A Study to Test the Addition of the Drug Cabozantinib to Chemotherapy in Patients With Newly Diagnosed Osteosarcoma

NCT ID: NCT05691478

Last Updated: 2025-11-12

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2/PHASE3

Total Enrollment

1122 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-03-03

Study Completion Date

2030-03-20

Brief Summary

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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

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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.

III. To prospectively validate that elevated circulating tumor DNA (ctDNA) levels greater than or equal to 5% at the time of diagnosis are associated with increased risk of EFS-event in patients with localized, resectable osteosarcoma.

IV. To prospectively validate that elevated ctDNA levels greater than or equal to 5% at the time of diagnosis are associated with increased risk of EFS-event in patients with metastatic, pelvic and unresectable osteosarcoma.

V. To prospectively validate that elevated ctDNA levels greater than or equal to 3% after initiation of therapy and prior to definitive surgery are associated with increased risk of EFS-event in patients with localized, resectable osteosarcoma.

VI. To prospectively validate that elevated ctDNA levels greater than or equal to 3% after initiation of therapy and prior to definitive surgery are associated with increased risk of EFS-event in patients with metastatic, pelvic and unresectable osteosarcoma.

VII. To determine whether MAP chemotherapy plus cabozantinib results in increased symptom burden and decreased tolerability to patients as measured by patient reported therapy-specific acute toxicities (Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events \[PRO-CTCAE\]).

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 compare the probability of Grade 3 or higher port site wound complications on the MAP plus cabozantinib regimen to that of MAP chemotherapy alone in patients with newly diagnosed osteosarcoma who received a port for the administration of chemotherapy.

IV. To describe frequency of application of local control methods (surgery, hypofractionated stereotactic body radiotherapy, or radiofrequency ablation) for extrapulmonary metastatic osteosarcoma.

V. To compare total cumulative delivered doses of MAP chemotherapy agents between standard and experimental arms across multiple phases of therapy.

VI. To assess the pharmacokinetics of cabozantinib when administered concomitantly with standard chemotherapy agents during feasibility.

VII. 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.

VIII. To determine whether ctDNA at diagnosis and early on-treatment, as a continuous measurement of ctDNA burden, is associated with an increased risk of EFS-event in patients with newly diagnosed osteosarcoma.

IX. To evaluate whether the magnitude of change in ctDNA levels from diagnosis to planned surgical procedure is associated with risk of EFS-event in patients with newly diagnosed osteosarcoma.

X. To determine whether ctDNA levels greater than or equal to 3% after planned surgical procedures are associated with increased risk of EFS-event.

XI. To describe the presence of specific copy-number alterations, including MYC amplifications, detected in ctDNA and matched diagnostic tumor samples in patients with newly diagnosed osteosarcoma and determine whether frequently occurring copy-number alterations are associated with increased risk of EFS-event.

XII. To determine whether ctDNA burden is predictive of response to the experimental therapy in patients with newly diagnosed osteosarcoma.

XIII. To prospectively compare the impact of combination therapy on symptom bother as measured by the Functional Assessment of Cancer Therapy-General Questionnaire (FACT-G) item GP5 in patients with osteosarcoma receiving MAP chemotherapy with or without cabozantinib, and to assess the relationship between symptom bother and number of patient-reported acute toxicities (as measured by the PRO-CTCAE).

OUTLINE: This is a dose-escalation study of cabozantinib (Feasibility Phase) followed by a randomized phase II/III study (Efficacy Phase).

FEASIBILITY PHASE (CLOSED TO ACCRUAL 05/09/2025): 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 one 35-day "consolidation" cycle with methotrexate IV, doxorubicin IV, and cisplatin IV, then a second 35-day "consolidation" cycle with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV, followed by two additional 35-day "consolidation" cycles with cabozantinib PO, methotrexate IV, and doxorubicin IV. 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 one 35-day "consolidation" cycle with methotrexate IV, doxorubicin IV, and cisplatin IV, then a second 35-day "consolidation" cycle with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV, followed by two additional 35-day "consolidation" cycles with cabozantinib PO, methotrexate IV, and doxorubicin IV. 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 additional time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.

Conditions

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High Grade Osteosarcoma Localized Osteosarcoma Metastatic Osteosarcoma Secondary Osteosarcoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SEQUENTIAL

Single-arm Feasibility Phase study followed by a randomized, parallel 4-arm Efficacy Phase study
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Efficacy Phase Arm A (MAP)

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 additional time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.

