Irinotecan Hydrochloride and Temozolomide With Temsirolimus or Dinutuximab in Treating Younger Patients With Refractory or Relapsed Neuroblastoma

Recurrent Neuroblastoma Clinical Trial

Official title:

A Phase II Randomized Trial of Irinotecan/Temozolomide With Temsirolimus (NSC# 683864) or Chimeric 14.18 Antibody (Ch14.18) (NSC# 764038) in Children With Refractory, Relapsed or Progressive Neuroblastoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01767194
• Other study ID #: NCI-2012-03125
• Secondary ID: NCI-2012-03125CD
• Status: Completed
• Phase: Phase 2
• Start date: February 12, 2013
• Est. completion date: September 30, 2022

Study information

• Verified date: October 2022
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase II trial studies how well irinotecan hydrochloride and temozolomide with temsirolimus or dinutuximab work in treating younger patients with neuroblastoma that has returned or does not respond to treatment. Drugs used in chemotherapy, such as irinotecan hydrochloride 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. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as dinutuximab, may find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving irinotecan hydrochloride and temozolomide together with temsirolimus or dinutuximab is more effective in treating neuroblastoma.

Description:

PRIMARY OBJECTIVES: I. To identify whether temsirolimus or ch14.18 (dinutuximab) is the optimal therapeutic agent to consider for further testing in a future Phase III randomized trial for treatment of newly diagnosed high-risk neuroblastoma. II. To determine the response rate of patients with relapsed, refractory or progressive neuroblastoma following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab) and to compare this with the known response rate of patients treated with irinotecan and temozolomide alone. EXPLORATORY OBJECTIVES: I. To compare the response rates (RR) for patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan (irinotecan hydrochloride) and temozolomide. II. To compare the progression free survival (PFS) and overall survival (OS) rates for patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan and temozolomide. III. To compare the toxicities associated with temsirolimus or ch14.18 (dinutuximab) when combined with irinotecan and temozolomide in patients with refractory, relapsed or progressive neuroblastoma. IV. To compare the ability to maintain intended dose intensity of all agents when temsirolimus or ch14.18 (dinutuximab) is combined with irinotecan and temozolomide in patients with refractory, relapsed or progressive neuroblastoma. V. To determine the concordance between tumor responses as defined by standard International Neuroblastoma Response Criteria (INRC) versus response per the revised INRC. VI. To study the clinical relevance of naturally occurring anti-glycan antibodies in patients receiving ch14.18 (dinutuximab) antibody. VII. To study the clinical relevance of natural killer (NK) receptor natural cytotoxicity triggering receptor 3 (NKp30) isoforms in patients receiving ch14.18 (dinutuximab) antibody or temsirolimus. VIII. To study the association between host factors and response to irinotecan, temozolomide and ch14.18 (dinutuximab). IX. To characterize the tumor immune-microenvironment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab). X. To study the association between changes in the tumor immune-microenvironment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) with response following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab). XI. To study the association between tumor genomic and transcriptomic aberrations as well as levels of circulating ganglioside (GD2) with response to irinotecan, temozolomide and ch14.18 (dinutuximab). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I (CLOSED TO ACCRUAL 06/17/2016): Patients receive temozolomide orally (PO) on days 1-5, irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. ARM II: Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim subcutaneously (SC) or IV over 2 hours on days 6-12. In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 73
• Est. completion date: September 30, 2022
• Est. primary completion date: June 30, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Patients must have had histologic verification of neuroblastoma or ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with elevated urinary catecholamines (i.e., > 2 x upper limit of normal [ULN]), at the time of initial diagnosis
• For the purposes of this study, aggressive multidrug chemotherapy is defined as chemotherapy including 2 or more agents that must include an alkylating agent and a

platinum-containing compound; patients must have ONE of the following:

• First episode of recurrent disease following completion of aggressive multi-drug frontline therapy
• First episode of progressive disease during aggressive multi-drug frontline therapy
• Primary resistant/refractory disease (less than partial response by INRC) detected at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (examples include A3973, ANBL0532, ANBL09P1, etc.)
• Patients must have at least ONE of the following:
• Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT) scan obtained within 3 weeks prior to study entry; measurable is defined as >= 10 mm in at least one dimension on spiral/helical CT that is metaiodobenzylguanidine (MIBG) avid or demonstrates increased fludeoxyglucose (FDG) uptake on positron emission tomography (PET) scan
• MIBG scan obtained within 3 weeks prior to study entry with positive uptake at a minimum of one site; this site must represent disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction
• Patients with resistant/refractory soft tissue disease that is not MIBG avid or does not demonstrate increased FDG uptake on PET scan must undergo biopsy to document the presence of viable neuroblastoma; biopsy is not required for patients who have new site of soft tissue disease (radiographic evidence of disease progression) regardless of whether progression occurs while receiving therapy or after completion of therapy
• Note: Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow disease only are NOT eligible for this study
• 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 of age
• Patients must have received frontline therapy (including surgery, chemotherapy, autologous stem cell transplant [SCT] +/- MIBG, immunotherapy, radiotherapy, and retinoids) but may NOT have received second line chemotherapy for resistant/refractory, relapsed disease or progressive disease
• At least 14 days must have elapsed since completion of myelosuppressive therapy
• At least 7 days must have elapsed since the completion of therapy with a non-myelosuppressive biologic agent or retinoid
• No interim time prior to study entry is required following prior radiation therapy (RT) for non-target lesions; however, patients must not have received radiation for a minimum of 4 weeks prior to study entry at the site of any lesion that will be identified as a target lesion to measure tumor response; lesions that have been previously radiated cannot be used as target lesions unless there is radiographic evidence of progression at the site following radiation or a biopsy done following radiation shows viable neuroblastoma; palliative radiation is allowed to sites that will not be used to measure response during this study
• Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell infusions as long as hematologic and other eligibility criteria have been met
• Patients are eligible >= 6 weeks after therapeutic 131I-MIBG provided that all other eligibility criteria are met
• Subjects who have previously received anti-GD2 monoclonal antibodies for biologic therapy or for tumor imaging are eligible unless they have had progressive disease while receiving prior anti-GD2 therapy; subjects who have received autologous marrow infusions or autologous stem cell infusions that were purged using monoclonal antibody linked to beads, but no other form of anti-GD2 monoclonal antibody, are eligible
• 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 >= 75,000/uL (transfusion independent)
• Patients known to have bone marrow involvement with neuroblastoma are eligible provided that minimum ANC and platelet count criteria are met but are not evaluable for hematological toxicity
• Creatinine clearance or estimated radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or
• A serum creatinine =< upper limit of normal (ULN) based on age/gender as follows:
• Age 1 month to < 6 months: 0.4 for males, 0.4 for females
• Age 6 months to < 1 year: 0.5 for males, 0.5 for females
• Age 1 to < 2 years: 0.6 for males, 0.6 for females
• Age 2 to < 6 years: 0.8 for males, 0.8 for females
• Age 6 to < 10 years: 1 for males, 1 for females
• Age 10 to < 13 years: 1.2 for males, 1.2 for females
• Age 13 to < 16 years: 1.5 for males, 1.4 for females
• Age >= 16 years: 1.7 for males, 1.4 for females
• Total bilirubin =< 1.5 x ULN for age AND
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x ULN for age (=< 225 U/L); for the purpose of this study, the ULN for SGPT is 45 U/L
• Adequate central nervous system function defined as:
• Patients with a history of central nervous system (CNS) disease must have no clinical or radiological evidence of CNS disease at the time of study enrollment
• Patients with seizure disorders may be enrolled if seizures are well controlled on anticonvulsants
• CNS toxicity =< grade 2
• Shortening fraction of >= 27% by echocardiogram (ECHO) OR
• Ejection fraction >= 50% by ECHO or gated radionuclide study
• Adequate coagulation defined as:
• Prothrombin time (PT) =< 1.2 x upper limit of normal
• Adequate pulmonary function defined as:
• No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen requirement, and room air pulse oximetry > 94% if there is a clinical indication for pulse oximetry; normal pulmonary function tests in patients who are capable of cooperating with testing (including diffusion capacity of the lung of carbon monoxide [DLCO]) are required if there is a clinical indication for determination; for patients who do not have respiratory symptoms, full pulmonary function tests (PFTs) are NOT required

Exclusion Criteria:

• Men and women of childbearing potential and their partners must agree to use adequate contraception while enrolled on this study; based on the established teratogenic potential of alkylating agents, pregnant women will be excluded from this study; female patients who are lactating must agree to stop breastfeeding or will otherwise be excluded from this study; females of childbearing potential must have a negative pregnancy test to be eligible for this study
• Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow disease only are NOT eligible for this study
• 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; 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 must not have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study enrollment; patients receiving non-enzyme inducing anticonvulsants such as gabapentin or levetiracetam will be eligible
• 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 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

