Larotrectinib in Treating Patients With Previously Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia

Sponsor

Children's Oncology Group (Other)

Overall Status

Recruiting

CT.gov ID

NCT03834961

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

42.4

Anticipated Duration (Months)

0.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects and how well larotrectinib works in treating patients with previously untreated TRK fusion solid tumors and TRK fusion acute leukemia that has come back. Larotrectinib may stop the growth of cancer cells with TRK fusions by blocking the TRK enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Central Nervous System Neoplasm Infantile Fibrosarcoma Recurrent Acute Leukemia Refractory Acute Leukemia Solid Neoplasm	Drug: Larotrectinib Sulfate	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

To determine the objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control.

SECONDARY OBJECTIVES:

To determine event-free survival (EFS), overall survival (OS), and duration of response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control.
To determine the ORR, EFS, OS, and DoR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control.
To describe the toxicity of larotrectinib in children with solid tumors and acute leukemia.
To determine the percentage of patients with TRK fusion solid tumors with detectable circulating tumor deoxyribonucleic acid (DNA) at baseline and after 2 weeks, 4 weeks, 24 weeks of treatment, at the time of discontinuation of larotrectinib therapy, and at progression.

EXPLORATORY OBJECTIVES:

To determine the EFS, OS, and DoR of children with TRK fusion solid tumors other than IFS treated with adjuvant larotrectinib following upfront surgery with positive margins after neoadjuvant larotrectinib.
To determine the EFS, OS, and DoR of children with TRK fusion solid tumors who experience a complete response to larotrectinib and subsequently discontinue larotrectinib therapy.
To determine the remission induction rate for patients with recurrent/refractory TRK fusion leukemia when treated with larotrectinib.
To evaluate the surgical morbidity and extent of resection of initially unresectable tumors in patients with TRK fusion solid tumors who undergo surgical resection following neoadjuvant larotrectinib.
To evaluate mechanisms of response and resistance to larotrectinib in children with TRK fusion cancers.
To evaluate the morphologic features of TRK fusion solid tumors at time of initial biopsy to further define criteria for pathologic diagnosis of these tumors.
To evaluate immunohistochemistry for pan-TRK as a screening method for TRK fusion tumors and in resection specimens following neoadjuvant treatment with larotrectinib.
To evaluate the histologic response to larotrectinib in resection specimens following neoadjuvant treatment.
To evaluate circulating tumor DNA for the detection of the emergence of resistance mutations and recurrence in patients with TRK fusion solid tumors treated with larotrectinib.
To evaluate the ratio of cerebrospinal fluid (CSF) to concurrent plasma concentrations of larotrectinib in patients with leukemia.
To evaluate the change in neurocognitive/behavioral functioning over time between baseline and 2 years post-diagnosis of patients treated on this protocol using parent-reported adaptive functioning (Adaptive Behavior Assessment System [ABAS]-III General Adaptive Composite), executive function (Behavior Rating Inventory of Executive Function Scales-Preschool Version [BRIEF-P] or BRIEF-2 Global Executive Composite Score), psychosocial functioning (Behavior Assessment System for Children [BASC]-3 Internalizing, Externalizing and Behavioral Symptoms Indices) and quality of life (Pediatric Quality of Life Inventory [PedsQL] Total score).

OUTLINE:

Patients receive larotrectinib orally (PO) or by nasogastric (NG) or gastric tube (G-tube) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients whose tumors shrink sufficiently while taking larotrectinib may undergo surgical resection of their tumor while on study.

After completion of study treatment, patients are followed up at 3, 6, 12, 18, 24, 30, 36, and 48 months and annually thereafter for up to 5 years from the date of study entry.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

70 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Larotrectinib (LOXO-101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias

Actual Study Start Date :

Sep 18, 2019

Anticipated Primary Completion Date :

Mar 31, 2023

Anticipated Study Completion Date :

Mar 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (larotrectinib) Patients receive larotrectinib PO or by NG or G-tube BID on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity, or complete surgical resection of tumor.	Drug: Larotrectinib Sulfate Given PO or via NG or G tube Other Names: ARRY 470 Sulfate LOXO 101 Sulfate LOXO-101 Sulfate Vitrakvi

Arm

Intervention/Treatment

Experimental: Treatment (larotrectinib)

Patients receive larotrectinib PO or by NG or G-tube BID on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity, or complete surgical resection of tumor.

Drug: Larotrectinib Sulfate

Given PO or via NG or G tube

Other Names:

ARRY 470 Sulfate

LOXO 101 Sulfate

LOXO-101 Sulfate

Vitrakvi

Outcome Measures

Primary Outcome Measures

Objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control [Up to 5 years]
Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.

