High Grade OsteosarcomaPhase 2/3NCT05691478
A Study to Test the Addition of the Drug Cabozantinib to Chemotherapy in Patients With Newly Diagnosed Osteosarcoma
A Phase 2/3 study testing Bone Scan, Cabozantinib S-malate and Cisplatin in people with High Grade Osteosarcoma and Localized Osteosarcoma, run by National Cancer Institute (NCI) at 202 sites in 4 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 40 years
- Conditions the study is for
- High Grade Osteosarcoma, Localized Osteosarcoma, Metastatic Osteosarcoma
- What is being tested?
- Bone Scan, Cabozantinib S-malate and Cisplatin
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,122 participants
- Where
- 202 sitesin 4 countries
- Study dates
- 3 Mar 2023to 20 Mar 2030
- Phase
- Phase 2/3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 40 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
202 sites in 4 countries.
202 sites in 4 countries
United States181 sites
Children's Hospital Medical Center of Akron
Akron, Ohio, 44308
Albany Medical Center
Albany, New York, 12208
C S Mott Children's Hospital
Ann Arbor, Michigan, 48109
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan, 48109
Children's Healthcare of Atlanta - Arthur M Blank Hospital
Atlanta, Georgia, 30329
Augusta University Medical Center
Augusta, Georgia, 30912
Children's Hospital Colorado
Aurora, Colorado, 80045
Dell Children's Medical Center of Central Texas
Austin, Texas, 78723
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, 21201
Sinai Hospital of Baltimore
Baltimore, Maryland, 21215
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
Eastern Maine Medical Center
Bangor, Maine, 04401
Walter Reed National Military Medical Center
Bethesda, Maryland, 20889-5600
Children's Hospital of Alabama
Birmingham, Alabama, 35233
Saint Luke's Cancer Institute - Boise
Boise, Idaho, 83712
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Henry Ford Cancer Institute-Downriver
Brownstown, Michigan, 48183
Roswell Park Cancer Institute
Buffalo, New York, 14263
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599
Medical University of South Carolina
Charleston, South Carolina, 29425
Vandalia Health/CAMC Institute for Academic Medicine
Charleston, West Virginia, 25304
Carolinas Medical Center/Levine Cancer Institute
Charlotte, North Carolina, 28203
Novant Health Presbyterian Medical Center
Charlotte, North Carolina, 28204
Atrium Health Pineville/LCI-Pineville
Charlotte, North Carolina, 28210
University of Virginia Cancer Center
Charlottesville, Virginia, 22908
Lurie Children's Hospital-Chicago
Chicago, Illinois, 60611
Northwestern University
Chicago, Illinois, 60611
University of Illinois
Chicago, Illinois, 60612
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
Rainbow Babies and Childrens Hospital
Cleveland, Ohio, 44106
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Henry Ford Macomb Hospital-Clinton Township
Clinton Township, Michigan, 48038
University of Missouri Children's Hospital
Columbia, Missouri, 65212
Prisma Health Richland Hospital
Columbia, South Carolina, 29203
Nationwide Children's Hospital
Columbus, Ohio, 43205
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Driscoll Children's Hospital
Corpus Christi, Texas, 78411
Medical City Dallas Hospital
Dallas, Texas, 75230
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390
Geisinger Medical Center
Danville, Pennsylvania, 17822
Dayton Children's Hospital
Dayton, Ohio, 45404
Henry Ford Medical Center-Fairlane
Dearborn, Michigan, 48126
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Denver, Colorado, 80218
Blank Children's Hospital
Des Moines, Iowa, 50309
Children's Hospital of Michigan
Detroit, Michigan, 48201
Henry Ford Hospital
Detroit, Michigan, 48202
Kaiser Permanente Downey Medical Center
Downey, California, 90242
City of Hope Comprehensive Cancer Center
Duarte, California, 91010
Duke University Medical Center
Durham, North Carolina, 27710
El Paso Children's Hospital
El Paso, Texas, 79905
Sanford Broadway Medical Center
Fargo, North Dakota, 58122
Golisano Children's Hospital of Southwest Florida
Fort Myers, Florida, 33908
Cook Children's Medical Center
Fort Worth, Texas, 76104
Gibbs Cancer Center-Gaffney
Gaffney, South Carolina, 29341
UF Health Cancer Institute - Gainesville
Gainesville, Florida, 32610
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
Grand Rapids, Michigan, 49503
Saint Vincent Hospital Cancer Center Green Bay
Green Bay, Wisconsin, 54301
East Carolina University
Greenville, North Carolina, 27834
Saint Francis Hospital
Greenville, South Carolina, 29601
