Testing the Addition of 131I-MIBG or Lorlatinib to Intensive Therapy in People With High-Risk Neuroblastoma (NBL)

Sponsor

Children's Oncology Group (Other)

Overall Status

Recruiting

CT.gov ID

NCT03126916

Collaborator

National Cancer Institute (NCI) (NIH)

658

Enrollment

159

Locations

Arms

100.7

Anticipated Duration (Months)

4.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase III trial studies iobenguane I-131 or lorlatinib and standard therapy in treating younger patients with newly-diagnosed high-risk neuroblastoma or ganglioneuroblastoma. Radioactive drugs, such as iobenguane I-131, may carry radiation directly to tumor cells and not harm normal cells. Lorlatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving iobenguane I-131 or lorlatinib and standard therapy may work better compared to lorlatinib and standard therapy alone in treating younger patients with neuroblastoma or ganglioneuroblastoma.

Condition or Disease	Intervention/Treatment	Phase
Ganglioneuroblastoma Neuroblastoma	Procedure: Autologous Hematopoietic Stem Cell Transplantation Drug: Busulfan Drug: Carboplatin Drug: Cisplatin Drug: Cyclophosphamide Drug: Dexrazoxane Hydrochloride Biological: Dinutuximab Drug: Doxorubicin Hydrochloride Drug: Etoposide Phosphate Radiation: External Beam Radiation Therapy Radiation: Iobenguane I-131 Drug: Isotretinoin Drug: Lorlatinib Drug: Melphalan Hydrochloride Biological: Sargramostim Procedure: Therapeutic Conventional Surgery Drug: Thiotepa Drug: Topotecan Hydrochloride Drug: Vincristine Sulfate	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

To determine in the context of a randomized trial whether the event-free survival (EFS) of patients with newly diagnosed high-risk neuroblastoma (NBL) is improved with the addition of iobenguane I-131 (131I-MIBG) during induction, prior to tandem autologous stem cell transplantation (ASCT).
To determine whether the addition of lorlatinib to intensive multimodality therapy for patients with high-risk NBL whose tumors harbor activating point mutations in or amplification of the ALK gene with a variant allele frequency (VAF) >= 5% results in superior EFS compared to a contemporaneously treated cohort of patients with tumors without documented ALK activating mutations.

SECONDARY OBJECTIVES:

To describe the toxicities associated with treatment for high-risk NBL with and without the addition of 131I-MIBG or ALK inhibitor therapy.
To estimate EFS and describe toxicity in patients with newly diagnosed high-risk NBL randomized to treatment with an 131I-MIBG-containing induction prior to busulfan/melphalan (BuMel) ASCT.
To describe the overall survival (OS) and response rates (evaluated per International Neuroblastoma Response Criteria [INRC] criteria prior to ASCT and prior to post-consolidation therapy) for patients with high-risk neuroblastoma treated with or without 131I-MIBG or ALK inhibitor therapy.
To prospectively evaluate the relationship of response rate per revised International Neuroblastoma Response Criteria (INRC) to EFS and OS in patients with high-risk NBL treated with and without the addition of 131I-MIBG or ALK inhibitor therapy.

EXPLORATORY OBJECTIVES:

