Combination Chemotherapy, Autologous Stem Cell Transplant, and/or Radiation Therapy in Treating Young Patients With Extraocular Retinoblastoma

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00554788
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 60
• Locations: 73
• Arm: 1
• Anticipated Duration (Months): 202.9
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase III trial is studying the side effects and how well giving combination chemotherapy together with autologous stem cell transplant and/or radiation therapy works in treating young patients with extraocular retinoblastoma. Giving chemotherapy before an autologous stem cell transplant stops the growth of tumor cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient?s blood and/or bone marrow and stored. More chemotherapy is given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Radiation therapy uses high energy x-rays to kill tumor cells. Giving radiation therapy after combination chemotherapy and/or autologous stem cell transplant may kill any remaining tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Extraocular Retinoblastoma	Procedure: Autologous Bone Marrow Transplantation; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Drug: Carboplatin; Drug: Cisplatin; Drug: Cyclophosphamide; Drug: Etoposide; Biological: Filgrastim; Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation; Radiation: Radiation Therapy; Drug: Thiotepa; Drug: Vincristine Sulfate	Phase 3

Detailed Description

OBJECTIVES:

1. To estimate the proportion of 3 groups of patients with extraocular retinoblastoma (stage 2 and 3: regional extra-ocular disease;, stage 4a: disseminated metastatic disease not involving the central nervous system [CNS]; or stage 4b: patients with CNS disease) who achieve long-term event-free survival after treatment with aggressive multimodality therapy compared to historical controls.

2. To estimate the response rate to the induction phase of the regimen. III. To evaluate the toxicities associated with this regimen.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive vincristine intravenously (IV) on days 0, 7, and 14, cisplatin IV over 6 hours on day 0, cyclophosphamide IV over 1 hour and etoposide IV over 1 hour on days 1 and 2, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 3 and continuing until blood counts recover.

Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of induction chemotherapy, patients with stage 2 or 3 disease who have at least a partial response proceed to radiotherapy. Patients with stage 4a or 4b disease who have at least a partial response proceed to high-dose consolidation chemotherapy and autologous stem cell infusion.

STEM CELL HARVESTING (stage 4a or 4b disease only): Peripheral blood stem cells (preferred) or bone marrow cells are collected after at least 1 course of induction chemotherapy.

HIGH-DOSE CONSOLIDATION CHEMOTHERAPY (stage 4a or 4b disease only): Patients receive carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3.

AUTOLOGOUS STEM CELL INFUSION (stage 4a or 4b disease only): Patients undergo autologous stem cell infusion on day 0. Patients then receive filgrastim subcutaneously (SC) beginning on day 1 and continuing until blood counts recover.

RADIOTHERAPY: Patients with stage 2 or 3 disease (orbital and/or regional involvement) undergo radiotherapy to sites that were initially involved beginning within 42 days after the start of course 4 of induction chemotherapy. Patients with stage 4a or 4b disease undergo radiotherapy to sites initially involved based on response beginning approximately 42 days after autologous stem cell infusion. Patients with stage 4a disease who achieve a complete response to induction chemotherapy or with less than 5 mm of residual tumor at the time of planned irradiation, or patients with stage 4b disease who achieve a complete response to induction chemotherapy do not undergo radiotherapy.

After completion of study therapy, patients are followed every 3 months for 1 year and then annually thereafter for 9 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Trial of Intensive Multi-Modality Therapy for Extra-Ocular Retinoblastoma
• Actual Study Start Date: Feb 4, 2008
• Actual Primary Completion Date: Jun 30, 2018
• Anticipated Study Completion Date: Dec 31, 2024

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy, radiotherapy, autologous SCI) INDUCTION: Patients receive vincristine IV; cisplatin IV; cyclophosphamide IV; and G-CSF SC beginning on day 3 and continuing until blood counts recover. CONSOLIDATION (stage 4a or 4b disease only): Patients receive carboplatin IV; thiotepa IV; and etoposide IV. AUTOLOGOUS STEM CELL INFUSION (stage 4a or 4b disease only): Patients undergo autologous stem cell infusion on day 0 and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. RADIOTHERAPY: Patients with stage 2 or 3 disease (orbital and/or regional involvement) undergo radiotherapy to sites that were initially involved beginning within 42 days after the start of course 4 of induction chemotherapy. Patients with stage 4a or 4b disease undergo radiotherapy to sites initially involved based on response beginning approximately 42 days after autologous stem cell infusion.

