Chemotherapy for the Treatment of Patients With Newly Diagnosed Very Low-Risk and Low Risk Fusion Negative Rhabdomyosarcoma

Sponsor

Children's Oncology Group (Other)

Overall Status

Recruiting

CT.gov ID

NCT05304585

Collaborator

National Cancer Institute (NCI) (NIH)

205

Enrollment

Locations

Arms

96.3

Anticipated Duration (Months)

4.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Rhabdomyosarcoma is a type of cancer that occurs in the soft tissues in the body. This phase III trial aims to maintain excellent outcomes in patients with very low risk rhabdomyosarcoma (VLR-RMS) while decreasing the burden of therapy using treatment with 24 weeks of vincristine and dactinomycin (VA) and examines the use of centralized molecular risk stratification in the treatment of rhabdomyosarcoma. Another aim of the study it to find out how well patients with low risk rhabdomyosarcoma (LR-RMS) respond to standard chemotherapy when patients with VLR-RMS and patients who have rhabdomyosarcoma with DNA mutations get separate treatment. Finally, this study examines the effect of therapy intensification in patients who have RMS cancer with DNA mutations to see if their outcomes can be improved.

Condition or Disease	Intervention/Treatment	Phase
Embryonal Rhabdomyosarcoma Fusion-Negative Alveolar Rhabdomyosarcoma Spindle Cell/Sclerosing Rhabdomyosarcoma	Drug: Cyclophosphamide Biological: Dactinomycin Radiation: Radiation Therapy Drug: Vincristine	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

To evaluate the failure free survival (FFS) of patients with very low-risk (VLR) rhabdomyosarcoma (RMS) (fusion negative [FN], stage 1, clinical group [CG] I, MYOD1 wildtype [WT], TP53 [WT]) when treated with 24 weeks of vincristine and dactinomycin (VA).
To evaluate the FFS of patients with low-risk (LR) RMS (FN, stage 1 CG II, or stage 2 CG I/II or CG III [orbit only], MYOD1 WT, TP53 WT) when treated with 12 weeks of vincristine, dactinomycin and cyclophosphamide (VAC) followed by 12 weeks of VA.

SECONDARY OBJECTIVES:

To evaluate the overall survival (OS) of patients with VLR RMS treated with 24 weeks of VA.
To evaluate the OS of patients with LR RMS treated with 12 weeks of VAC followed by 12 weeks of VA.
To demonstrate the feasibility of central molecular risk stratification of patients with newly diagnosed RMS in the context of a prospective clinical trial.

EXPLORATORY OBJECTIVES:

To collect blood and tissue samples for banking at baseline, during treatment, at the end of therapy, and at the time of progression to bank for future research.
To describe the methylation array profile of patients with fusion negative, low-risk rhabdomyosarcoma.
To describe the outcomes of patients with VLR or LR RMS and MYOD1 or TP53 mutations treated with intensified therapy.

OUTLINE: Patients are assigned to 1 of 2 regimens based on clinical features. Patients with positive mutation status are transitioned to a third regimen, Regimen M.

REGIMEN VA: Patients with VLR RMS receive vincristine intravenously (IV) on day 1 of each cycle and days 8 and 15 of cycles 1, 3, 5, and 7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3).

REGIMEN VAC/VA: Patients with LR RMS receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 1-3. Patients also receive dactinomycin IV over 1-5 minutes or 10-15 minutes and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 5-7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). Patients may also undergo radiation therapy at cycle 5.

REGIMEN M: Patients receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 2-4, 7-8, and 11-12 and dactinomycin IV over 1-5 minutes or 10-15 minutes on day 1 of cycles 2-5 and 8-14. Patients also receive cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 12-13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo radiation therapy at cycle 5.