Group Type ACTIVE_COMPARATOR

Bone Scan

Intervention Type PROCEDURE

Undergo bone scintography

Cisplatin

Intervention Type DRUG

Given IV

Computed Tomography

Intervention Type PROCEDURE

Undergo CT

Doxorubicin Hydrochloride

Intervention Type DRUG

Given IV

Magnetic Resonance Imaging

Intervention Type PROCEDURE

Undergo MRI

Methotrexate

Intervention Type DRUG

Given IV

Surgical Procedure

Intervention Type PROCEDURE

Undergo surgery

X-Ray Imaging

Intervention Type PROCEDURE

Undergo X-ray

Efficacy Phase Arm B (cabozantinib, MAP)

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 one 35-day "consolidation" cycle with methotrexate IV, doxorubicin IV, and cisplatin IV, then a second 35-day "consolidation" cycle with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV, followed by two additional 35-day "consolidation" cycles with cabozantinib PO, methotrexate IV, and doxorubicin IV. 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 additional time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.

Group Type EXPERIMENTAL

Bone Scan

Intervention Type PROCEDURE

Undergo bone scintography

Cabozantinib S-malate

Intervention Type DRUG

Given PO

Cisplatin

Intervention Type DRUG

Given IV

Computed Tomography

Intervention Type PROCEDURE

Undergo CT

Doxorubicin Hydrochloride

Intervention Type DRUG

Given IV

Magnetic Resonance Imaging

Intervention Type PROCEDURE

Undergo MRI

Methotrexate

Intervention Type DRUG

Given IV

Surgical Procedure

Intervention Type PROCEDURE

Undergo surgery

X-Ray Imaging

Intervention Type PROCEDURE

Undergo X-ray

Efficacy Phase Arm C (MAP)

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 additional time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.

Group Type ACTIVE_COMPARATOR

Bone Scan

Intervention Type PROCEDURE

Undergo bone scintography

Cisplatin

Intervention Type DRUG

Given IV

Computed Tomography

Intervention Type PROCEDURE

Undergo CT

Doxorubicin Hydrochloride

Intervention Type DRUG

Given IV

Magnetic Resonance Imaging

Intervention Type PROCEDURE

Undergo MRI

Methotrexate

Intervention Type DRUG

Given IV

Surgical Procedure

Intervention Type PROCEDURE

Undergo surgery

X-Ray Imaging

Intervention Type PROCEDURE

Undergo X-ray

Efficacy Phase Arm D (cabozantinib, MAP)

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 one 35-day "consolidation" cycle with methotrexate IV, doxorubicin IV, and cisplatin IV, then a second 35-day "consolidation" cycle with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV, followed by two additional 35-day "consolidation" cycles with cabozantinib PO, methotrexate IV, and doxorubicin IV. 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 additional time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.

Group Type EXPERIMENTAL

Bone Scan

Intervention Type PROCEDURE

Undergo bone scintography

Cabozantinib S-malate

Intervention Type DRUG

Given PO

Cisplatin

Intervention Type DRUG

Given IV

Computed Tomography

Intervention Type PROCEDURE

Undergo CT

Doxorubicin Hydrochloride

Intervention Type DRUG

Given IV

Magnetic Resonance Imaging

Intervention Type PROCEDURE

Undergo MRI

Methotrexate

Intervention Type DRUG

Given IV

X-Ray Imaging

Intervention Type PROCEDURE

Undergo X-ray

Feasibility phase (cabozantinib, MAP)

(CLOSED TO ACCRUAL 05/09/2025): 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.