Procedure: Autologous Bone Marrow Transplantation; Undergo peripheral blood stem cell or bone marrow transplant; Other Names: ABMT Autologous Bone Marrow Transplant Autologous Marrow Transplantation ; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo peripheral blood stem cell or bone marrow transplant; Other Names: Autologous Hematopoietic Cell Transplantation autologous stem cell transplantation ; Drug: Carboplatin; Given IV; Other Names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo ; Drug: Cisplatin; Given IV; Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin ; Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Etoposide; Given IV; Other Names: Demethyl Epipodophyllotoxin Ethylidine Glucoside EPEG Lastet Toposar Vepesid VP 16-213 VP-16 VP-16-213 ; Biological: Filgrastim; Given SC; Other Names: FILGRASTIM, LICENSE HOLDER UNSPECIFIED G-CSF Neupogen r-metHuG-CSF Recombinant Methionyl Human Granulocyte Colony Stimulating Factor rG-CSF Tevagrastim ; Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation; Undergo peripheral blood stem cell or bone marrow transplant; Other Names: in vitro-treated PBPC transplantation in vitro-treated peripheral blood progenitor cell transplantation ; Radiation: Radiation Therapy; Undergo radiotherapy; Other Names: Cancer Radiotherapy Irradiate Irradiated irradiation Radiation Radiotherapeutics RADIOTHERAPY RT Therapy, Radiation ; Drug: Thiotepa; Given IV; Other Names: 1,1',1''-Phosphinothioylidynetrisaziridine Girostan N,N', N''-Triethylenethiophosphoramide Oncotiotepa STEPA Tepadina TESPA Tespamin Tespamine Thio-Tepa Thiofosfamide Thiofozil Thiophosphamide Thiophosphoramide Thiotef Tifosyl TIO TEF Tio-tef Triethylene thiophosphoramide Triethylenethiophosphoramide Tris(1-aziridinyl)phosphine sulfide TSPA WR 45312 ; Drug: Vincristine Sulfate; Given IV; Other Names: Kyocristine Leurocristine sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate

Outcome Measures

Primary Outcome Measures

1. Event-free Survival (EFS) [At 1 year]

   The probability of surviving patients who did not experience events at 1 year following enrollment. An event is defined as relapse, second malignancy, or death from any cause.

Secondary Outcome Measures

1. Response Rate to the Induction Phase of the Regimen [12 weeks after participant received the first dose]

   This study used a modified version of the international criteria for neuroblastoma response. The response rate to the induction phase of the regimen and a corresponding 95% confidence interval will be calculated for all strata combined.

2. Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [Up to 30 days after completion of study treatment]

   Grade 3 and higher toxicities will be descriptively summarized.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 10 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologic or cytologic verification of extra-ocular retinoblastoma; extra-ocular disease includes orbital disease, optic nerve involvement at the surgical margin, regional nodal disease, and/or overt distant metastatic disease (at sites such as bone, bone marrow, liver and/or the central nervous system); patients with trilateral retinoblastoma will also be included in this protocol

• Patients with a CNS lesion consistent with trilateral or stage 4b disease may be enrolled without tissue confirmation if (1) unequivocal leptomeningeal disease is present on brain or spine magnetic resonance imaging (MRI) scan and/or (2) the primary tumor is at least 2 cm in diameter, predominantly solid, and demonstrates enhancement on the post-gadolinium images; however, even in such cases surgery should be given serious consideration