Related Conditions & MeSH terms

• Ganglioneuroblastoma
• Neuroblastoma
• Recurrent Neuroblastoma

Intervention

Biological:
• Dinutuximab
Given IV

Drug:
• Irinotecan Hydrochloride
Given IV

Other:
• Laboratory Biomarker Analysis
Optional correlative studies

Biological:
• Sargramostim
Given SC or IV

Drug:
• Temozolomide
Given PO
• Temsirolimus
Given IV

Locations

Country	Name	City	State
Australia	Royal Children's Hospital-Brisbane	Herston	Queensland
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	Queensland Children's Hospital	South Brisbane	Queensland
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Children's Hospital	London	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Centre Hospitalier Universitaire de Quebec	Quebec
Canada	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Starship Children's Hospital	Grafton	Auckland
Puerto Rico	San Jorge Children's Hospital	San Juan
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Mission Hospital	Asheville	North Carolina
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	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
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	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
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	Prisma Health Richland Hospital	Columbia	South Carolina
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	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Lee Memorial Health System	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	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
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	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Nevada Cancer Research Foundation NCORP	Las Vegas	Nevada
United States	Summerlin Hospital Medical Center	Las Vegas	Nevada
United States	Sunrise Hospital and Medical Center	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
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	Valley Children's Hospital	Madera	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Nicklaus Children's Hospital	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	NYU Winthrop Hospital	Mineola	New York
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	West Virginia University Healthcare	Morgantown	West Virginia
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	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
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	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois
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	AdventHealth Orlando	Orlando	Florida
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Nemours Children's Clinic - Pensacola	Pensacola	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	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
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	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Saint Mary's Hospital	West Palm Beach	Florida
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	United Therapeutics

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Progression-free Survival	Kaplan-Meier method will be used to estimate progression-free survival. Progression-free survival will be defined as the time from enrollment to relapse, progressive disease, or death attributable to tumor or treatment.	Up to 3 years
Other	Overall Survival	Kaplan-Meier method will be used to estimate overall survival. Overall survival is defined as the time from enrollment on the study until death.	Up to 3 years
Other	Occurrence of Unacceptable Toxicities	The proportion of patients with at least one grade 3 or higher toxicity, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.	Up to 1 year
Other	Ability to Maintain Intended Treatment Without a Dose Reduction or Going Off Protocol Therapy for Toxicity	The proportion of patients who required a dose modification or went off protocol therapy for toxicity will be calculated for each treatment group.	Up to 1 year
Other	Overall Response	The proportion of patients achieving each type of overall response (complete response, partial response, stable disease, progressive disease) will be calculated according to the International Neuroblastoma Response Criteria (INRC).	Up to the first 6 cycles of treatment
Primary	Percentage of Randomized Patients Who Are Responders	The percentage of patients who are responders will be tabulated, including a 95% confidence interval on the response rate. Responders are defined as patients who achieve a best overall response of complete response (CR), very good partial response (VGPR), or partial response (PR) per the International Neuroblastoma Response Criteria (INRC). Per INRC: CR= Disappearance of all target lesions. No evidence of tumor at any site; VGPR= >90% decrease of the disease measurement for CT/MRI target lesions. All pre-existing bone lesions with CR by MIBG; MIBG scan can be stable disease (SD) or CR in soft tissue lesions corresponding to lesions on CT/MRI. CR in bone marrow. No new sites of tumor; PR= >=30% decrease in the disease measurement for CT/MRI target lesions. Bone marrow with CR. MIBG with either PR/CR in bone lesions; MIBG may be SD or CR in soft tissue lesions corresponding to lesions on CT/MRI. Homovanillic acid (HVA)/Vanillylmandelic acid (VMA) may still be elevated.	Up to the first 6 cycles of treatment
Primary	Percentage of Patients in the Dinutuximab Arm Who Are Responders	Percentage of patients who are responders to therapy with dinutuximab will be tabulated, including a 95% confidence interval on the response rate. Responders are defined as patients who achieve a best overall response of complete response (CR), very good partial response (VGPR), or partial response (PR) per the International Neuroblastoma Response Criteria (INRC). Per INRC: CR= Disappearance of all target lesions. No evidence of tumor at any site; VGPR= >90% decrease of disease measurement for CT/MRI target lesions. All pre-existing bone lesions with CR by MIBG; MIBG scan can be stable disease (SD) or CR in soft tissue lesions corresponding to lesions on CT/MRI. CR in bone marrow. No new sites of tumor; PR= =30% decrease in disease measurement for CT/MRI target lesions. Bone marrow with CR. MIBG with either PR/CR in bone lesions; MIBG may be SD or CR in soft tissue lesions corresponding to lesions on CT/MRI. Homovanillic acid (HVA)/ Vanillylmandelic acid (VMA) may still be elevated.	Up to the first 6 cycles of treatment