Group Type EXPERIMENTAL

Bone Scan

Intervention Type PROCEDURE

Undergo bone scintography

Cabozantinib S-malate

Intervention Type DRUG

Given PO

Cisplatin

Intervention Type DRUG

Given IV

Computed Tomography

Intervention Type PROCEDURE

Undergo CT

Doxorubicin Hydrochloride

Intervention Type DRUG

Given IV

Magnetic Resonance Imaging

Intervention Type PROCEDURE

Undergo MRI

Methotrexate

Intervention Type DRUG

Given IV

Surgical Procedure

Intervention Type PROCEDURE

Undergo surgery

X-Ray Imaging

Intervention Type PROCEDURE

Undergo X-ray

Interventions

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Bone Scan

Undergo bone scintography

Intervention Type PROCEDURE

Cabozantinib S-malate

Given PO

Intervention Type DRUG

Cisplatin

Given IV

Intervention Type DRUG

Computed Tomography

Undergo CT

Intervention Type PROCEDURE

Doxorubicin Hydrochloride

Given IV

Intervention Type DRUG

Magnetic Resonance Imaging

Undergo MRI

Intervention Type PROCEDURE

Methotrexate

Given IV

Intervention Type DRUG

Surgical Procedure

Undergo surgery

Intervention Type PROCEDURE

X-Ray Imaging

Undergo X-ray

Intervention Type PROCEDURE

Other Intervention Names

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Bone Scintigraphy BMS-907351 Cabometyx Cometriq XL 184 XL-184 XL184 Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin CAT CAT Scan Computed Axial Tomography Computerized Axial Tomography Computerized axial tomography (procedure) Computerized Tomography Computerized Tomography (CT) scan CT CT Scan Diagnostic CAT Scan Diagnostic CAT Scan Service Type tomography 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin HCl Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 FI106 hydroxydaunorubicin Rubex Magnetic Resonance Magnetic Resonance Imaging (MRI) Magnetic resonance imaging (procedure) Magnetic Resonance Imaging Scan Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance MR MR Imaging MRI MRI Scan MRIs NMR Imaging NMRI Nuclear Magnetic Resonance Imaging sMRI Structural MRI Abitrexate Alpha-Methopterin Amethopterin Brimexate CL 14377 CL-14377 Emtexate Emthexat Emthexate Farmitrexat Fauldexato Folex Folex PFS Jylamvo Lantarel Ledertrexate Lumexon Maxtrex Medsatrexate Metex Methoblastin Methotrexate LPF Methotrexate Methylaminopterin Methotrexatum Metotrexato Metrotex Mexate Mexate-AQ MTX Novatrex Rheumatrex Texate Tremetex Trexeron Trixilem WR-19039 Operation Surgery Surgery Type Surgery, NOS Surgical Surgical Intervention Surgical Interventions Surgical Procedures Type of Surgery Conventional X-Ray Diagnostic Radiology Medical Imaging, X-Ray Plain film radiographs Radiographic Imaging Radiographic imaging procedure (procedure) Radiography RG Static X-Ray X-Ray

Eligibility Criteria

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Inclusion Criteria

* 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 (NOTE: as of Amendment #2B, the feasibility phase has been completed) 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:

* 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.
* 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) NOTE: as of Amendment #2B, the efficacy phase is open for enrollment.

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.
* 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/sex as follows (within 7 days prior to enrollment unless otherwise indicated):
* (Age: Maximum Serum Creatinine \[mg/dL\]; Sex)

* 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
* Shortening fraction of \>= 27%, or
* Ejection fraction of \>= 50%
* 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.

Exclusion Criteria

* 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 sex 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.
Maximum Eligible Age

40 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Cancer Institute (NCI)

NIH

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Michael W Bishop

Role: PRINCIPAL_INVESTIGATOR

Children's Oncology Group

Locations

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Children's Hospital of Alabama