To evaluate whole body radiation dose, tumor factors, and host factors as potential predictors of efficacy and/or toxicity associated with 131I-MIBG therapy and transplant conditioning.
To describe end-Induction response, EFS, and OS according to specific ALK mutations, VAF, ALK amplification, the presence of additional genomic findings, or the ALK inhibitor administered.
To characterize changes in tumor markers (circulating tumor deoxyribonucleic acid [DNA], including ALK and other tumor specific genetic aberrations, and circulating GD2) over time in response to protocol therapy.
To correlate results of tumor and host profiling with end-induction response and EFS.
To prospectively evaluate EFS for patients with MIBG non-avid high-risk NBL compared to patients with MIBG-avid high-risk NBL who are randomized to treatment without 131I-MIBG.
To correlate Curie scores calculated from 131I-MIBG post-treatment scans with end-induction response, EFS and OS.
To describe changes in image defined risk factors (IDRFs) over the course of induction therapy, with correlation to surgical outcomes and local failure rates following primary tumor resection.
To define patterns of failure at time of first relapse or progression in patients with high-risk NBL.
To determine the feasibility of prospectively monitoring adverse events using electronic health records.
To compare local, central, and computer assisted Curie score assignment at baseline and during therapy in patients with MIBG-avid high-risk NBL.
To compare late toxicities (including impaired organ function and secondary tumor occurrence) in patients treated with 131I-MIBG or ALK inhibitor therapy to late toxicities in patients who have not received these therapies.
To determine the association between household material hardship (HMH) and clinical outcomes, including event free and overall survival, and 131I-MIBG receipt.
To compare the outcomes (EFS, OS, and toxicity) of patients treated with post-consolidation therapy that does not contain aldesleukin to historical outcome data for patients treated with similar induction and consolidation regimens followed by post-consolidation therapy that contained aldesleukin.
To characterize and describe longitudinal neuropsychological and behavioral effects of high-risk neuroblastoma therapy.
To evaluate change in neurobehavioral outcomes over time in patients with neuroblastoma treated with high-risk neuroblastoma therapy plus lorlatinib compared to high-risk therapy alone using parent- or self-report measures of adaptive, executive, and psychosocial functioning.

OUTLINE: Patients are randomized or assigned to 1 of 5 arms.

All patients receive cyclophosphamide intravenously (IV) over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 during cycle 1 of induction therapy in the absence of disease progression or unacceptable toxicity. Patients not assigned to an Arm by the end of cycle 1 may receive an addition cycle of cyclophosphamide and topotecan.

ARM A:

INDUCTION THERAPY: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 of cycle 2 and cisplatin IV over 4 hours and etoposide phosphate IV over 2 hours on days 1-3 of cycles 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on day 1 and dexrazoxane hydrochloride IV over 5-15 minutes, doxorubicin hydrochloride IV over 1-15 minutes, and cyclophosphamide IV over 1-6 hours on days 1-2 of cycle 4 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY:

HSCT#1: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 in the absence of disease progression or unacceptable toxicity.

HSCT#2: Patients receive melphalan hydrochloride IV over 30 minutes on days -7 to -5, and etoposide phosphate IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4 in the absence of disease progression or unacceptable toxicity.

POST-CONSOLIDATION THERAPY: Patients receive sargramostim subcutaneously (SC) on days 1-14, dinutuximab IV over 10 hours on days 4-7 of cycles 1-5, and isotretinoin orally (PO) twice daily (BID) on days 11-24 of cycles 1-5, and days 15-28 during cycle 6 in the absence of disease progression or unacceptable toxicity.

ARM B:

INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, and etoposide phosphate as in Arm A, iobenguane I-131 IV over 1.5-2 hours on day 1 beginning 3 weeks after the start of cycle 3, and vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm A beginning no sooner than 35 days after the infusion of iobenguane I-131.

CONSOLIDATION THERAPY:

HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A.

HSCT#2: Patients receive melphalan, etoposide phosphate, and carboplatin as in Arm A.

POST-CONSLIDATION THERAPY: Patients receive sargramostim, dinutuximab, and isotretinoin as in Arm A-D.

ARM C (CLOSED TO ACCRUAL AS OF DECEMBER 17, 2020):

INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, etoposide phosphate, iobenguane I-131, vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm B.

CONSOLIDATION THERAPY: Patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan hydrochloride IV over 30 minutes on day -1 in the absence of disease progression or unacceptable toxicity.

POST-CONSOLIDATION THERAPY: Patients receive sargramostim, dinutuximab, and isotretinoin as in Arm A.

ARM D: Patients receive treatment identical to Arm A.

ARM E:

INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, etoposide phosphate, vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm A. Patients also receive lorlatinib PO once daily (QD) starting cycle 2 prior to HSCT #1 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY:

HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A. Patients also receive lorlatinib PO QD until day -8 of HSCT#2 in the absence of disease progression or unacceptable toxicity.

HSCT#2: Patients receive melphalan hydrochloride, etoposide phosphate, carboplatin as in Arm

Lorlatinib is restarted when patient has reached at least day +14 post-HSCT#2 and is able to tolerate enteral medications, provided there is no evidence of disease progression or unacceptable toxicity.

RADIATION THERAPY: Patients receive lorlatinib PO QD concurrently with radiation therapy in the absence of disease progression or unacceptable toxicity.