• 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

• No prior chemotherapy or radiotherapy for the extra-ocular retinoblastoma may have been administered prior to entering this study; prior treatment (chemotherapy and/or radiation therapy) for intra-ocular retinoblastoma is permissible

• Peripheral absolute neutrophil count (ANC) >= 750/uL

• If the ANC and/or platelet count are not adequate, but due to bone marrow metastatic disease, these criteria will be waived

• Platelet count >= 75,000/uL (transfusion independent)

• If the ANC and/or platelet count are not adequate, but due to bone marrow metastatic disease, these criteria will be waived

• Creatinine clearance OR radioisotope glomerular filtration rate >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

• 0.4 mg/dL (1 month to < 6 months of age)

• 0.5 mg/dL (6 months to < 1 year of age)

• 0.6 mg/dL (1 years to < 2 years of age)

• 0.8 mg/dL (2 years to < 6 years of age)

• 1.0 mg/dL (6 years to < 10 years of age)

• 1.2 mg/dL (10 years to < 13 years of age)

• 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 years to < 16 years of age)

• 1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age)

• Total bilirubin =< 1.5 times upper limit of normal (ULN)

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN)

• 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) for human studies must be met

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
3	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
4	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
5	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
6	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
7	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
8	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
9	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
10	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
11	Children's Hospital Colorado	Aurora	Colorado	United States	80045
12	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
13	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
14	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
15	Children's National Medical Center	Washington	District of Columbia	United States	20010
16	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
17	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
18	Nemours Children's Clinic - Orlando	Orlando	Florida	United States	32806
19	Nemours Children's Hospital	Orlando	Florida	United States	32827
20	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
21	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
22	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida	United States	33607
23	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
24	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
25	University of Illinois	Chicago	Illinois	United States	60612
26	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
27	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
28	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
29	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
30	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
31	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
32	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
33	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
34	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
35	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
36	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
37	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada	United States	89135
38	Summerlin Hospital Medical Center	Las Vegas	Nevada	United States	89144
39	Morristown Medical Center	Morristown	New Jersey	United States	07960
40	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
41	New York Medical College	Valhalla	New York	United States	10595
42	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
43	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
44	Duke University Medical Center	Durham	North Carolina	United States	27710
45	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
46	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
47	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
48	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
49	Dayton Children's Hospital	Dayton	Ohio	United States	45404
50	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
51	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
52	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
53	Childrens Oncology Group	Philadelphia	Pennsylvania	United States	19104
54	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
55	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
56	Medical City Dallas Hospital	Dallas	Texas	United States	75230
57	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
58	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
59	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
60	M D Anderson Cancer Center	Houston	Texas	United States	77030
61	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
62	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
63	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
64	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
65	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
66	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
67	Hospital de Pediatria Juan P Garrahan	Buenos Aires		Argentina	C1245AAL
68	The Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
69	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
70	Instituto De Oncologia Pediatrica	Sao Paulo		Brazil	04023-062
71	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
72	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
73	Children's Cancer Hospital	El Saida Zenab	Cairo	Egypt	11787

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ira J Dunkel, Children's Oncology Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 14, 2014

More Information

Additional Information:

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00554788
• Other Study ID Numbers: ARET0321; NCI-2009-00421; COG-ARET0321; ARET0321; CDR0000573987; ARET0321; ARET0321; U10CA180886; U10CA098543
• First Posted: Nov 7, 2007
• Last Update Posted: Jul 12, 2022
• Last Verified: Jul 1, 2022

• Additional relevant MeSH terms: Retinoblastoma; Cyclophosphamide; Thiotepa; Cisplatin; Carboplatin; Etoposide; Vincristine; Etoposide phosphate; Podophyllotoxin; Lenograstim