Birmingham, Alabama, United States

Site Status RECRUITING

Banner Children's at Desert

Mesa, Arizona, United States

Site Status RECRUITING

Phoenix Childrens Hospital

Phoenix, Arizona, United States

Site Status RECRUITING

Arkansas Children's Hospital

Little Rock, Arkansas, United States

Site Status RECRUITING

Kaiser Permanente Downey Medical Center

Downey, California, United States

Site Status RECRUITING

City of Hope Comprehensive Cancer Center

Duarte, California, United States

Site Status RECRUITING

Loma Linda University Medical Center

Loma Linda, California, United States

Site Status RECRUITING

Miller Children's and Women's Hospital Long Beach

Long Beach, California, United States

Site Status RECRUITING

Children's Hospital Los Angeles

Los Angeles, California, United States

Site Status RECRUITING

Cedars Sinai Medical Center

Los Angeles, California, United States

Site Status RECRUITING

Mattel Children's Hospital UCLA

Los Angeles, California, United States

Site Status RECRUITING

Valley Children's Hospital

Madera, California, United States

Site Status RECRUITING

UCSF Benioff Children's Hospital Oakland

Oakland, California, United States

Site Status RECRUITING

Kaiser Permanente-Oakland

Oakland, California, United States

Site Status RECRUITING

Children's Hospital of Orange County

Orange, California, United States

Site Status RECRUITING

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, United States

Site Status RECRUITING

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States

Site Status RECRUITING

Rady Children's Hospital - San Diego

San Diego, California, United States

Site Status RECRUITING

UCSF Medical Center-Mission Bay

San Francisco, California, United States

Site Status RECRUITING

Children's Hospital Colorado

Aurora, Colorado, United States

Site Status RECRUITING

Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center

Denver, Colorado, United States

Site Status RECRUITING

Connecticut Children's Medical Center

Hartford, Connecticut, United States

Site Status RECRUITING

Yale University

New Haven, Connecticut, United States

Site Status RECRUITING

Alfred I duPont Hospital for Children

Wilmington, Delaware, United States

Site Status RECRUITING

Children's National Medical Center

Washington D.C., District of Columbia, United States

Site Status RECRUITING

Golisano Children's Hospital of Southwest Florida

Fort Myers, Florida, United States

Site Status RECRUITING

University of Florida Health Science Center - Gainesville

Gainesville, Florida, United States

Site Status RECRUITING

Memorial Regional Hospital/Joe DiMaggio Children's Hospital

Hollywood, Florida, United States

Site Status RECRUITING

Nemours Children's Clinic-Jacksonville

Jacksonville, Florida, United States

Site Status RECRUITING

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, United States

Site Status RECRUITING

Nicklaus Children's Hospital

Miami, Florida, United States

Site Status RECRUITING

AdventHealth Orlando

Orlando, Florida, United States

Site Status RECRUITING

Arnold Palmer Hospital for Children

Orlando, Florida, United States

Site Status RECRUITING

Nemours Children's Hospital

Orlando, Florida, United States

Site Status RECRUITING

Saint Joseph's Hospital/Children's Hospital-Tampa

Tampa, Florida, United States

Site Status RECRUITING

Children's Healthcare of Atlanta - Arthur M Blank Hospital

Atlanta, Georgia, United States

Site Status RECRUITING

Augusta University Medical Center

Augusta, Georgia, United States

Site Status RECRUITING

Kapiolani Medical Center for Women and Children

Honolulu, Hawaii, United States

Site Status RECRUITING

Saint Luke's Cancer Institute - Boise

Boise, Idaho, United States

Site Status RECRUITING

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States

Site Status RECRUITING

Northwestern University

Chicago, Illinois, United States

Site Status RECRUITING

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, United States

Site Status RECRUITING

Saint Jude Midwest Affiliate

Peoria, Illinois, United States

Site Status RECRUITING

Riley Hospital for Children

Indianapolis, Indiana, United States

Site Status RECRUITING

University of Iowa/Holden Comprehensive Cancer Center

Iowa City, Iowa, United States

Site Status SUSPENDED

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, United States

Site Status RECRUITING

Norton Children's Hospital

Louisville, Kentucky, United States

Site Status RECRUITING

Ochsner Medical Center Jefferson

New Orleans, Louisiana, United States

Site Status RECRUITING

Maine Children's Cancer Program

Scarborough, Maine, United States

Site Status RECRUITING

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, United States

Site Status RECRUITING

Sinai Hospital of Baltimore

Baltimore, Maryland, United States

Site Status RECRUITING

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States

Site Status RECRUITING

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Site Status RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Site Status RECRUITING