Secondary Outcome Measures

Event-free survival (EFS) of children with IFS treated with neoadjuvant larotrectinib prior to local control [Up to 5 years]
Will be computed one year after the last enrollment in a stratum.
Overall survival (OS) of children with IFS treated with neoadjuvant larotrectinib prior to local control [Up to 5 years]
Will be computed one year after the last enrollment in a stratum.
Duration of response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control [From first observation of either partial response (PR) or complete response (CR) until either the first observation of progressive disease (PD) (event) or last known observation of the patient (censored observation), assessed up to 5 years]
Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.
ORR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control [Up to 5 years]
Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.
EFS of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control [Up to 5 years]
Will be computed one year after the last enrollment in a stratum.
OS of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control [Up to 5 years]
Will be computed one year after the last enrollment in a stratum.
DoR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control [From first observation of either partial response (PR) or complete response (CR) until either the first observation of progressive disease (PD) (event) or last known observation of the patient (censored observation), assessed up to 5 years]
Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.
Incidence of adverse events [Up to 5 years]
Per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the attribution(s) to the study regimen.
Percentage of patients with TRK fusion solid tumors with detectable circulating tumor deoxyribonucleic acid (DNA) [Baseline up to 5 years]
The percentage of ctDNA and frequency with which patients have detectable ctDNA prior to the start of therapy and at times during therapy when subsequent serial samples are obtained will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). In cases of treatment resistance, we will also perform exploratory deep sequencing of ctDNA to determine whether this method can detect the emergence of resistance mutations.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

COHORT A: Patients must have a histologic diagnosis of infantile fibrosarcoma with an NTRK1, NTRK2, or NTRK3 fusion identified in a Clinical Laboratory Improvement Act/College of American Pathologists (CLIA/CAP) certified laboratory. Fusions may be identified by fluorescence in situ hybridization (FISH) or molecular techniques (reverse transcriptase-polymerase chain reaction [RT-PCR] using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, an ETV6 rearrangement is sufficient for eligibility in Cohort A. Identification of the upstream TRK fusion partner is not required.
COHORT B: Patients must have a histologic diagnosis of any solid tumor other than infantile fibrosarcoma, including central nervous system (CNS) tumors but excluding high grade gliomas. An NTRK1, NTRK2, or NTRK3 fusion must be identified in a CLIA/CAP certified laboratory. Fusions may be identified by FISH or molecular techniques (RT-PCR using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility) unless the patient has a diagnosis of congenital mesoblastic nephroma in which case an ETV6 rearrangement is sufficient for eligibility. Identification of the upstream TRK fusion partner is not required.
COHORT C: Patients must have a histologic diagnosis of relapsed or refractory acute leukemia with an NTRK1, NTRK2, or NTRK3 fusion identified in a CLIA/CAP certified laboratory. Fusions may be identified by FISH or molecular techniques (RT-PCR using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility). Identification of the upstream TRK fusion partner is not required.
SOLID TUMORS (COHORTS A AND B): Patients must have measurable disease. Patients must have disease that cannot be completely resected without a predicted functional, neurologic, or significant cosmetic deficit in the opinion of the investigator.
LEUKEMIA (COHORT C): Patients must have >= 5% blasts in the bone marrow. Extramedullary disease is permitted.
Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age. NOTE: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. 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 the performance score.
COHORTS A AND B: No prior anti-cancer therapy, including radiotherapy, other than surgical resection is permitted.
Patients who experience recurrence after surgery alone and no other anti-cancer therapy will be eligible.
If not eligible due to prior anticancer therapy, patients may be eligible for the larotrectinib arm of Pediatric MATCH (APEC1621A) or treatment with commercial larotrectinib off study.
COHORT C: Patients with relapsed leukemia (Cohort C) must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately.
Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment.
A waiting period prior to enrollment is not required for patients receiving standard cytotoxic maintenance chemotherapy (i.e., corticosteroid, vincristine, thioguanine [6MP], and/or methotrexate).
A waiting period is not required for patients receiving a single dose of intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days prior to enrollment
= 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy.
Note: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy.
Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil [ANC] counts): >= 7 days after the last dose of agent. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment.
Anti-cancer agents that are antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1. There is an exception for blinatumomab infusions, for which patients must have been off for at least 3 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria.
Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid. A waiting period prior to enrollment is not required for patients receiving corticosteroid for leukemia therapy/cytoreduction.
Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator.
Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors )
Stem cell infusions (with or without total body irradiation [TBI]):
Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion:

= 84 days after infusion and no evidence of graft versus host disease (GVHD).