Study Results

Participant Flow

Arm/Group Title	Stage 2/3 Patients	Stage 4a Patients	Stage 4b Patients
Arm/Group Description	Patients with orbital disease (including microscopic trans-scleral invasion seen on enucleation pathology), optic nerve margin (+), and/or regional nodal disease, but no other sites of metastases. Stage 2 and 3 patients will receive Induction chemotherapy and External Beam Radiation Therapy, but will not receive Consolidation therapy (High-Dose Chemotherapy with Stem Cell Rescue).	Patients with overt distant metastatic disease (such as bone, bone marrow, and/or liver) but no detectable CNS involvement. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy.	Patients with overt CNS involvement (brain parenchyma, leptomeninges and CSF cytology). Patients with trilateral retinoblastoma will be included. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy.
Period Title: Overall Study
STARTED	21	18	21
COMPLETED	14	12	7
NOT COMPLETED	7	6	14

Baseline Characteristics

Arm/Group Title	Stage 2/3 Patients	Stage 4a Patients	Stage 4b Patients	Total
Arm/Group Description	Patients with orbital disease (including microscopic trans-scleral invasion seen on enucleation pathology), optic nerve margin (+), and/or regional nodal disease, but no other sites of metastases. Stage 2 and 3 patients will receive Induction chemotherapy and External Beam Radiation Therapy, but will not receive Consolidation therapy (High-Dose Chemotherapy with Stem Cell Rescue).	Patients with overt distant metastatic disease (such as bone, bone marrow, and/or liver) but no detectable CNS involvement. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy.	Patients with overt CNS involvement (brain parenchyma, leptomeninges and CSF cytology). Patients with trilateral retinoblastoma will be included. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy.	Total of all reporting groups
Overall Participants	21	18	21	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.24 (1.36)	3.96 (2.27)	2.91 (1.83)	3.34 (1.85)
Sex: Female, Male (Count of Participants)
Female	4 19%	9 50%	14 66.7%	27 45%
Male	17 81%	9 50%	7 33.3%	33 55%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 38.1%	7 38.9%	8 38.1%	23 38.3%
Not Hispanic or Latino	13 61.9%	10 55.6%	13 61.9%	36 60%
Unknown or Not Reported	0 0%	1 5.6%	0 0%	1 1.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 4.8%	2 11.1%	0 0%	3 5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	3 14.3%	2 11.1%	5 23.8%	10 16.7%
White	11 52.4%	11 61.1%	12 57.1%	34 56.7%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	6 28.6%	3 16.7%	4 19%	13 21.7%
Region of Enrollment (Count of Participants)
United States	14 66.7%	14 77.8%	13 61.9%	41 68.3%
Canada	1 4.8%	0 0%	0 0%	1 1.7%
Argentina	3 14.3%	4 22.2%	2 9.5%	9 15%
Egypt	3 14.3%	0 0%	4 19%	7 11.7%
Brazil	0 0%	0 0%	1 4.8%	1 1.7%
Chile	0 0%	0 0%	1 4.8%	1 1.7%

Outcome Measures

1. Primary Outcome

Title	Event-free Survival (EFS)
Description	The probability of surviving patients who did not experience events at 1 year following enrollment. An event is defined as relapse, second malignancy, or death from any cause.
Time Frame	At 1 year

Outcome Measure Data

Analysis Population Description

Ineligible patients were excluded from analysis

Arm/Group Title	Stage 2/3 Patients	Stage 4a Patients	Stage 4b Patients
Arm/Group Description	Patients with orbital disease (including microscopic trans-scleral invasion seen on enucleation pathology), optic nerve margin (+), and/or regional nodal disease, but no other sites of metastases. Stage 2 and 3 patients will receive Induction chemotherapy and External Beam Radiation Therapy, but will not receive Consolidation therapy (High-Dose Chemotherapy with Stem Cell Rescue).	Patients with overt distant metastatic disease (such as bone, bone marrow, and/or liver) but no detectable CNS involvement. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy.	Patients with overt CNS involvement (brain parenchyma, leptomeninges and CSF cytology). Patients with trilateral retinoblastoma will be included. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy.
Measure Participants	19	18	20
Number (95% Confidence Interval) [Probability]	88	83	28