After completion of study treatment, patients are followed up every 3 months during the first year, then every 4 months for years 2 and 3, every 6 months for year 4, and finally at 5 years post treatment conclusion date.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

205 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Prospective Phase 3 Study of Patients With Newly Diagnosed Very Low-Risk and Low-Risk Fusion Negative Rhabdomyosarcoma

Actual Study Start Date :

Jun 22, 2022

Anticipated Primary Completion Date :

Jun 30, 2030

Anticipated Study Completion Date :

Jun 30, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regimen M (positive mutation) Patients receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 2-4, 7-8, and 11-12 and dactinomycin IV over 1-5 minutes or 10-15 minutes on day 1 of cycles 2-5 and 8-14. Patients also receive cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 12-13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo radiation therapy at cycle 5.	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 Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 Biological: Dactinomycin Given IV Other Names: Actinomycin A IV Actinomycin C1 Actinomycin D Actinomycin I1 Actinomycin IV Actinomycin X 1 Actinomycin-[thr-val-pro-sar-meval] Cosmegen DACT Dactinomycine Lyovac Cosmegen Meractinomycin Radiation: Radiation Therapy Undergo radiation Other Names: Cancer Radiotherapy ENERGY_TYPE Irradiate Irradiated Irradiation Radiation Radiation Therapy, NOS Radiotherapeutics Radiotherapy RT Therapy, Radiation Drug: Vincristine Given IV Other Names: Leurocristine VCR Vincrystine
Experimental: Regimen VA (VLR RMS) Patients with VLR RMS receive vincristine intravenously (IV) on day 1 of each cycle and days 8 and 15 of cycles 1, 3, 5, and 7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3).	Biological: Dactinomycin Given IV Other Names: Actinomycin A IV Actinomycin C1 Actinomycin D Actinomycin I1 Actinomycin IV Actinomycin X 1 Actinomycin-[thr-val-pro-sar-meval] Cosmegen DACT Dactinomycine Lyovac Cosmegen Meractinomycin Drug: Vincristine Given IV Other Names: Leurocristine VCR Vincrystine
Experimental: Regimen VAC/VA (VL RMS) Patients with LR RMS receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 1-3. Patients also receive dactinomycin IV over 1-5 minutes or 10-15 minutes and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 5-7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). Radiation therapy (if needed) will be administered at cycle 5.	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 Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 Biological: Dactinomycin Given IV Other Names: Actinomycin A IV Actinomycin C1 Actinomycin D Actinomycin I1 Actinomycin IV Actinomycin X 1 Actinomycin-[thr-val-pro-sar-meval] Cosmegen DACT Dactinomycine Lyovac Cosmegen Meractinomycin Drug: Vincristine Given IV Other Names: Leurocristine VCR Vincrystine

Arm

Intervention/Treatment

Experimental: Regimen M (positive mutation)

Patients receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 2-4, 7-8, and 11-12 and dactinomycin IV over 1-5 minutes or 10-15 minutes on day 1 of cycles 2-5 and 8-14. Patients also receive cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 12-13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo radiation therapy at cycle 5.

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

Cyclophosphamide Monohydrate

Cyclophosphamidum

Cyclophosphan

Cyclophosphane

Cyclophosphanum

Cyclostin

Cyclostine

Cytophosphan

Cytophosphane

Cytoxan

Fosfaseron

Genoxal

Genuxal

Ledoxina

Mitoxan

Neosar

Revimmune

Syklofosfamid

WR- 138719

Biological: Dactinomycin

Given IV

Other Names:

Actinomycin A IV

Actinomycin C1

Actinomycin D

Actinomycin I1

Actinomycin IV

Actinomycin X 1

Actinomycin-[thr-val-pro-sar-meval]

Cosmegen

DACT

Dactinomycine

Lyovac Cosmegen

Meractinomycin

Radiation: Radiation Therapy

Undergo radiation

Other Names:

Cancer Radiotherapy

ENERGY_TYPE

Irradiate

Irradiated

Irradiation

Radiation

Radiation Therapy, NOS

Radiotherapeutics

Radiotherapy

Therapy, Radiation

Drug: Vincristine

Given IV

Other Names:

Leurocristine

VCR

Vincrystine

Experimental: Regimen VA (VLR RMS)

Patients with VLR RMS receive vincristine intravenously (IV) on day 1 of each cycle and days 8 and 15 of cycles 1, 3, 5, and 7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3).

