Crizotinib and Combination Chemotherapy in Treating Younger Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma
- Conditions
- Childhood Solid NeoplasmRecurrent NeuroblastomaRecurrent Childhood Anaplastic Large Cell Lymphoma
- Interventions
- Other: Laboratory Biomarker AnalysisOther: Pharmacological StudyOther: Questionnaire Administration
- Registration Number
- NCT01606878
- Lead Sponsor
- Children's Oncology Group
- Brief Summary
This phase I trial studies the side effects and the best dose of crizotinib when given together with combination chemotherapy in treating younger patients with solid tumors or anaplastic large cell lymphoma that has returned or does not respond to treatment. Crizotinib may stop the growth of tumor or cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, topotecan hydrochloride, dexrazoxane hydrochloride, doxorubicin hydrochloride, and vincristine sulfate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving crizotinib together with combination chemotherapy may be a better treatment for patients with solid tumors or anaplastic large cell lymphoma.
- Detailed Description
PRIMARY OBJECTIVES:
I. To estimate the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) of crizotinib administered orally twice daily in combination with topotecan (topotecan hydrochloride) and cyclophosphamide in children with refractory/relapsed solid tumors or anaplastic large cell lymphoma (ALCL).
II. To define and describe the toxicities of crizotinib in combination with topotecan and cyclophosphamide administered on this schedule.
III. To estimate the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) of crizotinib administered orally twice daily in combination with vincristine (vincristine sulfate) and doxorubicin (doxorubicin hydrochloride)/dexrazoxane (dexrazoxane hydrochloride) in children with refractory/relapsed solid tumors or ALCL.
IV. To define and describe the toxicities of crizotinib in combination with vincristine and doxorubicin/dexrazoxane administered on this schedule.
V. To characterize the pharmacokinetics of crizotinib in children with relapsed/refractory cancer when combined with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane.
SECONDARY OBJECTIVES:
I. To preliminarily define the antitumor activity of crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane within the confines of a Phase 1 study.
II. To preliminarily examine the relationship between anaplastic lymphoma kinase (ALK) status in patients with neuroblastoma or ALCL and response to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane.
III. To preliminarily examine the relationship between minimal residual disease (MRD) status and clinical response to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane in patients with ALCL.
IV. To use a questionnaire to gather preliminary information on the palatability of the oral solution formulation of crizotinib.
V. To examine ALK and MET proto-oncogene (c-Met) expression, copy number and mutations status in archival tumor tissue from solid tumor and ALCL patients.
VI. To use a questionnaire to gather information on the acceptability of the crizotinib capsule formulation.
OUTLINE: This is a dose-escalation study of crizotinib. Patients are assigned to Part A or Part B based on the treating physician's choice and availability of a reservation. After closure of Part A and Part B, patients are assigned to Part C.
PART A (CLOSED TO ACCRUAL 10/3/14): Patients receive crizotinib (oral solution) orally (PO) twice daily (BID) on days 1-21, cyclophosphamide intravenously (IV) once daily (QD) on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
PART B (CLOSED TO ACCRUAL 10/3/14): Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
PART C: Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
PART D: Patients receive crizotinib (microsphere formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 46
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Patients must have had histologic verification of malignancy at original diagnosis or relapse; all patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma (ALCL) are eligible except for patients with primary or metastatic central nervous system (CNS) tumors or patients with primary cutaneous ALCL
-
Patients must have either measurable or evaluable disease
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Patients current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
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Karnofsky >= 60% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: 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 chemotherapy
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Myelosuppressive chemotherapy:
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Solid tumors: at least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
-
ALCL:
- Patients with ALCL who relapse while receiving standard maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study
- Patients who relapse while they are not receiving standard maintenance therapy, must have fully recovered from all acute toxic effects of prior therapy; at least 14 days must have elapsed after the completion of cytotoxic therapy
-
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Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) 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
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Biologic (anti-neoplastic agent): at least 7 days after the last dose of a biologic agent; 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
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Immunotherapy: at least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines
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Monoclonal antibodies: at least 3 half-lives of the antibody after the last dose of a monoclonal antibody
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Radiation therapy (XRT):
- Solid tumors: at least 14 days after local palliative XRT (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of metaiodobenzylguanidine (MIBG); at least 150 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation
- ALCL: at least 14 days after local palliative XRT (small port); at least 84 days must have elapsed if prior TBI, craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial BM radiation
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Stem cell infusion without TBI: no evidence of active graft vs. host disease and at least 84 days must have elapsed after transplant and >= 42 days for autologous stem cell infusion after iodine (I)131-MIBG therapy
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Patients must not have received prior therapy with crizotinib
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Prior anthracycline dose: patients with a total lifetime cumulative anthracycline dose of > 650 mg/m^2 at the time of enrollment are not eligible for Part B of the study
-
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For patients with solid tumors or ALCL without known bone marrow involvement:
- Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
- 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; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must 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 a serum creatinine based on age/gender as follows:
- Age 1 to < 2 years: 0.6 mg/dL
- Age 2 to < 6 years: 0.8 mg/dL
- Age 6 to < 10 years: 1 mg/dL
- Age 10 to < 13 years: 1.2 mg/dL
- Age 13 to < 16 years: 1.5 mg/dL (males) and 1.4 mg/dL (females)
- Age >= 16 years: 1.7 mg/dL (males) and 1.4 mg/dL (females)
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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]) =< 110 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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Corrected QT interval (QTc) =< 480 msec
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For patients on Part B: shortening fraction of >= 27% by echocardiogram or ejection fraction of >= 50% by gated radionuclide study
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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
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Part C: Patients must have a body surface area (BSA) >= 1.07 m^2 at the time of study enrollment
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Part D: Patients must have a body surface area (BSA) >= 0.43 m^2 at the time of study enrollment
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Tumor tissue must be sent; if tumor tissue is unavailable, the study chair must be notified prior to enrollment
- Pregnant or breast-feeding women will not be entered on this study; 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 during treatment and for 3 months after stopping treatment
- 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
- Patients who are currently receiving another investigational drug are not eligible
- Patients who are currently receiving other anti-cancer agents are not eligible
- 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 chronically receiving medications known to be metabolized by cytochrome P 450, family 3, subfamily A, polypeptide 4 (CYP3A4) and with narrow therapeutic indices including pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not eligible; the topical use of these medications (if applicable) is allowed
- Patients chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited to ketoconazole, itraconazole, miconazole, clarithromycin, erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice are not eligible; the topical use of these medications (if applicable), e.g. 2% ketoconazole cream, is allowed
- Patients chronically receiving drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, tipranavir, ritonavir, and St. John?s wort are not eligible; the topical use of these medications (if applicable) is allowed
- Patients receiving PPIs and H2 blockers are not eligible for Part D
- Patients who have an uncontrolled infection are not eligible
- Patients who have received a prior solid organ transplantation are not eligible
- Patients who have a primary or metastatic CNS tumor at the time of study enrollment are not eligible; a prior history of metastatic CNS tumor is allowed as long as there is no evidence of CNS disease at study enrollment
- 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
- Parts A and B: Patients who are able to swallow liquid or use a nasogastric or gastrostomy (G) tube are eligible
- Part C: Patients must be able to swallow intact capsules
- Part D: Patients must be able to swallow liquid
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part B (crizotinib, vincristine, dexrazoxane, doxorubicin) Laboratory Biomarker Analysis Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part A (crizotinib, cyclophosphamide, topotecan hydrochloride) Laboratory Biomarker Analysis Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV QD on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part A (crizotinib, cyclophosphamide, topotecan hydrochloride) Questionnaire Administration Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV QD on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part A (crizotinib, cyclophosphamide, topotecan hydrochloride) Topotecan Hydrochloride Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV QD on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part B (crizotinib, vincristine, dexrazoxane, doxorubicin) Vincristine Sulfate Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part