A Study to Test the Addition of the Drug Cabozantinib to Chemotherapy in Patients With Newly Diagnosed Osteosarcoma
- Conditions
- Localized OsteosarcomaMetastatic OsteosarcomaSecondary OsteosarcomaHigh Grade Osteosarcoma
- Interventions
- Procedure: Bone ScanProcedure: Computed TomographyProcedure: Magnetic Resonance ImagingProcedure: Surgical ProcedureProcedure: X-Ray Imaging
- Registration Number
- NCT05691478
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
This phase II/III trial tests the safety, side effects, and best dose of the drug cabozantinib in combination with standard chemotherapy, and to compare the effect of adding cabozantinib to standard chemotherapy alone in treating patients with newly diagnosed osteosarcoma. Cabozantinib is in a class of medications called kinase inhibitors which block protein signals affecting new blood vessel formation and the ability to activate growth signaling pathways. This may help slow the growth of tumor cells. The drugs used in standard chemotherapy for this trial are methotrexate, doxorubicin, and cisplatin (MAP). Methotrexate stops cells from making DNA and may kill tumor cells. It is a type of antimetabolite. Doxorubicin is in a class of medications called anthracyclines. It works by slowing or stopping the growth of tumor cells in the body. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Adding cabozantinib to standard chemotherapy may work better in treating newly diagnosed osteosarcoma.
- Detailed Description
PRIMARY OBJECTIVES:
I. To determine the feasibility of adding cabozantinib S-malate (cabozantinib) to standard MAP (high dose methotrexate, doxorubicin hydrochloride \[doxorubicin\], and cisplatin) chemotherapy in patients with newly diagnosed metastatic osteosarcoma with a resectable primary tumor.
II. To determine whether MAP chemotherapy plus cabozantinib results in more favorable event-free survival (EFS) than MAP chemotherapy alone in patients with localized, resectable osteosarcoma.
III. To determine whether MAP chemotherapy plus cabozantinib results in more favorable event-free survival (EFS) than MAP chemotherapy alone in patients with metastatic, pelvic and unresectable osteosarcoma.
SECONDARY OBJECTIVES:
I. To determine whether MAP chemotherapy plus cabozantinib results in more favorable overall survival (OS) than MAP chemotherapy alone in patients with localized, resectable osteosarcoma.
II. To determine whether MAP chemotherapy plus cabozantinib results in more favorable overall survival (OS) than MAP chemotherapy alone in patients with metastatic, pelvic and unresectable osteosarcoma.
EXPLORATORY OBJECTIVES:
I. To determine the rate of good histologic response (\> 90%) of resected primary tumor specimens following neoadjuvant chemotherapy with MAP plus cabozantinib and compare with response rates for MAP chemotherapy alone.
II. To describe the toxicities of the addition of cabozantinib to MAP chemotherapy in patients with newly diagnosed osteosarcoma.
III. To describe frequency of application of local control methods (surgery, hypofractionated stereotactic body radiotherapy, or radiofrequency ablation) for extrapulmonary metastatic osteosarcoma.
IV. To compare total cumulative delivered doses of MAP chemotherapy agents between standard and experimental arms across multiple phases of therapy.
V. To assess the pharmacokinetics of cabozantinib when administered concomitantly with standard chemotherapy agents during feasibility.
VI. To collect pulmonary metastatic lesions, paired primary tumor tissue, and serial blood samples for tumor profiling, liquid biopsies, and future testing of correlative biology studies.
OUTLINE: This is a dose-escalation study of cabozantinib (Feasibility Phase) followed by a randomized phase II/III study (Efficacy Phase).
FEASIBILITY PHASE: Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles.
EFFICACY PHASE: Patients with standard risk osteosarcoma are randomized to Arm A or Arm B. Patients with high risk osteosarcoma are randomized to Arm C or Arm D.
ARM A: Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles.
ARM B: Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles.
ARM C: High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles.
ARM D: High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles.
All patients also undergo X-ray, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.
Recruitment & Eligibility
- Status
- SUSPENDED
- Sex
- All
- Target Recruitment
- 1122
- Patients must be < 40 years of age at the time of enrollment.
- Patients must have a body surface area of >= 0.8 m^2 at the time of enrollment.
- Patients must have histologic diagnosis (by institutional pathologist) of newly diagnosed high grade osteosarcoma. Primary tumors of all extremity and axial sites are eligible as long as diagnosis of high-grade osteosarcoma is established. Osteosarcoma as a second malignancy is eligible if no prior exposure to systemic chemotherapies.