2. Secondary Outcome

Title	Response Rate to the Induction Phase of the Regimen
Description	This study used a modified version of the international criteria for neuroblastoma response. The response rate to the induction phase of the regimen and a corresponding 95% confidence interval will be calculated for all strata combined.
Time Frame	12 weeks after participant received the first dose

Outcome Measure Data

Analysis Population Description

Ineligible patients were excluded from analysis

Arm/Group Title	All Eligible Patients
Arm/Group Description	All eligible Stage 2/3, Stage 4a, and Stage 4b patients
Measure Participants	57
Number (95% Confidence Interval) [percentage of participants]	68 323.8%

3. Secondary Outcome

Title	Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Description	Grade 3 and higher toxicities will be descriptively summarized.
Time Frame	Up to 30 days after completion of study treatment

Outcome Measure Data

Analysis Population Description

Three ineligible patients were excluded from this analysis. Two patients who did not receive therapy were also excluded from this analysis.

Arm/Group Title	Stage 2/3 Patients	Stage 4a Patients	Stage 4b Patients
Arm/Group Description	Patients with orbital disease (including microscopic trans-scleral invasion seen on enucleation pathology), optic nerve margin (+), and/or regional nodal disease, but no other sites of metastases. Stage 2 and 3 patients will receive Induction chemotherapy and External Beam Radiation Therapy, but will not receive Consolidation therapy (High-Dose Chemotherapy with Stem Cell Rescue).	Patients with overt distant metastatic disease (such as bone, bone marrow, and/or liver) but no detectable CNS involvement. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy.	Patients with overt CNS involvement (brain parenchyma, leptomeninges and CSF cytology). Patients with trilateral retinoblastoma will be included. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy.
Measure Participants	18	18	19
Abdominal pain	0 0%	5.6 31.1%	0 0%
Acute kidney injury	0 0%	5.6 31.1%	0 0%
Alanine aminotransferase increased	0 0%	16.7 92.8%	5.3 25.2%
Anemia	0 0%	0 0%	5.3 25.2%
Anorexia	11.1 52.9%	33.3 185%	15.8 75.2%
Apnea	0 0%	0 0%	5.3 25.2%
Aspartate aminotransferase increased	0 0%	11.1 61.7%	5.3 25.2%
Catheter related infection	11.1 52.9%	0 0%	0 0%
Dehydration	0 0%	11.1 61.7%	10.5 50%
Depressed level of consciousness	0 0%	0 0%	5.3 25.2%
Diarrhea	5.6 26.7%	16.7 92.8%	0 0%
Encephalopathy	0 0%	0 0%	5.3 25.2%
Enterocolitis	0 0%	5.6 31.1%	0 0%
Enterocolitis infectious	5.6 26.7%	11.1 61.7%	5.3 25.2%
Esophagitis	0 0%	5.6 31.1%	0 0%
Febrile neutropenia	55.6 264.8%	55.6 308.9%	36.8 175.2%
Fever	11.1 52.9%	0 0%	5.3 25.2%
GGT increased	0 0%	5.6 31.1%	0 0%
Gastric hemorrhage	0 0%	5.6 31.1%	0 0%
Hearing impaired	11.1 52.9%	5.6 31.1%	5.3 25.2%
Hypermagnesemia	5.6 26.7%	0 0%	0 0%
Hypertension	0 0%	5.6 31.1%	0 0%
Hypoalbuminemia	0 0%	0 0%	5.3 25.2%
Hypocalcemia	5.6 26.7%	5.6 31.1%	10.5 50%
Hypoglycemia	0 0%	0 0%	5.3 25.2%
Hypokalemia	27.8 132.4%	16.7 92.8%	21.1 100.5%
Hypomagnesemia	5.6 26.7%	5.6 31.1%	10.5 50%
Hyponatremia	11.1 52.9%	0 0%	15.8 75.2%
Hypophosphatemia	22.2 105.7%	0 0%	10.5 50%
Hypotension	0 0%	11.1 61.7%	0 0%
Hypoxia	0 0%	2.6 14.4%	0 0%
Infections and infestations - Other, specify	27.8 132.4%	33.3 185%	21.1 100.5%
Lower gastrointestinal hemorrhage	0 0%	5.6 31.1%	0 0%
Lung infection	16.7 79.5%	0 0%	0 0%
Lymphocyte count decreased	0 0%	0 0%	5.3 25.2%
Mucositis oral	5.6 26.7%	27.8 154.4%	5.3 25.2%
Nausea	16.7 79.5%	11.1 61.7%	5.3 25.2%
Nervous system disorders - Other, specify	0 0%	0 0%	10.5 50%
Neutrophil count decreased	5.6 26.7%	0 0%	5.3 25.2%
Oral pain	0 0%	5.6 31.1%	0 0%
Pain	0 0%	5.6 31.1%	0 0%
Peripheral motor neuropathy	5.6 26.7%	0 0%	0 0%
Pharyngeal mucositis	0 0%	5.6 31.1%	0 0%
Platelet count decreased	5.6 26.7%	0 0%	5.3 25.2%
Pneumonitis	5.6 26.7%	0 0%	0 0%
Rectal pain	0 0%	5.6 31.1%	0 0%
Seizure	0 0%	0 0%	5.3 25.2%
Sepsis	0 0%	11.1 61.7%	0 0%
Sinus tachycardia	0 0%	5.6 31.1%	0 0%
Sinusitis	11.1 52.9%	0 0%	0 0%
Skin infection	0 0%	5.6 31.1%	5.3 25.2%
Upper respiratory infection	11.1 52.9%	5.6 31.1%	0 0%
Vomiting	11.1 52.9%	22.2 123.3%	5.3 25.2%
White blood cell decreased	5.6 26.7%	0 0%	5.3 25.2%