POST-CONSOLIDATION THERAPY: Patients receive sargramostim and dinutuximab as in Arm A-D. Patients also receive isotretinoin PO BID on days 11-24 of cycles 1-5 and days 15-28 of cycle 6, and lorlatinib PO QD on days 1-28 of cycles 1-6 in the absence of disease progression or unacceptable toxicity.

CONTINUATION THERAPY: Patients receive lorlatininb PO QD on days 1-28. Cycles repeat every 28 days for 18 months in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients in Arms A-D are followed up every 3 months for 18 months, and then every 6 months for 42 months; patients in Arm E are followed up every 3 months for 6 months, and then every 6 months for 42 months.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

658 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 3 Study of 131I-Metaiodobenzylguanidine (131I-MIBG) or ALK Inhibitor Therapy Added to Intensive Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma (NBL)

Actual Study Start Date :

May 9, 2018

Anticipated Primary Completion Date :

Sep 30, 2026

Anticipated Study Completion Date :

Sep 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (chemotherapy, HSCT, EBRT) See Arm A in detailed description.	Procedure: Autologous Hematopoietic Stem Cell Transplantation Undergo autologous HSCT Drug: Carboplatin Given IV Drug: Cisplatin Given IV Drug: Cyclophosphamide Given IV Drug: Dexrazoxane Hydrochloride Given IV Biological: Dinutuximab Given IV Drug: Doxorubicin Hydrochloride Given IV Drug: Etoposide Phosphate Given IV Radiation: External Beam Radiation Therapy Undergo EBRT Drug: Isotretinoin Given PO Biological: Sargramostim Given SC Procedure: Therapeutic Conventional Surgery Undergo standard of care surgery Drug: Thiotepa Given IV Drug: Topotecan Hydrochloride Given IV Drug: Vincristine Sulfate Given IV
Experimental: Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT) See Arm B in detailed description.	Procedure: Autologous Hematopoietic Stem Cell Transplantation Undergo autologous HSCT Drug: Carboplatin Given IV Drug: Cisplatin Given IV Drug: Cyclophosphamide Given IV Drug: Dexrazoxane Hydrochloride Given IV Biological: Dinutuximab Given IV Drug: Doxorubicin Hydrochloride Given IV Drug: Etoposide Phosphate Given IV Radiation: External Beam Radiation Therapy Undergo EBRT Radiation: Iobenguane I-131 Given IV Drug: Isotretinoin Given PO Biological: Sargramostim Given SC Procedure: Therapeutic Conventional Surgery Undergo standard of care surgery Drug: Thiotepa Given IV Drug: Topotecan Hydrochloride Given IV Drug: Vincristine Sulfate Given IV
Experimental: Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT) See Arm C in detailed description. Closed to accrual as of 12/17/20.	Procedure: Autologous Hematopoietic Stem Cell Transplantation Undergo autologous HSCT Drug: Busulfan Given IV Drug: Cisplatin Given IV Drug: Cyclophosphamide Given IV Drug: Dexrazoxane Hydrochloride Given IV Biological: Dinutuximab Given IV Drug: Doxorubicin Hydrochloride Given IV Drug: Etoposide Phosphate Given IV Radiation: External Beam Radiation Therapy Undergo EBRT Radiation: Iobenguane I-131 Given IV Drug: Isotretinoin Given PO Drug: Melphalan Hydrochloride Given IV Biological: Sargramostim Given SC Procedure: Therapeutic Conventional Surgery Undergo standard of care surgery Drug: Thiotepa Given IV Drug: Topotecan Hydrochloride Given IV Drug: Vincristine Sulfate Given IV
Experimental: Arm D (chemotherapy, HSCT, EBRT) See Arm D in detailed description.	Procedure: Autologous Hematopoietic Stem Cell Transplantation Undergo autologous HSCT Drug: Carboplatin Given IV Drug: Cisplatin Given IV Drug: Cyclophosphamide Given IV Drug: Dexrazoxane Hydrochloride Given IV Biological: Dinutuximab Given IV Drug: Doxorubicin Hydrochloride Given IV Drug: Etoposide Phosphate Given IV Radiation: External Beam Radiation Therapy Undergo EBRT Drug: Isotretinoin Given PO Biological: Sargramostim Given SC Procedure: Therapeutic Conventional Surgery Undergo standard of care surgery Drug: Thiotepa Given IV Drug: Topotecan Hydrochloride Given IV Drug: Vincristine Sulfate Given IV
Experimental: Arm E (lorlatinib, chemotherapy, HSCT, EBRT) See Arm E in detailed description.	Procedure: Autologous Hematopoietic Stem Cell Transplantation Undergo autologous HSCT Drug: Carboplatin Given IV Drug: Cisplatin Given IV Drug: Cyclophosphamide Given IV Drug: Dexrazoxane Hydrochloride Given IV Biological: Dinutuximab Given IV Drug: Doxorubicin Hydrochloride Given IV Drug: Etoposide Phosphate Given IV Radiation: External Beam Radiation Therapy Undergo EBRT Drug: Isotretinoin Given PO Drug: Lorlatinib Given PO Biological: Sargramostim Given SC Procedure: Therapeutic Conventional Surgery Undergo standard of care surgery Drug: Thiotepa Given IV Drug: Topotecan Hydrochloride Given IV