UMass Memorial Medical Center - University Campus

Worcester, Massachusetts, United States

Site Status RECRUITING

C S Mott Children's Hospital

Ann Arbor, Michigan, United States

Site Status RECRUITING

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

Site Status RECRUITING

Children's Hospital of Michigan

Detroit, Michigan, United States

Site Status RECRUITING

Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital

Grand Rapids, Michigan, United States

Site Status RECRUITING

Bronson Methodist Hospital

Kalamazoo, Michigan, United States

Site Status RECRUITING

Corewell Health Children's

Royal Oak, Michigan, United States

Site Status RECRUITING

Children's Hospitals and Clinics of Minnesota - Minneapolis

Minneapolis, Minnesota, United States

Site Status RECRUITING

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, United States

Site Status RECRUITING

University of Mississippi Medical Center

Jackson, Mississippi, United States

Site Status RECRUITING

Children's Mercy Hospitals and Clinics

Kansas City, Missouri, United States

Site Status RECRUITING

Cardinal Glennon Children's Medical Center

St Louis, Missouri, United States

Site Status RECRUITING

Washington University School of Medicine

St Louis, Missouri, United States

Site Status RECRUITING

Mercy Hospital Saint Louis

St Louis, Missouri, United States

Site Status RECRUITING

Children's Hospital and Medical Center of Omaha

Omaha, Nebraska, United States

Site Status RECRUITING

University of Nebraska Medical Center

Omaha, Nebraska, United States

Site Status RECRUITING

Alliance for Childhood Diseases/Cure 4 the Kids Foundation

Las Vegas, Nevada, United States

Site Status RECRUITING

Summerlin Hospital Medical Center

Las Vegas, Nevada, United States

Site Status RECRUITING

Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center

Lebanon, New Hampshire, United States

Site Status RECRUITING

Hackensack University Medical Center

Hackensack, New Jersey, United States

Site Status RECRUITING

Morristown Medical Center

Morristown, New Jersey, United States

Site Status RECRUITING

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital

New Brunswick, New Jersey, United States

Site Status RECRUITING

Newark Beth Israel Medical Center

Newark, New Jersey, United States

Site Status RECRUITING

Saint Joseph's Regional Medical Center

Paterson, New Jersey, United States

Site Status RECRUITING

Albany Medical Center

Albany, New York, United States

Site Status RECRUITING

Roswell Park Cancer Institute

Buffalo, New York, United States

Site Status RECRUITING

NYU Langone Hospital - Long Island

Mineola, New York, United States

Site Status RECRUITING

The Steven and Alexandra Cohen Children's Medical Center of New York

New Hyde Park, New York, United States

Site Status RECRUITING

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York, United States

Site Status RECRUITING

NYP/Weill Cornell Medical Center

New York, New York, United States

Site Status RECRUITING

University of Rochester

Rochester, New York, United States

Site Status RECRUITING

Stony Brook University Medical Center

Stony Brook, New York, United States

Site Status RECRUITING

State University of New York Upstate Medical University

Syracuse, New York, United States

Site Status RECRUITING

Montefiore Medical Center - Moses Campus

The Bronx, New York, United States

Site Status RECRUITING

New York Medical College

Valhalla, New York, United States

Site Status RECRUITING

Novant Health Presbyterian Medical Center

Charlotte, North Carolina, United States

Site Status RECRUITING

Duke University Medical Center

Durham, North Carolina, United States

Site Status RECRUITING

East Carolina University

Greenville, North Carolina, United States

Site Status RECRUITING

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States

Site Status RECRUITING

Sanford Broadway Medical Center

Fargo, North Dakota, United States

Site Status RECRUITING

Children's Hospital Medical Center of Akron

Akron, Ohio, United States

Site Status RECRUITING

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Site Status RECRUITING

Rainbow Babies and Childrens Hospital

Cleveland, Ohio, United States

Site Status RECRUITING

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Site Status RECRUITING

Nationwide Children's Hospital

Columbus, Ohio, United States

Site Status RECRUITING

Dayton Children's Hospital

Dayton, Ohio, United States

Site Status RECRUITING

ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital

Toledo, Ohio, United States

Site Status RECRUITING

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Site Status RECRUITING

Oregon Health and Science University

Portland, Oregon, United States

Site Status RECRUITING

Geisinger Medical Center

Danville, Pennsylvania, United States

Site Status RECRUITING

Penn State Children's Hospital

Hershey, Pennsylvania, United States

Site Status RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Site Status RECRUITING