Autologous stem cell infusion including boost infusion: >= 42 days.
Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial BM radiation.
Radiopharmaceutical therapy (e.g., radiolabeled antibody): >= 42 days after systemically administered radiopharmaceutical therapy.
Patients must not have received prior exposure to TRK inhibitors (including larotrectinib, LOXO-195, entrectinib, lorlatinib, crizotinib, or lestaurtinib).
For patients with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days prior to enrollment)
For patients with solid tumors without known bone marrow involvement: Platelet count

= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

For patients with solid tumors without known bone marrow involvement: Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions).
Patients with solid tumors with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts above (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity.
For patients with leukemia: Platelet count >= 20,000/mm^3 (within 7 days prior to enrollment) (may receive platelet transfusions; must not be known to be refractory to red cell or platelet transfusion)
For patients with leukemia: Hemoglobin >= 8.0 g/dL at baseline (within 7 days prior to enrollment) (may receive RBC transfusions; must not be known to be refractory to red cell or platelet transfusion)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL)
6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL)
1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)
2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)
6 to < 10 years (male 1 mg/dL, female 1 mg/dL)
10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)
13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)
= 16 years (male 1.7 mg/dL, female 1.4 mg/dL)
For patients < 1 month of age, serum creatinine levels must be < 1.5 x the treating institution's creatinine upper limit of normal (ULN) for patients < 1 month of age or the creatinine clearance or radioisotope GFR must be >= 70 mL/min/1.73 m^2.
Patients with solid tumors: Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment). After approval of the study chair or designee, infants with a higher total bilirubin due to physiologic or breast milk jaundice are eligible if the conjugated (direct) bilirubin is =< 2 mg/dL
Patients with solid tumors: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
Patients with solid tumors: Serum albumin >= 2 g/dL (within 7 days prior to enrollment).
Patients with leukemias: Conjugated (direct) bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment).
Patients with leukemias: SGPT (ALT) =< 225 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
Patients with leukemias: Serum albumin >= 2 g/dL (within 7 days prior to enrollment).
Patients with seizure disorder may be enrolled if on a stable antiepileptic regimen for >= 14 days and well controlled.
Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5) except tendon reflex decreased resulting from prior therapy must be =< grade 2.
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:

Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Female patients of reproductive potential may not participate unless they have agreed to use a highly effective contraceptive method for the duration of study therapy and for at least one month after the final dose of larotrectinib. Males of reproductive potential with a non-pregnant female partner of child-bearing potential must use a highly effective contraception for the duration of the study and for at least one month after the final dose of larotrectinib. Because of the unknown risk of larotrectinib in nursing infants, nursing women should discontinue breastfeeding during treatment with larotrectinib and for 3 days following the final dose.
Patients with solid tumors, including CNS tumors, requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. Patients with leukemia may receive systemic corticosteroids for cytoreduction up to 24 hours prior to the start of protocol therapy. If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid.
Patients who are currently receiving another investigational drug are not eligible.
Patients who are currently receiving other anti-cancer agents are not eligible [except leukemia patients receiving corticosteroids or hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy]. Patients with leukemia should receive a single dose of intrathecal cytarabine, hydrocortisone, and/or methotrexate within 7 days prior to Day 1 of Cycle 1 at the time of the baseline lumbar puncture.
Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial.
Patients currently receiving a strong CYP3A4 inducer or inhibitor are not eligible. Strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study. Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed.
Patients with malabsorption syndrome or other conditions that significantly limit enteral absorption are not eligible.
Patients who are unable to swallow capsules or liquid and do not have gastric access via a nasogastric or gastrostomy tube are not eligible.
Patients who have an uncontrolled infection are not eligible.
Patients who have received prior solid organ transplantation are not eligible.
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
Patients with high grade gliomas (HGG) are not eligible.

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	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
4	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
5	Kaiser Permanente-Oakland	Oakland	California	United States	94611
6	Children's Hospital of Orange County	Orange	California	United States	92868
7	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
8	Children's Hospital Colorado	Aurora	Colorado	United States	80045
9	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
10	Yale University	New Haven	Connecticut	United States	06520
11	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
12	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
13	Children's National Medical Center	Washington	District of Columbia	United States	20010
14	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
15	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
16	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
17	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
18	Jackson Memorial Hospital-Holtz Children's Hospital	Miami	Florida	United States	33136
19	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
20	Nicklaus Children's Hospital	Miami	Florida	United States	33155
21	Nemours Children's Hospital	Orlando	Florida	United States	32827
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	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
25	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
26	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
27	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
28	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
29	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
30	Norton Children's Hospital	Louisville	Kentucky	United States	40202
31	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
32	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
33	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
34	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
35	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
36	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
37	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
38	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
39	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
40	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
41	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
42	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
43	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
44	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
45	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
46	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
47	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
48	Morristown Medical Center	Morristown	New Jersey	United States	07960
49	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
50	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
51	Mission Hospital	Asheville	North Carolina	United States	28801
52	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
53	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
54	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
55	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
56	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
57	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
58	Dayton Children's Hospital	Dayton	Ohio	United States	45404
59	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
60	Oregon Health and Science University	Portland	Oregon	United States	97239
61	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania	United States	18103
62	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
63	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
64	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
65	Rhode Island Hospital	Providence	Rhode Island	United States	02903
66	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
67	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
68	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
69	Medical City Dallas Hospital	Dallas	Texas	United States	75230
70	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
71	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
72	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
73	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
74	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
75	Seattle Children's Hospital	Seattle	Washington	United States	98105
76	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
77	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
78	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792
79	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin	United States	54449
80	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
81	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
82	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5