BI-LO Charities Children's Cancer Center
Greenville, South Carolina, 29605
Saint Francis Cancer Center
Greenville, South Carolina, 29607
Gibbs Cancer Center-Pelham
Greer, South Carolina, 29651
Hackensack University Medical Center
Hackensack, New Jersey, 07601
Connecticut Children's Medical Center
Hartford, Connecticut, 06106
Penn State Children's Hospital
Hershey, Pennsylvania, 17033
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
Hollywood, Florida, 33021
Kapiolani Medical Center for Women and Children
Honolulu, Hawaii, 96826
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston, Texas, 77030
UT MD Anderson Cancer Center
Houston, Texas, 77030
Riley Hospital for Children
Indianapolis, Indiana, 46202
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242
Allegiance Health
Jackson, Michigan, 49201
University of Mississippi Medical Center
Jackson, Mississippi, 39216
Nemours Children's Clinic-Jacksonville
Jacksonville, Florida, 32207
Bronson Methodist Hospital
Kalamazoo, Michigan, 49007
Children's Mercy Hospitals and Clinics
Kansas City, Missouri, 64108
East Tennessee Childrens Hospital
Knoxville, Tennessee, 37916
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
Las Vegas, Nevada, 89135
Summerlin Hospital Medical Center
Las Vegas, Nevada, 89144
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Lebanon, New Hampshire, 03756
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536
Arkansas Children's Hospital
Little Rock, Arkansas, 72202-3591
Loma Linda University Medical Center
Loma Linda, California, 92354
Miller Children's and Women's Hospital Long Beach
Long Beach, California, 90806
Children's Hospital Los Angeles
Los Angeles, California, 90027
Cedars-Sinai Medical Center
Los Angeles, California, 90048
Mattel Children's Hospital UCLA
Los Angeles, California, 90095
Norton Children's Hospital
Louisville, Kentucky, 40202
Covenant Children's Hospital
Lubbock, Texas, 79410
UMC Cancer Center / UMC Health System
Lubbock, Texas, 79415
Valley Children's Hospital
Madera, California, 93636
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792
Marshfield Medical Center-Marshfield
Marshfield, Wisconsin, 54449
Saint Jude Children's Research Hospital
Memphis, Tennessee, 38105
Banner Children's at Desert
Mesa, Arizona, 85202
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
Nicklaus Children's Hospital
Miami, Florida, 33155
Miami Cancer Institute
Miami, Florida, 33176
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, 53226
NYU Langone Hospital - Long Island
Mineola, New York, 11501
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis, Minnesota, 55404
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, 55455
Morristown Medical Center
Morristown, New Jersey, 07960
The Children's Hospital at TriStar Centennial
Nashville, Tennessee, 37203
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
New Brunswick, New Jersey, 08903
Yale University
New Haven, Connecticut, 06520
The Steven and Alexandra Cohen Children's Medical Center of New York
New Hyde Park, New York, 11040
Children's Hospital New Orleans
New Orleans, Louisiana, 70118
Ochsner Medical Center Jefferson
New Orleans, Louisiana, 70121
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
NYP/Weill Cornell Medical Center
New York, New York, 10065
Newark Beth Israel Medical Center
Newark, New Jersey, 07112
Children's Hospital of The King's Daughters
Norfolk, Virginia, 23507
Henry Ford Medical Center-Columbus
Novi, Michigan, 48377
UCSF Benioff Children's Hospital Oakland
Oakland, California, 94609
Kaiser Permanente-Oakland
Oakland, California, 94611
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Children's Hospital and Medical Center of Omaha
Omaha, Nebraska, 68114
University of Nebraska Medical Center
Omaha, Nebraska, 68198
Children's Hospital of Orange County
Orange, California, 92868
AdventHealth Orlando
Orlando, Florida, 32803
Arnold Palmer Hospital for Children
Orlando, Florida, 32806
Nemours Children's Hospital
Orlando, Florida, 32827
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, 94304
Saint Joseph's Regional Medical Center
Paterson, New Jersey, 07503
Nemours Children's Clinic - Pensacola
Pensacola, Florida, 32504
OSF Children's Hospital of Illinois
Peoria, Illinois, 61637
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107
Saint Christopher's Hospital for Children
Philadelphia, Pennsylvania, 19134
Phoenix Childrens Hospital
Phoenix, Arizona, 85016
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, 85054
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, 15224