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, United States

Site Status RECRUITING

Saint Christopher's Hospital for Children

Philadelphia, Pennsylvania, United States

Site Status RECRUITING

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Site Status RECRUITING

Prisma Health Richland Hospital

Columbia, South Carolina, United States

Site Status RECRUITING

Saint Francis Hospital

Greenville, South Carolina, United States

Site Status RECRUITING

BI-LO Charities Children's Cancer Center

Greenville, South Carolina, United States

Site Status RECRUITING

Saint Francis Cancer Center

Greenville, South Carolina, United States

Site Status RECRUITING

Sanford USD Medical Center - Sioux Falls

Sioux Falls, South Dakota, United States

Site Status RECRUITING

East Tennessee Childrens Hospital

Knoxville, Tennessee, United States

Site Status RECRUITING

Saint Jude Children's Research Hospital

Memphis, Tennessee, United States

Site Status RECRUITING

The Children's Hospital at TriStar Centennial

Nashville, Tennessee, United States

Site Status RECRUITING

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, United States

Site Status RECRUITING

Dell Children's Medical Center of Central Texas

Austin, Texas, United States

Site Status RECRUITING

Medical City Dallas Hospital

Dallas, Texas, United States

Site Status RECRUITING

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas, United States

Site Status RECRUITING

El Paso Children's Hospital

El Paso, Texas, United States

Site Status RECRUITING

Cook Children's Medical Center

Fort Worth, Texas, United States

Site Status RECRUITING

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, United States

Site Status RECRUITING

M D Anderson Cancer Center

Houston, Texas, United States

Site Status RECRUITING

Covenant Children's Hospital

Lubbock, Texas, United States

Site Status RECRUITING

UMC Cancer Center / UMC Health System

Lubbock, Texas, United States

Site Status RECRUITING

Children's Hospital of San Antonio

San Antonio, Texas, United States

Site Status RECRUITING

Methodist Children's Hospital of South Texas

San Antonio, Texas, United States

Site Status RECRUITING

University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

Site Status RECRUITING

Primary Children's Hospital

Salt Lake City, Utah, United States

Site Status RECRUITING

University of Virginia Cancer Center

Charlottesville, Virginia, United States

Site Status RECRUITING

Children's Hospital of The King's Daughters

Norfolk, Virginia, United States

Site Status RECRUITING

VCU Massey Cancer Center at Stony Point

Richmond, Virginia, United States

Site Status RECRUITING

VCU Massey Comprehensive Cancer Center

Richmond, Virginia, United States

Site Status RECRUITING

Seattle Children's Hospital

Seattle, Washington, United States

Site Status RECRUITING

Providence Sacred Heart Medical Center and Children's Hospital

Spokane, Washington, United States

Site Status RECRUITING

Mary Bridge Children's Hospital and Health Center

Tacoma, Washington, United States

Site Status RECRUITING

Madigan Army Medical Center

Tacoma, Washington, United States

Site Status RECRUITING

West Virginia University Charleston Division

Charleston, West Virginia, United States

Site Status RECRUITING

Saint Vincent Hospital Cancer Center Green Bay

Green Bay, Wisconsin, United States

Site Status RECRUITING

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin, United States

Site Status RECRUITING

Marshfield Medical Center-Marshfield

Marshfield, Wisconsin, United States

Site Status SUSPENDED

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Site Status RECRUITING

Sydney Children's Hospital

Randwick, New South Wales, Australia

Site Status SUSPENDED

The Children's Hospital at Westmead

Westmead, New South Wales, Australia

Site Status RECRUITING

Queensland Children's Hospital

South Brisbane, Queensland, Australia

Site Status RECRUITING

Royal Children's Hospital

Parkville, Victoria, Australia

Site Status RECRUITING

Perth Children's Hospital

Perth, Western Australia, Australia

Site Status RECRUITING

Alberta Children's Hospital

Calgary, Alberta, Canada

Site Status SUSPENDED

CancerCare Manitoba

Winnipeg, Manitoba, Canada

Site Status RECRUITING

IWK Health Centre

Halifax, Nova Scotia, Canada

Site Status RECRUITING

Children's Hospital

London, Ontario, Canada

Site Status RECRUITING

Children's Hospital of Eastern Ontario

Ottawa, Ontario, Canada

Site Status RECRUITING

Hospital for Sick Children

Toronto, Ontario, Canada

Site Status SUSPENDED

The Montreal Children's Hospital of the MUHC

Montreal, Quebec, Canada

Site Status RECRUITING

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec, Canada

Site Status RECRUITING

Centre Hospitalier Universitaire de Sherbrooke-Fleurimont

Sherbrooke, Quebec, Canada

Site Status RECRUITING

Jim Pattison Children's Hospital

Saskatoon, Saskatchewan, Canada

Site Status RECRUITING

CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)

Québec, , Canada

Site Status RECRUITING

Starship Children's Hospital

Grafton, Auckland, New Zealand

Site Status RECRUITING

Christchurch Hospital

Christchurch, , New Zealand

Site Status RECRUITING

Countries

Review the countries where the study has at least one active or historical site.

United States Australia Canada New Zealand

Facility Contacts

Find local site contact details for specific facilities participating in the trial.

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Other Identifiers

Review additional registry numbers or institutional identifiers associated with this trial.

NCI-2022-08567

Identifier Type: REGISTRY

Identifier Source: secondary_id

AOST2032

Identifier Type: OTHER

Identifier Source: secondary_id

AOST2032

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA180886

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2022-08567

Identifier Type: -

Identifier Source: org_study_id

NCT05683197

Identifier Type: -

Identifier Source: nct_alias