Biological: Dactinomycin

Given IV

Other Names:

Actinomycin A IV

Actinomycin C1

Actinomycin D

Actinomycin I1

Actinomycin IV

Actinomycin X 1

Actinomycin-[thr-val-pro-sar-meval]

Cosmegen

DACT

Dactinomycine

Lyovac Cosmegen

Meractinomycin

Drug: Vincristine

Given IV

Other Names:

Leurocristine

VCR

Vincrystine

Experimental: Regimen VAC/VA (VL RMS)

Patients with LR RMS receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 1-3. Patients also receive dactinomycin IV over 1-5 minutes or 10-15 minutes and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 5-7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). Radiation therapy (if needed) will be administered at cycle 5.

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

Cyclophosphamide Monohydrate

Cyclophosphamidum

Cyclophosphan

Cyclophosphane

Cyclophosphanum

Cyclostin

Cyclostine

Cytophosphan

Cytophosphane

Cytoxan

Fosfaseron

Genoxal

Genuxal

Ledoxina

Mitoxan

Neosar

Revimmune

Syklofosfamid

WR- 138719

Biological: Dactinomycin

Given IV

Other Names:

Actinomycin A IV

Actinomycin C1

Actinomycin D

Actinomycin I1

Actinomycin IV

Actinomycin X 1

Actinomycin-[thr-val-pro-sar-meval]

Cosmegen

DACT

Dactinomycine

Lyovac Cosmegen

Meractinomycin

Drug: Vincristine

Given IV

Other Names:

Leurocristine

VCR

Vincrystine

Outcome Measures

Primary Outcome Measures

Failure free survival (FFS) for very low risk patients [From study enrollment to disease progression, recurrence, or death as a first event, assessed up to 3 years]
The Kaplan-Meier method will be used to estimate 3-year FFS along with 80% log-minus-log transformed confidence limits for very low risk (VLR) patients.
Failure free survival (FFS) for low risk patients [From study enrollment to disease progression, recurrence, or death as a first event, assessed up to 3 years]
The Kaplan-Meier method will be used to estimate 3 year FFS along with 80% log-minus-log transformed confidence limits for low risk (LR) patients.

Secondary Outcome Measures

Overall survival (OS) for very low risk patients [From study entry to death of any cause, assessed up to 5 years]
Log-rank test will be used to compare the OS of patients with VLR rhabdomyosarcoma (RMS) treated with 24 weeks of vincristine, dactinomycin (VA) to the VLR RMS patients from ARST0331 and D9602 with the same inclusion criteria.
Overall survival (OS) for low risk patients [From study entry to death of any cause, assessed up to 5 years]
Log-rank test will be used to compare the OS from LR RMS patients to LR RMS patients from ARST0331 and D9602 with the same inclusion criteria.
Feasibility of central molecular risk stratification of patients assessed by the percentage of patients who have molecular testing results returned by 6 weeks [Up to 24 weeks]
If the percentage of patients who have molecular testing results returned by 6 weeks is >= 80% then the central molecular risk stratification is considered feasible.