- Feasibility Phase:
Patients must have metastatic disease and a resectable primary tumor. Designation of a primary tumor as resectable will be determined at the time of diagnosis by the institutional multidisciplinary team.
For this study, metastatic disease is defined as one or more of the following:
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Lesions which are discontinuous from the primary tumor, are not regional lymph nodes, and do not share a bone or body cavity with the primary tumor. Skip lesions in the same bone as the primary tumor do not constitute metastatic disease. Skip lesions in an adjacent bone are considered bone metastases.
-
Lung metastases: defined as biopsy-proven metastasis or the presence of one or more pulmonary lesions >= 5 mm, OR multiple pulmonary lesions >= 3 mm or greater in size.
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Bone metastases: Areas suspicious for bone metastasis based on fludeoxyglucose F-18 (18F-FDG)-positron emission tomography (PET) scan (or whole body technetium-99 bone scan if 18F-FDG-PET is unavailable at the treating institution) require confirmatory biopsy or supportive anatomic imaging of at least one suspicious site with either magnetic resonance imaging (MRI) or computed tomography (CT) (whole body 18F-FDG-PET/CT or 18F-FDG-PET/MR scans are acceptable).
- Efficacy Phases (Phase 2/3)
Patients with both localized and metastatic disease are eligible for the efficacy phase, regardless of resectability. Patients will be enrolled to two separate cohorts:
-
Cohort 1 (Standard Risk): Patients with non-pelvic primary osteosarcoma deemed to be resectable at the time of diagnosis by the institutional multidisciplinary team, without evidence of metastatic lesions.
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Cohort 2 (High-Risk): Patients with a primary pelvic tumor, a primary tumor designated as unresectable by the institutional multidisciplinary team, AND/OR radiographic evidence of metastatic lesions.
- A serum creatinine based on age/gender as follows (within 7 days prior to enrollment unless otherwise indicated):
-
(Age: Maximum Serum Creatinine [mg/dL]; Gender)
- 1 month to < 6 months: 0.4 (male); 0.4 (female)
- 6 months to < 1 year: 0.5 (male); 0.5 (female)
- 1 to < 2 years: 0.6 (male); 0.6 (female)
- 2 to < 6 years: 0.8 (male); 0.8 (female)
- 6 to < 10 years: 1 (male); 1 (female)
- 10 to < 13 years: 1.2 (male); 1.2 (female)
- 13 to < 16 years: 1.5 (male); 1.4 (female)
- >= 16 years: 1.7 (male); 1.4 (female)
-
OR - a 24 hour urine creatinine clearance >= 70 mL/min/1.73 m^2
-
OR - a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).
-
Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment unless otherwise indicated)
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment unless otherwise indicated)
-
-
Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
- No history of congenital prolonged corrected QT (QTc) syndrome, New York Heart Association (NYHA) Class III or IV congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias or
-
Shortening fraction of >= 27%, or
-
Ejection fraction of >= 50%, or
-
Corrected QT interval by Fridericia (QTcF) < 480 msec on electrocardiogram. Patients with Grade 1 prolonged QTc (450-480 msec) at time of study enrollment should have correctable causes of prolonged QTc addressed if possible (i.e., electrolytes, medications).
- Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment unless otherwise indicated)
- Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to enrollment) (within 7 days prior to enrollment unless otherwise indicated)
- Hemoglobin >= 8.0 g/dL (within 7 days prior to enrollment unless otherwise indicated)
- International normalized ratio (INR) =< 1.5 (within 7 days prior to enrollment unless otherwise indicated)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible as long as they are NOT receiving anti-retroviral agents that are strong inhibitors or inducers of CYP3A4, CYP2D6, and/or MRP2 transporter protein.
- 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.
- Patients who have received previous systemic therapy for osteosarcoma or a prior oncologic diagnosis.
- Patients who have central nervous system metastases.
- Patients with central cavitating pulmonary lesions invading or encasing any major blood vessels in the lung.
- Patients who are unable to swallow tablets. Tablets cannot be crushed or chewed.
- Patients with gastrointestinal disorders including active disorders associated with a high risk of perforation or fistula formation. Specifically, no clinically significant gastrointestinal (GI) bleeding, GI perforation, bowel obstruction, intra-abdominal abscess or fistula for 6 months prior to enrollment, no hemoptysis or other signs of pulmonary hemorrhage for 3 months prior to enrollment.
- Patients with active bleeding or bleeding diathesis. No clinically significant hematuria, hematemesis, or hemoptysis or other history of significant bleeding within 3 months prior to enrollment.
- Patients with uncompensated or symptomatic hypothyroidism. Patients who have hypothyroidism controlled with thyroid replacement hormone are eligible.
