risk classification. The following disease groups are eligible:

• Patients with International Neuroblastoma Risk Group (INRG) Stage M disease with any of the following features:

• MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR
• Age > 547 days at the time of diagnosis regardless of biologic features; OR
• Age 365-547 days at the time of diagnosis with tumors with unfavorable histology and/or deoxyribonucleic acid (DNA) index = 1
• Patients with INRG Stage MS disease with MYCN amplification
• Patients with INRG Stage L2 disease with either of the following features:

• MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR
• Age > 547 days at the time of diagnosis with MYCN non-amplified tumors with unfavorable histology
• Note: Patients observed or patients 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 criteria will also be eligible
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years
• Prior therapy

• All patients must have completed high-risk Induction therapy with 4-6 cycles of chemotherapy
• After completion of Induction therapy, patients may have received no more than 4 cycles of bridging chemotherapy or chemo-immunotherapy prior to ASCT
• Patients cannot have previously progressed on immunotherapy with dinutuximab or other anti-GD2 monoclonal antibody
• All patients must have had undergone surgical resection of their primary tumor as part of frontline therapy. Exceptions to this requirement include patients who had a complete response to Induction chemotherapy, patients with no identifiable primary tumor, and patients for whom the institutional surgical team determined that potential risks outweighed potential benefits of resection
• All patients must have undergone tandem high-dose chemotherapy with ASCT as part of Consolidation
• Patients must enroll between day +56 and day +200 from the peripheral blood stem cell (PBSC) infusion following the last dose of high-dose chemotherapy during Consolidation
• All patients must have undergone external beam radiation therapy. Exceptions to this requirement include patients who had no identifiable primary tumor and no persistent metastatic disease at the end of Induction. For patients who received radiotherapy, at least 7 days must have elapsed between completion of radiotherapy and enrollment on this study
• Patients must not have received long-acting myeloid growth factors (e.g., Neulasta) within 14 days of entry on this study. Seven days must have elapsed since administration of a short-acting myeloid growth factor
• Peripheral absolute neutrophil count (ANC) >= 750/uL
• Platelet count >= 50,000/uL (transfusion independent for >= 7 days)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2, or a serum creatinine based on age/gender as follows:

• Age: Maximum Serum Creatinine (mg/dL)
• 6 months to < 1 year: 0.5 (male and female)
• 1 to < 2 years: 0.6 (male and female)
• 2 to < 6 years: 0.8 (male and female)
• 6 to < 10 years: 1 (male and female)
• 10 to < 13 years: 1.2 (male and female)
• 13 to < 16 years: 1.5 (male), 1.4 (female)
• >= 16 years: 1.7 (male), 1.4 (female)

• Note: Patients with history of transplant associated-thrombotic microangiopathy (TA-TMA) must have a creatinine clearance or radioisotope GFR at baseline to assess renal function and must meet the above criteria
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x ULN for age (=< 225 U/L)

• 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
• Absence of dyspnea at rest
• If pulmonary function tests (PFTs) are performed, forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) must be > 60%
• No clinical evidence of active central nervous system (CNS) disease at the time of study enrollment
• Patients with seizure disorder may be enrolled if on non-enzyme-inducing anticonvulsants and well controlled
• CNS toxicity from prior therapy =< grade 2

Exclusion Criteria

• Patients must not have had progressive disease (PD) per the revised International Neuroblastoma Risk Criteria (INRC) since the initial diagnosis of high-risk neuroblastoma

• Exception: Progressive disease within the first 2 cycles of Induction chemotherapy consisting of cyclophosphamide and topotecan is allowed. Patients with progression subsequent to initial cyclophosphamide and topotecan cycles are excluded
• Patients may not have received additional systemic cancer-directed therapy following completion of the last planned high-dose chemotherapy with ASCT prior to enrollment on this trial
• Patients may not have received iodine-131 (131I)-metaiodobenzylguanidine (MIBG) therapy at any time prior to enrollment on this trial
• Patients who received single (rather than tandem) high-dose chemotherapy with ASCT are excluded
• Patients cannot be receiving other ongoing anticancer therapy
• Patients who were enrolled onto ANBL1531 AND underwent arm assignment are not eligible. Patients who enrolled onto ANBL1531 who declined second consent may be eligible for ANBL19P1 if all other criteria are met
• Patients enrolled onto ANBL17P1 are not eligible
• Patients must have been off pharmacologic doses of systemic steroids for at least 7 days prior to enrollment
• Patients who require or are likely to require pharmacologic doses of systemic corticosteroids while receiving treatment on this study are ineligible. The only exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood product administration in order to avoid allergic transfusion reactions

• Note: The use of conventional doses of inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for patients with known adrenal insufficiency
• Patients on any other immunosuppressive medications (e.g., cyclosporine, tacrolimus) are not eligible. However, prior or planned concomitant treatment with eculizumab is permitted (e.g., treatment of TA-TMA)
• Patients must not have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study enrollment