A (crizotinib, cyclophosphamide, topotecan hydrochloride) Pharmacological Study Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV QD on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part B (crizotinib, vincristine, dexrazoxane, doxorubicin) Dexrazoxane Hydrochloride Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part B (crizotinib, vincristine, dexrazoxane, doxorubicin) Questionnaire Administration Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part C (crizotinib, cyclophosphamide, topotecan hydrochloride) Laboratory Biomarker Analysis Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part C (crizotinib, cyclophosphamide, topotecan hydrochloride) Pharmacological Study Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part B (crizotinib, vincristine, dexrazoxane, doxorubicin) Pharmacological Study Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part C (crizotinib, cyclophosphamide, topotecan hydrochloride) Topotecan Hydrochloride Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part C (crizotinib, cyclophosphamide, topotecan hydrochloride) Questionnaire Administration Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part D (crizotinib, cyclophosphamide, topotecan hydrochloride) Questionnaire Administration Patients receive crizotinib (microsphere formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part D (crizotinib, cyclophosphamide, topotecan hydrochloride) Cyclophosphamide Patients receive crizotinib (microsphere formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part D (crizotinib, cyclophosphamide, topotecan hydrochloride) Pharmacological Study Patients receive crizotinib (microsphere formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part D (crizotinib, cyclophosphamide, topotecan hydrochloride) Laboratory Biomarker Analysis Patients receive crizotinib (microsphere formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part D (crizotinib, cyclophosphamide, topotecan hydrochloride) Topotecan Hydrochloride Patients receive crizotinib (microsphere formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part A (crizotinib, cyclophosphamide, topotecan hydrochloride) Cyclophosphamide Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV QD on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part A (crizotinib, cyclophosphamide, topotecan hydrochloride) Crizotinib Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV QD on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part B (crizotinib, vincristine, dexrazoxane, doxorubicin) Crizotinib Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part B (crizotinib, vincristine, dexrazoxane, doxorubicin) Doxorubicin Hydrochloride Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14) Part C (crizotinib, cyclophosphamide, topotecan hydrochloride) Crizotinib Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part C (crizotinib, cyclophosphamide, topotecan hydrochloride) Cyclophosphamide Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Part D (crizotinib, cyclophosphamide, topotecan hydrochloride) Crizotinib Patients receive crizotinib (microsphere formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Maximum Tolerated Dose (MTD) of Crizotinib Up to 21 days The MTD of crizotinib administered with combination chemotherapy based on the incidence of dose-limiting toxicity (DLT) at which fewer than one-third of patients experience DLT, as assessed by NCI CTCAE version 4.0.
Area Under the Concentration Up to 21 days Median (min, max) of the area under the concentration time curve for crizotinib assessed in course 1 at 1, 2, 4, 6-8 hours, and 15-21 days post-administration stratified by dose level and study part.
Number of Patients With Dose Limiting Toxicity (DLT) Up to 21 days Number of patients of all DLT reported as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. stratified by dose level and study part.
- Secondary Outcome Measures
Name Time Method Response Rate Up to 2 years Number of patients of response-evaluable participants with response (CR/PR) assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 including CR: disappearance of all target and non-target lesions; PR: at least 30% decrease in the sum of the diameters of target lesions
ALK Status and Response to Crizotinib up to 2 years Number of patients who respond (CR/PR) to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexraroxane stratified by ALK positive or negative status
Acceptability of Crizotinib Microsphere Formulation Palatability Up to 1 week Number of patients who at least accept palatability of microsphere formation in the first week
MRD Status and Response to Crizotinib Up to 2 years Frequency (%) of patients who respond (CR/PR) to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexraroxane stratified by MRD status
ALK Expression for Crizotinib Up to 7 days Median (p25, p75) ALK expression stratified by dose level and study part
Acceptability of Crizotinib Capsule Formulation Palatability Up to 1 week Number of patients who at least accept palatability of capsule formulation in the first week
Trial Locations
- Locations (23)
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
UCSF Medical Center-Mission Bay
🇺🇸San Francisco, California, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
Lurie Children's Hospital-Chicago
🇺🇸Chicago, Illinois, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸Atlanta, Georgia, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
C S Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Columbia University/Herbert Irving Cancer Center
🇺🇸New York, New York, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸Houston, Texas, United States
UCSF Medical Center-Parnassus
🇺🇸San Francisco, California, United States