Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
Study Details
Study Description
Brief Summary
This phase II Pediatric MATCH trial studies how well larotrectinib works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with NTRK fusions that have spread to other places in the body and have come back or do not respond to treatment. Larotrectinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVE:
- To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with larotrectinib sulfate (LOXO-101 [larotrectinib]) with advanced solid tumors (including central nervous system [CNS] tumors), non-Hodgkin lymphomas or histiocytic disorders harboring NTRK 1/2/3 fusions.
SECONDARY OBJECTIVES:
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To estimate the progression free survival in pediatric patients treated with LOXO-101 (larotrectinib) with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders with NTRK 1/2/3 fusions.
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To obtain additional information about the tolerability of LOXO-101 (larotrectinib) in children with relapsed or refractory cancer.
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To provide preliminary estimates of the pharmacokinetics of LOXO-101 (larotrectinib) in children with relapsed or refractory cancer.
EXPLORATORY OBJECTIVE:
- To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA).
OUTLINE:
Patients receive larotrectinib sulfate orally (PO) or via nasogastric (NG)- or gastric (G)-tube twice per day (BID) on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then periodically thereafter.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Treatment (larotrectinib sulfate) Patients receive larotrectinib sulfate PO or via NG- or G-tube twice per day (BID) on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. |
Drug: Larotrectinib Sulfate
Given PO or via nasogastric- or gastric-tube
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Objective response rate [Up to 5 years]
Will be determined by Response Evaluation Criteria in Solid Tumors.
Secondary Outcome Measures
- Progression free survival [The time from the initiation of protocol treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause, assessed up to 5 years]
Progression free survival along with the confidence intervals will be estimated using the Kaplan-Meier method. Patients with local calls of disease progression (i.e. calls made by the treating institution), will be counted as having had an event, even if the central review does not declare progression. Progression free survival will be reported based on central radiology review as a secondary analysis, if adequate number of disagreements in progressions exist between the treating institutions and the central radiology review to make such an analysis meaningful.
Other Outcome Measures
- Incidence of adverse events [Up to 5 years]
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 probable association with the study regimen.
- Pharmacokinetics of larotrectinib [Pre-dose, 1, 2, 4, and 6-8 hours after morning dose of day 1 cycle 1 and pre-dose of day 1 cycle 2]
A descriptive analysis of pharmacokinetic parameters of LOXO-101 (larotrectinib) will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The pharmacokinetic parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). All these analyses will be descriptive and exploratory and hypotheses generating in nature.
- Ability to detect NTRK fusions in circulating cell-free tumor deoxyribonucleic acid in plasma [Up to 5 years]
A descriptive analysis of the exploratory aims will be performed and will be summarized with simple summary statistics. All of these analyses will be descriptive in nature.
Eligibility Criteria
Criteria
Inclusion Criteria:
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APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621A based on the presence of an actionable mutation as defined in APEC1621SC
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Patients must have radiographically measurable disease at the time of study enrollment; patients with neuroblastoma who do not have measurable disease but have iobenguane (MIBG)+ evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT); Note: The following do not qualify as measurable disease:
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Malignant fluid collections (e.g., ascites, pleural effusions)
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Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
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Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
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Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
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Previously radiated lesions that have not demonstrated clear progression post radiation
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Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
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Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: neurologic deficits in patients with CNS tumors must have been relatively 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
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Patients 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 time frame, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
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Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive; for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
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= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
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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; for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
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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
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Corticosteroids: if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
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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 growth factors 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
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Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
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Stem cell Infusions (with or without total body irradiation [TBI]):
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Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor leukocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
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Autologous stem cell infusion including boost infusion: >= 42 days
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Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.)