- Patients with moderate to severe hepatic impairment (Child-Pugh B or C).
- Patients who have had primary tumor resection or attempted curative resection of metastases prior to enrollment.
- Patients who have undergone other major surgical procedure (eg, laparotomy) within 14 days prior to enrollment. Thoracoscopic procedures for diagnostic purposes (biopsy of lung nodule) and central access such as port-a-cath placement are allowed.
- Patients with a history of serious or non-healing wound or bone fracture (pathologic fracture of primary tumor is not considered exclusion).
- Patients with any medical or surgical conditions that would interfere with gastrointestinal absorption of cabozantinib.
- Patients with previously identify allergy or hypersensitivity to components of the study treatment formulations.
- Patients who are receiving any other investigational agent not defined within this protocol 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 who received enzyme-inducing anticonvulsants within 14 days prior to enrollment.
- Patients with a prior history of hypertension (> 95th percentile for age, height, and gender for patients < 18 years and > 140/90 mmHg for patients >= 18 years requiring medication for blood pressure control.
- Patients who are receiving drugs that prolong QTc.
- Patients receiving anticoagulation with oral coumarin agents (eg warfarin), direct thrombin inhibitors (eg dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (eg, clopidogrel). Low dose aspirin for cardioprotection (per local applicable guidelines) and low dose, low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH and direct factor Xa inhibitors rivaroxaban or apixaban are allowed in subjects who are on a stable dose for at least 6 weeks before the first dose of study treatment, and who have had no complications from a thromboembolic event or the anticoagulation regimen.
- Patients receiving strong CYP3A4 inducers or strong CYP3A4 inhibitors.
- 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 protocol therapy.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Efficacy Phase Arm D (cabozantinib, MAP) Cabozantinib S-malate High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm A (MAP) Bone Scan Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm A (MAP) Cisplatin Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm A (MAP) Computed Tomography Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm A (MAP) Doxorubicin Hydrochloride Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm A (MAP) Magnetic Resonance Imaging Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm A (MAP) Methotrexate Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm A (MAP) Surgical Procedure Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm A (MAP) X-Ray Imaging Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm B (cabozantinib, MAP) Bone Scan Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm B (cabozantinib, MAP) Cabozantinib S-malate Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm B (cabozantinib, MAP) Cisplatin Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm B (cabozantinib, MAP) Computed Tomography Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm B (cabozantinib, MAP) Doxorubicin Hydrochloride Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm B (cabozantinib, MAP) Magnetic Resonance Imaging Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm B (cabozantinib, MAP) Methotrexate Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm B (cabozantinib, MAP) Surgical Procedure Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm B (cabozantinib, MAP) X-Ray Imaging Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm C (MAP) Bone Scan High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm C (MAP) Cisplatin High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm C (MAP) Computed Tomography High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm C (MAP) Doxorubicin Hydrochloride High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm C (MAP) Magnetic Resonance Imaging High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm C (MAP) Methotrexate High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm C (MAP) Surgical Procedure High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm C (MAP) X-Ray Imaging High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm D (cabozantinib, MAP) Bone Scan High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm D (cabozantinib, MAP) Cisplatin High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm D (cabozantinib, MAP) Computed Tomography High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm D (cabozantinib, MAP) Doxorubicin Hydrochloride High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm D (cabozantinib, MAP) Magnetic Resonance Imaging High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm D (cabozantinib, MAP) Methotrexate High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Efficacy Phase Arm D (cabozantinib, MAP) X-Ray Imaging High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study. Feasibility phase (cabozantinib, MAP) Bone Scan Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Feasibility phase (cabozantinib, MAP) Cabozantinib S-malate Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Feasibility phase (cabozantinib, MAP) Cisplatin Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Feasibility phase (cabozantinib, MAP) Computed Tomography Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Feasibility phase (cabozantinib, MAP) Doxorubicin Hydrochloride Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Feasibility phase (cabozantinib, MAP) Magnetic Resonance Imaging Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Feasibility phase (cabozantinib, MAP) Methotrexate Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Feasibility phase (cabozantinib, MAP) Surgical Procedure Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Feasibility phase (cabozantinib, MAP) X-Ray Imaging Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles.
- Primary Outcome Measures
Name Time Method Occurrence of dose-limiting toxicity (DLT) (Feasibility) Baseline up to 6 weeks Only patients with high risk osteosarcoma who have a primary tumor considered resectable at the time of enrollment will be enrolled to this part of the trial. If a feasible dose cannot be established, the study committee will consult with Children's Oncology Group (COG) leadership and National Cancer Institute Cancer Therapy Evaluation Program (NCI CTEP) regarding possible modifications of the regimen and subsequent protocol amendment.