Adverse Events

Time Frame	Up to 30 days after completion of study treatment.
Adverse Event Reporting Description	Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution, via expedited reporting (NCI AdEERs / CAeRs). The "AE Other" table reflects all CTCAEs collected excluding those that were reported as SAEs. Ineligible patients are excluded from reporting of adverse events.
Arm/Group Title	Stage 2/3 Patients		Stage 4a Patients		Stage 4b Patients
Arm/Group Description	Patients with orbital disease (including microscopic trans-scleral invasion seen on enucleation pathology), optic nerve margin (+), and/or regional nodal disease, but no other sites of metastases. Stage 2 and 3 patients will receive Induction chemotherapy and External Beam Radiation Therapy, but will not receive Consolidation therapy (High-Dose Chemotherapy with Stem Cell Rescue).		Patients with overt distant metastatic disease (such as bone, bone marrow, and/or liver) but no detectable CNS involvement. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy.		Patients with overt CNS involvement (brain parenchyma, leptomeninges and CSF cytology). Patients with trilateral retinoblastoma will be included. Patients will receive Induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem Cell Rescue, and depending on response to Induction chemotherapy, possibly External Beam Radiation Therapy.
All Cause Mortality
	Stage 2/3 Patients		Stage 4a Patients		Stage 4b Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/18 (11.1%)		5/18 (27.8%)		15/19 (78.9%)
Serious Adverse Events
	Stage 2/3 Patients		Stage 4a Patients		Stage 4b Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)		2/18 (11.1%)		0/19 (0%)
Blood and lymphatic system disorders
Febrile neutropenia	1/18 (5.6%)		1/18 (5.6%)		0/19 (0%)
Infections and infestations
Sepsis	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Stage 2/3 Patients		Stage 4a Patients		Stage 4b Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/18 (72.2%)		12/18 (66.7%)		10/19 (52.6%)
Blood and lymphatic system disorders
Anemia	0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Febrile neutropenia	9/18 (50%)		9/18 (50%)		7/19 (36.8%)
Cardiac disorders
Sinus tachycardia	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Ear and labyrinth disorders
Hearing impaired	2/18 (11.1%)		1/18 (5.6%)		1/19 (5.3%)
Gastrointestinal disorders
Abdominal pain	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Diarrhea	1/18 (5.6%)		3/18 (16.7%)		0/19 (0%)
Enterocolitis	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Esophagitis	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Gastric hemorrhage	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Lower gastrointestinal hemorrhage	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Mucositis oral	1/18 (5.6%)		5/18 (27.8%)		1/19 (5.3%)
Nausea	3/18 (16.7%)		2/18 (11.1%)		1/19 (5.3%)