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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 brain metastases (BM) radiation; Note: radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
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Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
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Patients must not have received prior exposure to other NTRK inhibitors including but not limited to LOXO-101 (larotrectinib), entrectinib (RXDX-101), DS6051, PLX7486
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For patients with solid tumors without known bone marrow involvement:
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Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
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Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
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Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (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
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Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or
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A serum creatinine based on age/gender as follows:
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Age: 1 to < 2 years; maximum serum creatinine (mg/dL); male: 0.6 female: 0.6
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Age: 2 to < 6 years; maximum serum creatinine (mg/dL); male: 0.8 female: 0.8
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Age: 6 to < 10 years; maximum serum creatinine (mg/dL); male: 1 female: 1
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Age: 10 to < 13 years; maximum serum creatinine (mg/dL); male: 1.2 female: 1.2
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Age: 13 to < 16 years; maximum serum creatinine (mg/dL); male: 1.5 female: 1.4
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Age: >= 16 years; maximum serum creatinine (mg/dL); male: 1.7 female: 1.4
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Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
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Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L; (for the purpose of this study, the ULN for SGPT is 45 U/L)
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Serum albumin >= 2 g/dL
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Patients with seizure disorder may be enrolled if on anti-convulsants and well controlled
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Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflect (DTR); any grade of DTR is eligible
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All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
Exclusion Criteria:
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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; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study treatment
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Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
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Patients who are currently receiving another investigational drug are not eligible
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Patients who are currently receiving other anti-cancer agents are not eligible
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Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease (GVHD) post bone marrow transplant are not eligible for this trial
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Patients who are currently receiving drugs that are strong inducers or inhibitors of CYP3A4 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
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Patients who have received prior therapy with a specific inhibitor of TRK (including but not limited to entrectinib [RXDX-101], DS-6051b, and PLX7486) are not eligible
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Patients who have an uncontrolled infection are not eligible
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Patients who have received a prior solid organ transplantation are not eligible
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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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Children's Hospital of Alabama | Birmingham | Alabama | United States | 35233 |
2 | Providence Alaska Medical Center | Anchorage | Alaska | United States | 99508 |
3 | Banner Children's at Desert | Mesa | Arizona | United States | 85202 |
4 | Banner University Medical Center - Tucson | Tucson | Arizona | United States | 85719 |
5 | Arkansas Children's Hospital | Little Rock | Arkansas | United States | 72202-3591 |
6 | Kaiser Permanente Downey Medical Center | Downey | California | United States | 90242 |
7 | Loma Linda University Medical Center | Loma Linda | California | United States | 92354 |
8 | Miller Children's and Women's Hospital Long Beach | Long Beach | California | United States | 90806 |
9 | Children's Hospital Los Angeles | Los Angeles | California | United States | 90027 |
10 | Valley Children's Hospital | Madera | California | United States | 93636 |