Outcome Measures

Primary Outcome Measures

Event free survival (EFS) (Arm A, B, D, and E) [3 years]
EFS time is calculated from date of randomization or assignment to first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred.

Secondary Outcome Measures

Incidence of adverse events [Up to 18 months for Arms A-D and 28 months for Arm E]
The proportion of patients with at least one Grade 3 or higher toxicity during protocol therapy, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, will be reported.
EFS (Arm C) [3 years]
EFS time is calculated from date of randomization to first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred.
Overall survival (OS) [3 years]
OS time is calculated from date of randomization or assignment until death, or until last contact if patient is alive.
Response rate [Up to 6 months]
The response rate will be calculated among all evaluable patients at end-Induction. Responders are defined as patients who achieve a >= partial response (PR) per the revised International Neuroblastoma Response Criteria (INRC).

Eligibility Criteria

Criteria

Ages Eligible for Study:

365 Days to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must be enrolled on ANBL00B1 (NCT00904241) or APEC14B1 (NCT02402244) prior to enrollment on ANBL1531 (NCT03126916)
Patient must be >= 365 days and =< 30 years of age at diagnosis
Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites; the following disease groups are eligible:
Patients with International Neuroblastoma Risk Group (INRG) stage M disease are eligible if found to have either of the following features:
MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR
Age > 547 days regardless of biologic features
Patients with INRG stage MS disease with MYCN amplification
Patients with INRG stage L2 disease with MYCN amplification
Patients > 547 days of age initially diagnosed with INRG stage L1, L2 or MS disease who progressed to stage M without prior chemotherapy may enroll within 4 weeks of progression to stage M
Patients >= 365 days of age initially diagnosed with MYCN amplified INRG stage L1 disease who progress to stage M without systemic therapy may enroll within 4 weeks of progression to stage M
Patients initially recognized to have high-risk disease must have had no prior systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing); patients observed or treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high risk disease but subsequently found to meet the criteria will also be eligible; patients who receive localized emergency radiation to sites of life-threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis will be eligible
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/sex as follows:
1 to < 2 years: male = 0.6; female = 0.6
2 to < 6 years: male = 0.8; female = 0.8
6 to < 10 years: male = 1; female = 1
10 to < 13 years: male = 1.2; female = 1.2
13 to < 16 years: male = 1.5; female = 1.4
= 16 years: male = 1.7; female = 1.4
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN; for the purposes of this study, ULN for SGPT (ALT) is 45
Shortening fraction of >= 27% by echocardiogram, or ejection fraction of > 50% by echocardiogram or radionuclide angiogram
No known contraindication to peripheral blood stem cell (PBSC) collection; examples of contraindications might be a weight or size less than the collecting institution finds feasible, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure

Exclusion Criteria:

Patients with INRG stage L2 tumors without amplification of MYCN regardless of tumor histology (may meet criteria for high risk classification but are not eligible for this trial)
Patients with bone marrow failure syndromes
Patients for whom targeted radiopharmaceutical therapy would be contraindicated due to underlying medical disorders
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
3	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
4	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
5	Loma Linda University Medical Center	Loma Linda	California	United States	92354
6	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
7	Mattel Children's Hospital UCLA	Los Angeles	California	United States	90095
8	Valley Children's Hospital	Madera	California	United States	93636
9	Kaiser Permanente-Oakland	Oakland	California	United States	94611
10	Children's Hospital of Orange County	Orange	California	United States	92868
11	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
12	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
13	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
14	Naval Medical Center -San Diego	San Diego	California	United States	92134
15	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
16	Children's Hospital Colorado	Aurora	Colorado	United States	80045
17	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
18	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
19	Yale University	New Haven	Connecticut	United States	06520
20	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
21	Children's National Medical Center	Washington	District of Columbia	United States	20010
22	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
23	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
24	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
25	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
26	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
27	Nicklaus Children's Hospital	Miami	Florida	United States	33155
28	AdventHealth Orlando	Orlando	Florida	United States	32803
29	Nemours Children's Hospital	Orlando	Florida	United States	32827
30	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
31	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
32	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
33	Memorial Health University Medical Center	Savannah	Georgia	United States	31404
34	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
35	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
36	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
37	University of Illinois	Chicago	Illinois	United States	60612
38	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
39	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois	United States	60453
40	Advocate Children's Hospital-Park Ridge	Park Ridge	Illinois	United States	60068
41	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
42	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
43	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
44	Blank Children's Hospital	Des Moines	Iowa	United States	50309
45	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
46	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
47	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
48	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
49	Eastern Maine Medical Center	Bangor	Maine	United States	04401
50	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
51	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
52	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
53	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
54	Tufts Children's Hospital	Boston	Massachusetts	United States	02111
55	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
56	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
57	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
58	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
59	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
60	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
61	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
62	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
63	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan	United States	48073
64	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
65	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
66	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
67	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
68	Columbia Regional	Columbia	Missouri	United States	65201
69	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
70	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
71	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
72	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
73	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
74	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
75	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
76	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada	United States	89135
77	Summerlin Hospital Medical Center	Las Vegas	Nevada	United States	89144
78	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
79	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
80	Morristown Medical Center	Morristown	New Jersey	United States	07960
81	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
82	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
83	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
84	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
85	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
86	Albany Medical Center	Albany	New York	United States	12208
87	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
88	Maimonides Medical Center	Brooklyn	New York	United States	11219
89	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
90	NYU Winthrop Hospital	Mineola	New York	United States	11501
91	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
92	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
93	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
94	University of Rochester	Rochester	New York	United States	14642
95	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
96	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
97	New York Medical College	Valhalla	New York	United States	10595
98	Mission Hospital	Asheville	North Carolina	United States	28801
99	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
100	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
101	Duke University Medical Center	Durham	North Carolina	United States	27710
102	East Carolina University	Greenville	North Carolina	United States	27834
103	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
104	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
105	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
106	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
107	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
108	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
109	Dayton Children's Hospital	Dayton	Ohio	United States	45404
110	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio	United States	43606
111	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
112	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
113	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania	United States	18103
114	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
115	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
116	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
117	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
118	Rhode Island Hospital	Providence	Rhode Island	United States	02903
119	Medical University of South Carolina	Charleston	South Carolina	United States	29425
120	Prisma Health Richland Hospital	Columbia	South Carolina	United States	29203
121	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
122	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
123	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
124	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
125	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
126	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
127	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
128	Medical City Dallas Hospital	Dallas	Texas	United States	75230
129	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
130	El Paso Children's Hospital	El Paso	Texas	United States	79905
131	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
132	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
133	Covenant Children's Hospital	Lubbock	Texas	United States	79410
134	UMC Cancer Center / UMC Health System	Lubbock	Texas	United States	79415
135	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
136	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
137	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
138	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
139	University of Vermont and State Agricultural College	Burlington	Vermont	United States	05405
140	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
141	Seattle Children's Hospital	Seattle	Washington	United States	98105
142	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
143	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
144	Madigan Army Medical Center	Tacoma	Washington	United States	98431
145	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
146	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
147	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792
148	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin	United States	54449
149	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
150	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
151	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
152	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador	Canada	A1B 3V6
153	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
154	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
155	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
156	Children's Hospital	London	Ontario	Canada	N6A 5W9
157	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
158	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
159	HIMA San Pablo Oncologic Hospital	Caguas		Puerto Rico	00726