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

Neuroblastoma Clinical Trial

Official title:

A Pilot Study of Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination With Irinotecan and Temozolomide in the Post-Consolidation Setting for High-Risk Neuroblastoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04385277
• Other study ID #: ANBL19P1
• Secondary ID: NCI-2020-02950AN
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 31, 2020
• Est. completion date: September 26, 2024

Study information

• Verified date: September 2023
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 34
• Est. completion date: September 26, 2024
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 30 Years

Eligibility

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

• Patients with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of study agents or to significantly increase the severity of the toxicities experienced from study treatment 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

Related Conditions & MeSH terms

• Ganglioneuroblastoma
• Ganglioneuroblastoma, Nodular
• Neuroblastoma

Intervention

Procedure:
• Biospecimen Collection
Correlative studies
• Bone Marrow Aspiration
Undergo BM aspiration
• Bone Marrow Biopsy
Undergo BM biopsy
• Computed Tomography
Undergo CT

Biological:
• Dinutuximab
Given IV

Procedure:
• FDG-Positron Emission Tomography
Undergo FDG-PET

Radiation:
• Iobenguane I-123
Undergo 123I-MIBG

Drug:
• Irinotecan
Given IV
• Isotretinoin
Given PO

Procedure:
• Magnetic Resonance Imaging
Undergo MRI
• Multigated Acquisition Scan
Undergo MUGA

Biological:
• Sargramostim
Given SC or IV

Drug:
• Temozolomide
Given PO or via enteral tube

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Parkville	Victoria
Australia	Perth Children's Hospital	Perth	Western Australia
Australia	Queensland Children's Hospital	South Brisbane	Queensland
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Canada	IWK Health Centre	Halifax	Nova Scotia
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Starship Children's Hospital	Grafton	Auckland
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
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	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	El Paso Children's Hospital	El Paso	Texas
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Covenant Children's Hospital	Lubbock	Texas
United States	UMC Cancer Center / UMC Health System	Lubbock	Texas
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Banner Children's at Desert	Mesa	Arizona
United States	NYU Winthrop Hospital	Mineola	New York
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	Morristown Medical Center	Morristown	New Jersey
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Kaiser Permanente-Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Nemours Children's Hospital	Orlando	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
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	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Primary Children's Hospital	Salt Lake City	Utah
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	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients who complete 5 cycles of dinutuximab + chemotherapy without progressive disease (PD)	Will be assessed by estimation of the feasibility therapy completion rate together with a 95% Wilson confidence interval (CI).	Within 30 weeks from the date of first treatment
Secondary	Event-free survival (EFS)	EFS Kaplan-Meier estimates will be generated.	From the time of start of protocol therapy to the occurrence of disease relapse or progression, secondary malignancy, or death, assessed up to 60 months
Secondary	Overall survival (OS)	OS Kaplan-Meier estimates will be generated.	From the time of start of protocol therapy to death, assessed up to 60 months