11 | UCSF Benioff Children's Hospital Oakland | Oakland | California | United States | 94609 |
12 | Kaiser Permanente-Oakland | Oakland | California | United States | 94611 |
13 | University of California Davis Comprehensive Cancer Center | Sacramento | California | United States | 95817 |
14 | UCSF Medical Center-Mission Bay | San Francisco | California | United States | 94158 |
15 | Children's Hospital Colorado | Aurora | Colorado | United States | 80045 |
16 | Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center | Denver | Colorado | United States | 80218 |
17 | Yale University | New Haven | Connecticut | United States | 06520 |
18 | Alfred I duPont Hospital for Children | Wilmington | Delaware | United States | 19803 |
19 | Children's National Medical Center | Washington | District of Columbia | United States | 20010 |
20 | University of Florida Health Science Center - Gainesville | Gainesville | Florida | United States | 32610 |
21 | Nemours Children's Clinic-Jacksonville | Jacksonville | Florida | United States | 32207 |
22 | University of Miami Miller School of Medicine-Sylvester Cancer Center | Miami | Florida | United States | 33136 |
23 | Nicklaus Children's Hospital | Miami | Florida | United States | 33155 |
24 | AdventHealth Orlando | Orlando | Florida | United States | 32803 |
25 | Arnold Palmer Hospital for Children | Orlando | Florida | United States | 32806 |
26 | Nemours Children's Hospital | Orlando | Florida | United States | 32827 |
27 | Nemours Children's Clinic - Pensacola | Pensacola | Florida | United States | 32504 |
28 | Johns Hopkins All Children's Hospital | Saint Petersburg | Florida | United States | 33701 |
29 | Saint Joseph's Hospital/Children's Hospital-Tampa | Tampa | Florida | United States | 33607 |
30 | Saint Mary's Hospital | West Palm Beach | Florida | United States | 33407 |
31 | Children's Healthcare of Atlanta - Egleston | Atlanta | Georgia | United States | 30322 |
32 | Saint Luke's Cancer Institute - Boise | Boise | Idaho | United States | 83712 |
33 | Lurie Children's Hospital-Chicago | Chicago | Illinois | United States | 60611 |
34 | University of Chicago Comprehensive Cancer Center | Chicago | Illinois | United States | 60637 |
35 | Saint Jude Midwest Affiliate | Peoria | Illinois | United States | 61637 |
36 | Southern Illinois University School of Medicine | Springfield | Illinois | United States | 62702 |
37 | Riley Hospital for Children | Indianapolis | Indiana | United States | 46202 |
38 | Saint Vincent Hospital and Health Care Center | Indianapolis | Indiana | United States | 46260 |
39 | Blank Children's Hospital | Des Moines | Iowa | United States | 50309 |
40 | University of Iowa/Holden Comprehensive Cancer Center | Iowa City | Iowa | United States | 52242 |
41 | Norton Children's Hospital | Louisville | Kentucky | United States | 40202 |
42 | Children's Hospital New Orleans | New Orleans | Louisiana | United States | 70118 |
43 | Ochsner Medical Center Jefferson | New Orleans | Louisiana | United States | 70121 |
44 | Eastern Maine Medical Center | Bangor | Maine | United States | 04401 |
45 | Sinai Hospital of Baltimore | Baltimore | Maryland | United States | 21215 |
46 | Johns Hopkins University/Sidney Kimmel Cancer Center | Baltimore | Maryland | United States | 21287 |
47 | C S Mott Children's Hospital | Ann Arbor | Michigan | United States | 48109 |
48 | Michigan State University Clinical Center | East Lansing | Michigan | United States | 48824-7016 |
49 | Helen DeVos Children's Hospital at Spectrum Health | Grand Rapids | Michigan | United States | 49503 |
50 | Bronson Methodist Hospital | Kalamazoo | Michigan | United States | 49007 |
51 | Children's Hospitals and Clinics of Minnesota - Minneapolis | Minneapolis | Minnesota | United States | 55404 |
52 | University of Minnesota/Masonic Cancer Center | Minneapolis | Minnesota | United States | 55455 |
53 | Mayo Clinic in Rochester | Rochester | Minnesota | United States | 55905 |
54 | University of Mississippi Medical Center | Jackson | Mississippi | United States | 39216 |
55 | Children's Mercy Hospitals and Clinics | Kansas City | Missouri | United States | 64108 |
56 | Cardinal Glennon Children's Medical Center | Saint Louis | Missouri | United States | 63104 |
57 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
58 | Mercy Hospital Saint Louis | Saint Louis | Missouri | United States | 63141 |
59 | Children's Hospital and Medical Center of Omaha | Omaha | Nebraska | United States | 68114 |
60 | University of Nebraska Medical Center | Omaha | Nebraska | United States | 68198 |
61 | University Medical Center of Southern Nevada | Las Vegas | Nevada | United States | 89102 |
62 | Sunrise Hospital and Medical Center | Las Vegas | Nevada | United States | 89109 |
63 | Alliance for Childhood Diseases/Cure 4 the Kids Foundation | Las Vegas | Nevada | United States | 89135 |
64 | Summerlin Hospital Medical Center | Las Vegas | Nevada | United States | 89144 |
65 | Hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
66 | Morristown Medical Center | Morristown | New Jersey | United States | 07960 |
67 | Saint Peter's University Hospital | New Brunswick | New Jersey | United States | 08901 |
68 | Albany Medical Center | Albany | New York | United States | 12208 |