Oral pain	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Rectal pain	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Vomiting	2/18 (11.1%)		4/18 (22.2%)		1/19 (5.3%)
General disorders
Fever	2/18 (11.1%)		0/18 (0%)		1/19 (5.3%)
Pain	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Infections and infestations
Catheter related infection	2/18 (11.1%)		0/18 (0%)		0/19 (0%)
Enterocolitis infectious	1/18 (5.6%)		2/18 (11.1%)		1/19 (5.3%)
Infections and infestations - Other, specify	5/18 (27.8%)		6/18 (33.3%)		4/19 (21.1%)
Lung infection	3/18 (16.7%)		0/18 (0%)		0/19 (0%)
Sepsis	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Sinusitis	2/18 (11.1%)		0/18 (0%)		0/19 (0%)
Skin infection	0/18 (0%)		1/18 (5.6%)		1/19 (5.3%)
Upper respiratory infection	2/18 (11.1%)		1/18 (5.6%)		0/19 (0%)
Investigations
Alanine aminotransferase increased	0/18 (0%)		3/18 (16.7%)		1/19 (5.3%)
Aspartate aminotransferase increased	0/18 (0%)		2/18 (11.1%)		1/19 (5.3%)
GGT increased	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Lymphocyte count decreased	0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Neutrophil count decreased	1/18 (5.6%)		0/18 (0%)		1/19 (5.3%)
Platelet count decreased	1/18 (5.6%)		0/18 (0%)		1/19 (5.3%)
White blood cell decreased	1/18 (5.6%)		0/18 (0%)		1/19 (5.3%)
Metabolism and nutrition disorders
Anorexia	2/18 (11.1%)		6/18 (33.3%)		3/19 (15.8%)
Dehydration	0/18 (0%)		2/18 (11.1%)		2/19 (10.5%)
Hypermagnesemia	1/18 (5.6%)		0/18 (0%)		0/19 (0%)
Hypoalbuminemia	0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Hypocalcemia	1/18 (5.6%)		1/18 (5.6%)		2/19 (10.5%)
Hypoglycemia	0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Hypokalemia	5/18 (27.8%)		3/18 (16.7%)		4/19 (21.1%)
Hypomagnesemia	1/18 (5.6%)		1/18 (5.6%)		2/19 (10.5%)
Hyponatremia	2/18 (11.1%)		0/18 (0%)		3/19 (15.8%)
Hypophosphatemia	4/18 (22.2%)		0/18 (0%)		2/19 (10.5%)
Nervous system disorders
Cognitive disturbance	0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Depressed level of consciousness	0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Encephalopathy	0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Nervous system disorders - Other, specify	0/18 (0%)		0/18 (0%)		2/19 (10.5%)
Peripheral motor neuropathy	1/18 (5.6%)		0/18 (0%)		0/19 (0%)
Seizure	0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Renal and urinary disorders
Acute kidney injury	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Respiratory, thoracic and mediastinal disorders
Apnea	0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Hypoxia	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Pharyngeal mucositis	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Pneumonitis	1/18 (5.6%)		0/18 (0%)		0/19 (0%)
Vascular disorders
Hypertension	0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Hypotension	0/18 (0%)		2/18 (11.1%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior Sponsor approval.