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
Legacy Emanuel Children's Hospital
Portland, Oregon, 97227
Oregon Health and Science University
Portland, Oregon, 97239
VCU Massey Cancer Center at Stony Point
Richmond, Virginia, 23235
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
University of Rochester
Rochester, New York, 14642
Corewell Health Children's
Royal Oak, Michigan, 48073
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
Primary Children's Hospital
Salt Lake City, Utah, 84113
Children's Hospital of San Antonio
San Antonio, Texas, 78207
Methodist Children's Hospital of South Texas
San Antonio, Texas, 78229
University of Texas Health Science Center at San Antonio
San Antonio, Texas, 78229
Rady Children's Hospital - San Diego
San Diego, California, 92123
UCSF Medical Center-Mission Bay
San Francisco, California, 94158
Memorial Health University Medical Center
Savannah, Georgia, 31404
Maine Children's Cancer Program
Scarborough, Maine, 04074
Seattle Children's Hospital
Seattle, Washington, 98105
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, 57117-5134
Spartanburg Medical Center
Spartanburg, South Carolina, 29303
Providence Sacred Heart Medical Center and Children's Hospital
Spokane, Washington, 99204
Southern Illinois University School of Medicine
Springfield, Illinois, 62702
Cardinal Glennon Children's Medical Center
St Louis, Missouri, 63104
Washington University School of Medicine
St Louis, Missouri, 63110
Mercy Hospital Saint Louis
St Louis, Missouri, 63141
Johns Hopkins All Children's Hospital
St. Petersburg, Florida, 33701
Stony Brook University Medical Center
Stony Brook, New York, 11794
State University of New York Upstate Medical University
Syracuse, New York, 13210
Mary Bridge Children's Hospital and Health Center
Tacoma, Washington, 98405
Madigan Army Medical Center
Tacoma, Washington, 98431
Saint Joseph's Hospital/Children's Hospital-Tampa
Tampa, Florida, 33607
Scott and White Memorial Hospital
Temple, Texas, 76508
Montefiore Medical Center - Moses Campus
The Bronx, New York, 10467
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
Toledo, Ohio, 43606
Banner University Medical Center - Tucson
Tucson, Arizona, 85719
New York Medical College
Valhalla, New York, 10595
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, 20007
Children's National Medical Center
Washington D.C., District of Columbia, 20010
Henry Ford West Bloomfield Hospital
West Bloomfield, Michigan, 48322
Alfred I duPont Hospital for Children
Wilmington, Delaware, 19803
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157
UMass Memorial Medical Center - University Campus
Worcester, Massachusetts, 01655
Henry Ford Wyandotte Hospital
Wyandotte, Michigan, 48192
Canada12 sites
Alberta Children's Hospital
Calgary, Alberta, T3B 6A8
University of Alberta Hospital
Edmonton, Alberta, T6G 2B7
IWK Health Centre
Halifax, Nova Scotia, B3K 6R8
Children's Hospital
London, Ontario, N6A 5W9
The Montreal Children's Hospital of the MUHC
Montreal, Quebec, H3H 1P3
Centre Hospitalier Universitaire Sainte-Justine
Montreal, Quebec, H3T 1C5
Children's Hospital of Eastern Ontario
Ottawa, Ontario, K1H 8L1
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
Québec, G1V 4G2
Jim Pattison Children's Hospital
Saskatoon, Saskatchewan, S7N 0W8
Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
Sherbrooke, Quebec, J1H 5N4
Hospital for Sick Children
Toronto, Ontario, M5G 1X8
CancerCare Manitoba
Winnipeg, Manitoba, R3E 0V9
Australia7 sites
Monash Medical Center-Clayton Campus
Clayton, Victoria, 3168
Women's and Children's Hospital-Adelaide
North Adelaide, South Australia, 5006
Royal Children's Hospital
Parkville, Victoria, 3052
Perth Children's Hospital
Perth, Western Australia, 6009
Sydney Children's Hospital
Randwick, New South Wales, 2031
Queensland Children's Hospital
South Brisbane, Queensland, 4101
The Children's Hospital at Westmead
Westmead, New South Wales, 2145
New Zealand2 sites
Christchurch Hospital
Christchurch, 8011
Starship Children's Hospital
Grafton, Auckland, 1145
About this study
Official title: A Feasibility and Randomized Phase 2/3 Study of the VEGFR2/MET Inhibitor Cabozantinib in Combination With Cytotoxic Chemotherapy for Newly Diagnosed Osteosarcoma
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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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.
- 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:
- 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.
- 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.