69 | Montefiore Medical Center - Moses Campus | Bronx | New York | United States | 10467 |
70 | Roswell Park Cancer Institute | Buffalo | New York | United States | 14263 |
71 | The Steven and Alexandra Cohen Children's Medical Center of New York | New Hyde Park | New York | United States | 11040 |
72 | NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center | New York | New York | United States | 10032 |
73 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
74 | NYP/Weill Cornell Medical Center | New York | New York | United States | 10065 |
75 | University of Rochester | Rochester | New York | United States | 14642 |
76 | Stony Brook University Medical Center | Stony Brook | New York | United States | 11794 |
77 | State University of New York Upstate Medical University | Syracuse | New York | United States | 13210 |
78 | New York Medical College | Valhalla | New York | United States | 10595 |
79 | Mission Hospital | Asheville | North Carolina | United States | 28801 |
80 | Carolinas Medical Center/Levine Cancer Institute | Charlotte | North Carolina | United States | 28203 |
81 | Novant Health Presbyterian Medical Center | Charlotte | North Carolina | United States | 28204 |
82 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
83 | Sanford Broadway Medical Center | Fargo | North Dakota | United States | 58122 |
84 | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States | 45229 |
85 | Rainbow Babies and Childrens Hospital | Cleveland | Ohio | United States | 44106 |
86 | Cleveland Clinic Foundation | Cleveland | Ohio | United States | 44195 |
87 | Nationwide Children's Hospital | Columbus | Ohio | United States | 43205 |
88 | Dayton Children's Hospital | Dayton | Ohio | United States | 45404 |
89 | ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital | Toledo | Ohio | United States | 43606 |
90 | University of Oklahoma Health Sciences Center | Oklahoma City | Oklahoma | United States | 73104 |
91 | Legacy Emanuel Children's Hospital | Portland | Oregon | United States | 97227 |
92 | Oregon Health and Science University | Portland | Oregon | United States | 97239 |
93 | Geisinger Medical Center | Danville | Pennsylvania | United States | 17822 |
94 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
95 | Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania | United States | 15224 |
96 | Prisma Health Richland Hospital | Columbia | South Carolina | United States | 29203 |
97 | BI-LO Charities Children's Cancer Center | Greenville | South Carolina | United States | 29605 |
98 | Sanford USD Medical Center - Sioux Falls | Sioux Falls | South Dakota | United States | 57117-5134 |
99 | East Tennessee Childrens Hospital | Knoxville | Tennessee | United States | 37916 |
100 | Saint Jude Children's Research Hospital | Memphis | Tennessee | United States | 38105 |
101 | The Children's Hospital at TriStar Centennial | Nashville | Tennessee | United States | 37203 |
102 | Vanderbilt University/Ingram Cancer Center | Nashville | Tennessee | United States | 37232 |
103 | Dell Children's Medical Center of Central Texas | Austin | Texas | United States | 78723 |
104 | Driscoll Children's Hospital | Corpus Christi | Texas | United States | 78411 |
105 | Medical City Dallas Hospital | Dallas | Texas | United States | 75230 |
106 | UT Southwestern/Simmons Cancer Center-Dallas | Dallas | Texas | United States | 75390 |
107 | Cook Children's Medical Center | Fort Worth | Texas | United States | 76104 |
108 | Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center | Houston | Texas | United States | 77030 |
109 | M D Anderson Cancer Center | Houston | Texas | United States | 77030 |
110 | Children's Hospital of San Antonio | San Antonio | Texas | United States | 78207 |
111 | Methodist Children's Hospital of South Texas | San Antonio | Texas | United States | 78229 |
112 | University of Texas Health Science Center at San Antonio | San Antonio | Texas | United States | 78229 |
113 | Scott and White Memorial Hospital | Temple | Texas | United States | 76508 |
114 | Primary Children's Hospital | Salt Lake City | Utah | United States | 84113 |
115 | Children's Hospital of The King's Daughters | Norfolk | Virginia | United States | 23507 |
116 | Virginia Commonwealth University/Massey Cancer Center | Richmond | Virginia | United States | 23298 |
117 | Seattle Children's Hospital | Seattle | Washington | United States | 98105 |
118 | Providence Sacred Heart Medical Center and Children's Hospital | Spokane | Washington | United States | 99204 |
119 | Madigan Army Medical Center | Tacoma | Washington | United States | 98431 |
120 | West Virginia University Healthcare | Morgantown | West Virginia | United States | 26506 |
121 | University of Wisconsin Carbone Cancer Center | Madison | Wisconsin | United States | 53792 |
122 | Children's Hospital of Wisconsin | Milwaukee | Wisconsin | United States | 53226 |
123 | San Jorge Children's Hospital | San Juan | Puerto Rico | 00912 | |
124 | University Pediatric Hospital | San Juan | Puerto Rico | 00926 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Katherine A Janeway, Children's Oncology Group
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2017-01264
- NCI-2017-01264
- APEC1621A
- APEC1621A
- APEC1621A
- U10CA180886