• Note: Patients receiving non-enzyme inducing anticonvulsants such as gabapentin or levetiracetam are eligible
• Patients must not have received drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment
• Patients must not have been diagnosed with myelodysplastic syndrome or with any malignancy other than neuroblastoma
• Patients with symptoms of congestive heart failure are not eligible
• Patients with moderate or large pericardial effusions are not eligible
• Patients must not have >= grade 2 diarrhea
• Patients must not have uncontrolled infection
• Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or reactions that required discontinuation of the anti-GD2 therapy are not eligible
• 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 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

• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Children's Oncology Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ami V Desai

Role: PRINCIPAL_INVESTIGATOR

Children's Oncology Group

Locations

Banner Children's at Desert

Mesa, Arizona, United States

Arkansas Children's Hospital

Little Rock, Arkansas, United States

Kaiser Permanente Downey Medical Center

Downey, California, United States

Children's Hospital Los Angeles

Los Angeles, California, United States

Kaiser Permanente-Oakland

Oakland, California, United States

Children's Hospital of Orange County

Orange, California, United States

UCSF Medical Center-Mission Bay

San Francisco, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center

Denver, Colorado, United States

Connecticut Children's Medical Center

Hartford, Connecticut, United States

Alfred I duPont Hospital for Children

Wilmington, Delaware, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Golisano Children's Hospital of Southwest Florida

Fort Myers, Florida, United States

University of Florida Health Science Center - Gainesville

Gainesville, Florida, United States

Memorial Regional Hospital/Joe DiMaggio Children's Hospital

Hollywood, Florida, United States

Nemours Children's Clinic-Jacksonville

Jacksonville, Florida, United States

Nemours Children's Hospital

Orlando, Florida, United States

Children's Healthcare of Atlanta - Egleston

Atlanta, Georgia, United States

Saint Luke's Cancer Institute - Boise

Boise, Idaho, United States

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States

University of Illinois

Chicago, Illinois, United States

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, United States

Saint Jude Midwest Affiliate

Peoria, Illinois, United States

Riley Hospital for Children

Indianapolis, Indiana, United States

University of Iowa/Holden Comprehensive Cancer Center

Iowa City, Iowa, United States

Norton Children's Hospital

Louisville, Kentucky, United States

Ochsner Medical Center Jefferson

New Orleans, Louisiana, United States

Walter Reed National Military Medical Center

Bethesda, Maryland, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

C S Mott Children's Hospital

Ann Arbor, Michigan, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis

Minneapolis, Minnesota, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

Children's Mercy Hospitals and Clinics

Kansas City, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

Mercy Hospital Saint Louis

St Louis, Missouri, United States

Children's Hospital and Medical Center of Omaha

Omaha, Nebraska, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Morristown Medical Center

Morristown, New Jersey, United States

Albany Medical Center

Albany, New York, United States

NYU Winthrop Hospital

Mineola, New York, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York, United States

State University of New York Upstate Medical University

Syracuse, New York, United States

Montefiore Medical Center - Moses Campus

The Bronx, New York, United States

Carolinas Medical Center/Levine Cancer Institute

Charlotte, North Carolina, United States

Sanford Broadway Medical Center

Fargo, North Dakota, United States

Children's Hospital Medical Center of Akron

Akron, Ohio, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Rainbow Babies and Childrens Hospital

Cleveland, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Saint Christopher's Hospital for Children

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Saint Jude Children's Research Hospital

Memphis, Tennessee, United States

The Children's Hospital at TriStar Centennial

Nashville, Tennessee, United States

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, United States

Dell Children's Medical Center of Central Texas

Austin, Texas, United States

Medical City Dallas Hospital

Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas, United States

El Paso Children's Hospital

El Paso, Texas, United States

Cook Children's Medical Center

Fort Worth, Texas, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, United States

Covenant Children's Hospital

Lubbock, Texas, United States

UMC Cancer Center / UMC Health System

Lubbock, Texas, United States

Children's Hospital of San Antonio

San Antonio, Texas, United States

Methodist Children's Hospital of South Texas

San Antonio, Texas, United States

Primary Children's Hospital

Salt Lake City, Utah, United States

Children's Hospital of The King's Daughters

Norfolk, Virginia, United States

Seattle Children's Hospital

Seattle, Washington, United States

The Children's Hospital at Westmead

Westmead, New South Wales, Australia

Queensland Children's Hospital

South Brisbane, Queensland, Australia

Royal Children's Hospital

Parkville, Victoria, Australia

Perth Children's Hospital

Perth, Western Australia, Australia

IWK Health Centre

Halifax, Nova Scotia, Canada

Starship Children's Hospital

Grafton, Auckland, New Zealand

Christchurch Hospital

Christchurch, , New Zealand

Countries

United States; Australia; Canada; New Zealand

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2020-02950

Identifier Type: REGISTRY

Identifier Source: secondary_id

ANBL19P1

Identifier Type: OTHER

Identifier Source: secondary_id

ANBL19P1

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA180886

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ANBL19P1

Identifier Type: -

Identifier Source: org_study_id