- 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
- High Grade Osteosarcoma, Localized Osteosarcoma, Metastatic Osteosarcoma, Secondary Osteosarcoma
- Being tested
- Bone Scan, Cabozantinib S-malate, Cisplatin, Computed Tomography, Doxorubicin Hydrochloride
- Medical subject headings
- Osteosarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Bone ScanProcedure or surgery
Also called Bone Scintigraphy
Undergo bone scintography
Cabozantinib S-malateDrug
Also called BMS-907351, Cabometyx, Cometriq, XL 184
Given PO
CisplatinDrug
Also called Abiplatin, Blastolem, Briplatin, CDDP
Given IV
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT
Also called 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
Given IV
Magnetic Resonance ImagingProcedure or surgery
Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan
Undergo MRI
MethotrexateDrug
Also called Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate
Given IV
Surgical ProcedureProcedure or surgery
Also called Operation, Surgery, Surgery Type, Surgery, NOS
Undergo surgery
X-Ray ImagingProcedure or surgery
Also called Conventional X-Ray, Diagnostic Radiology, Medical Imaging, X-Ray, Plain film radiographs
Undergo X-ray
| Study group | Role | What they receive |
|---|---|---|
| Efficacy Phase Arm A (MAP) | Active comparator | 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. Receives: Procedure: Bone Scan; Drug: Cisplatin; Procedure: Computed Tomography; Drug: Doxorubicin Hydrochloride; Procedure: Magnetic Resonance Imaging; Drug: Methotrexate; Procedure: Surgical Procedure; Procedure: X-Ray Imaging |
| Efficacy Phase Arm B (cabozantinib, MAP) | Experimental | 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. Receives: Procedure: Bone Scan; Drug: Cabozantinib S-malate; Drug: Cisplatin; Procedure: Computed Tomography; Drug: Doxorubicin Hydrochloride; Procedure: Magnetic Resonance Imaging; Drug: Methotrexate; Procedure: Surgical Procedure; Procedure: X-Ray Imaging |
| Efficacy Phase Arm C (MAP) | Active comparator | 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. Receives: Procedure: Bone Scan; Drug: Cisplatin; Procedure: Computed Tomography; Drug: Doxorubicin Hydrochloride; Procedure: Magnetic Resonance Imaging; Drug: Methotrexate; Procedure: Surgical Procedure; Procedure: X-Ray Imaging |
| Efficacy Phase Arm D (cabozantinib, MAP) | Experimental | 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. Receives: Procedure: Bone Scan; Drug: Cabozantinib S-malate; Drug: Cisplatin; Procedure: Computed Tomography; Drug: Doxorubicin Hydrochloride; Procedure: Magnetic Resonance Imaging; Drug: Methotrexate; Procedure: X-Ray Imaging |
| Feasibility phase (cabozantinib, MAP) | Experimental | (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. Receives: Procedure: Bone Scan; Drug: Cabozantinib S-malate; Drug: Cisplatin; Procedure: Computed Tomography; Drug: Doxorubicin Hydrochloride; Procedure: Magnetic Resonance Imaging; Drug: Methotrexate; Procedure: Surgical Procedure; Procedure: X-Ray Imaging |
What is being measured
The primary outcome is the main question the study is designed to answer.
Occurrence of dose-limiting toxicity (Feasibility)
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 leadership and National Cancer Institute Cancer Therapy Evaluation Program regarding possible modifications of the regimen and subsequent protocol amendment.
Measured: Baseline up to 6 weeks
Event-free survival (EFS) (Phase II)
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.
Measured: 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
EFS (Phase III)
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.
Measured: 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
Overall survival
The one-sided logrank test will be the primary statistical methodology for assessing the null statistical hypothesis. The assessment of the reduction in risk of EFS-event will be conducted in standard risk patients and high risk patients separately.
Measured: From randomization until death or last contact, whichever occurs first, assessed up to 5 years after completion of study treatment
Secondary outcomes (5)
EFS
Will validate whether elevated circulating tumor deoxyribonucleic acid (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.
Measured: 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
EFS
Will validate whether 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.
Measured: 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
EFS
Will validate whether 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.
Measured: 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
EFS
Will validate whether 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.
Measured: 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
Change in symptom burden and tolerability
Will determine whether methotrexate, doxorubicin, and cisplatin (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]).
Measured: Up to 5 years after completion of study treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jan 2023
- Study start3 Mar 2023
- Primary completion20 Mar 2030 (estimated)
- Study completion20 Mar 2030 (estimated)
Why it stopped: Other - Extend the observation period for current patients
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for High Grade OsteosarcomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- Single-arm Feasibility Phase study followed by a randomized, parallel 4-arm Efficacy Phase study
- Masking
- None (open label)
- Enrolment
- 1,122 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Michael W Bishop, Principal investigator, Children's Oncology Group
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05691478
- Sponsor's protocol ID
- NCI-2022-08567
- Other IDs
- NCI-2022-08567, AOST2032, AOST2032, U10CA180886
- Status last verified
- Aug 2026
- First submitted
- 18 Jan 2023
- Last updated
- 16 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.