Other Outcome Measures

Methylation array profile of patients with fusion negative, low-risk rhabdomyosarcoma [Up to 5 years]
Summary statistics will be used to describe the methylation array profile of patients with fusion negative, low-risk rhabdomyosarcoma. Correlation between methylation patterns and clinical presentation, histology, and genetics will be evaluated.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

All patients must be enrolled on APEC14B1 (NCT02402244) and consented to the Molecular Characterization Initiative (Part A) prior to enrollment and treatment on ARST2032 (this trial).
Patients must be =< 21 years at the time of enrollment.
Patients must have newly diagnosed embryonal rhabdomyosarcoma (ERMS), spindle cell/sclerosing RMS, or FOXO1 fusion negative alveolar rhabdomyosarcoma (ARMS) (institutional FOXO1 fusion results are acceptable). RMS types included under ERMS include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2020 World Health Organization (WHO) classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Enrollment in APEC14B1 is required for all patients.
All patients will be evaluated for stage and clinical group. Note that clinical group designation assigned at the time of enrollment on study remains unchanged regardless of any second-look operation that may be performed.
Patients will be eligible for the very low-risk stratum (Regimen VA) if they have Stage 1, CG I disease.
Patients will be eligible for the low-risk stratum (Regimen VAC/VA) if they have Stage 1, CG II disease, Stage 2, CG I or II disease, or Stage 1, CG III (orbit only) disease.
Paratesticular Tumors: Staging ipsilateral retroperitoneal lymph node sampling (SIRLNS) is required for all patients >= 10 years of age with paratesticular tumors who do not have gross nodal involvement on imaging.
Extremity Tumors: Regional lymph node sampling is required for histologic evaluation in patients with extremity tumors.
Clinically or radiographically enlarged nodes must be sampled for histologic evaluation.
Patients must have a Lansky (for patients =< 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of >= 50. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing performance score.
Peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to enrollment).
Platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to enrollment).
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine (within 7 days prior to enrollment) based on age/gender as follows:
Age: 1 month to < 6 months; Maximum serum creatinine (mg/dL): 0.4 (male) : 0.4 (female)
Age: 6 months to < 1 year; Maximum serum creatinine (mg/dL): 0.5 (male) : 0.5 (female)
Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male) : 0.6 (female)
Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male) : 0.8 (female)
Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male) : 1 (female)
Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male) : 1.2 (female)
Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male) : 1.4 (female)
Age >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male) : 1.4 (female)
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment), and
If there is evidence of biliary obstruction by the tumor, then the total bilirubin must be < 3 x ULN for age.
Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L.
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment).
All patients and/or their parents or legal guardians must sign a written informed consent.
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

Exclusion Criteria:

Patients who have received prior chemotherapy and/or radiation therapy for cancer prior to enrollment. Surgical resection alone of previous cancer(s) is permitted.
Patients who have received chemotherapy or radiation for non-malignant conditions (e.g., autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy.
Vincristine is sensitive substrate of the CYP450 3A4 isozyme. Patients must not have received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7 days prior to study enrollment.
Patients unable to undergo radiation therapy, if necessary, as specified in the protocol.
Evidence of uncontrolled infection.
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	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
3	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
4	Valley Children's Hospital	Madera	California	United States	93636
5	Children's Hospital of Orange County	Orange	California	United States	92868
6	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
7	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
8	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
9	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
10	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
11	Nemours Children's Hospital	Orlando	Florida	United States	32827
12	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
13	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
14	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
15	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
16	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
17	Norton Children's Hospital	Louisville	Kentucky	United States	40202
18	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
19	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
20	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
21	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
22	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts	United States	01655
23	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
24	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
25	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
26	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
27	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
28	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
29	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
30	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
31	Albany Medical Center	Albany	New York	United States	12208
32	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
33	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio	United States	43606
34	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
35	Prisma Health Richland Hospital	Columbia	South Carolina	United States	29203
36	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
37	The Children's Hospital at TriStar Centennial	Nashville	Tennessee	United States	37203
38	Medical City Dallas Hospital	Dallas	Texas	United States	75230
39	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
40	El Paso Children's Hospital	El Paso	Texas	United States	79905
41	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
42	M D Anderson Cancer Center	Houston	Texas	United States	77030
43	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
44	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
45	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
46	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
47	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
48	Madigan Army Medical Center	Tacoma	Washington	United States	98431
49	West Virginia University Charleston Division	Charleston	West Virginia	United States	25304