Event-free survival (EFS) (Phase III) From randomization until disease progression, relapse, diagnosis of a second malignant neoplasm, death or last contact, whichever occurs first, assessed up to 5 years after completion of study treatment Will consist of two randomized phase 3 sub-studies ('Phase 3'). One will be conducted in standard risk patients and one will be conducted in high risk patients.
Event-free survival (EFS) (Phase II) From randomization until disease progression, relapse, diagnosis of a second malignant neoplasm, death or last contact, whichever occurs first, assessed up to 5 years after completion of study treatment The randomization and analysis will be stratified according to risk group. An assessment of the reduction in risk for EFS-event at the designated landmark time will be used to determine whether the trial continues to part 3. If the study proceeds to part 3, patients enrolled to part 2 of the trial will contribute to the primary analyses for part 3 of the study. If the interim criterion for continuation is not obtained, accrual will be closed with the conclusion that cabozantinib does not reduce sufficiently the risk for EFS-event for patients with newly-diagnosed osteosarcoma.
Overall survival (OS) From randomization until death or last contact, whichever occurs first, assessed up to 5 years after completion of study treatment
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (92)
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
Alfred I duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Saint Francis Hospital
🇺🇸Greenville, South Carolina, United States
Marshfield Medical Center-Marshfield
🇺🇸Marshfield, Wisconsin, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Rainbow Babies and Childrens Hospital
🇺🇸Cleveland, Ohio, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸Houston, Texas, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸Las Vegas, Nevada, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Children's Hospital of San Antonio
🇺🇸San Antonio, Texas, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸Oakland, California, United States
Kaiser Permanente-Oakland
🇺🇸Oakland, California, United States
Rady Children's Hospital - San Diego
🇺🇸San Diego, California, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Valley Children's Hospital
🇺🇸Madera, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸Long Beach, California, United States
Lurie Children's Hospital-Chicago
🇺🇸Chicago, Illinois, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
University of Kentucky/Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Albany Medical Center
🇺🇸Albany, New York, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
NYU Langone Hospital - Long Island
🇺🇸Mineola, New York, United States
Stony Brook University Medical Center
🇺🇸Stony Brook, New York, United States
East Carolina University
🇺🇸Greenville, North Carolina, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸Toledo, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Saint Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
Medical City Dallas Hospital
🇺🇸Dallas, Texas, United States
El Paso Children's Hospital
🇺🇸El Paso, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
UMC Cancer Center / UMC Health System
🇺🇸Lubbock, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸San Antonio, Texas, United States
University of Virginia Cancer Center
🇺🇸Charlottesville, Virginia, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Children's Hospital of The King's Daughters
🇺🇸Norfolk, Virginia, United States
Madigan Army Medical Center
🇺🇸Tacoma, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸Spokane, Washington, United States
UCSF Medical Center-Mission Bay
🇺🇸San Francisco, California, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
New York Medical College
🇺🇸Valhalla, New York, United States
Summerlin Hospital Medical Center
🇺🇸Las Vegas, Nevada, United States
The Children's Hospital at TriStar Centennial
🇺🇸Nashville, Tennessee, United States
Maine Children's Cancer Program
🇺🇸Scarborough, Maine, United States
Prisma Health Richland Hospital
🇺🇸Columbia, South Carolina, United States
Saint Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
BI-LO Charities Children's Cancer Center
🇺🇸Greenville, South Carolina, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
Saint Joseph's Regional Medical Center
🇺🇸Paterson, New Jersey, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸Fort Myers, Florida, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Saint Francis Cancer Center
🇺🇸Greenville, South Carolina, United States
Morristown Medical Center
🇺🇸Morristown, New Jersey, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Nemours Children's Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
Children's Hospital of Michigan
🇺🇸Detroit, Michigan, United States
Children's Hospital and Medical Center of Omaha
🇺🇸Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Norton Children's Hospital
🇺🇸Louisville, Kentucky, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸Palo Alto, California, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸Iowa City, Iowa, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
🇺🇸Grand Rapids, Michigan, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Covenant Children's Hospital
🇺🇸Lubbock, Texas, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸Tacoma, Washington, United States
Children's Mercy Hospitals and Clinics
🇺🇸Kansas City, Missouri, United States
Kapiolani Medical Center for Women and Children
🇺🇸Honolulu, Hawaii, United States
University of Florida Health Science Center - Gainesville
🇺🇸Gainesville, Florida, United States
Ochsner Medical Center Jefferson
🇺🇸New Orleans, Louisiana, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
VCU Massey Cancer Center at Stony Point
🇺🇸Richmond, Virginia, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States