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Brief Title: A Study to Test the Addition of the Drug Cabozantinib to Chemotherapy in Patients With Newly Diagnosed Osteosarcoma
Official Title: A Feasibility and Randomized Phase 2/3 Study of the VEFGR2/MET Inhibitor Cabozantinib in Combination With Cytotoxic Chemotherapy for Newly Diagnosed Osteosarcoma
Study ID: NCT05691478
Brief Summary: This phase II/III trial tests the safety, side effects, and best dose of the drug cabozantinib in combination with standard chemotherapy, and to compare the effect of adding cabozantinib to standard chemotherapy alone in treating patients with newly diagnosed osteosarcoma. Cabozantinib is in a class of medications called kinase inhibitors which block protein signals affecting new blood vessel formation and the ability to activate growth signaling pathways. This may help slow the growth of tumor cells. The drugs used in standard chemotherapy for this trial are methotrexate, doxorubicin, and cisplatin (MAP). Methotrexate stops cells from making DNA and may kill tumor cells. It is a type of antimetabolite. Doxorubicin is in a class of medications called anthracyclines. It works by slowing or stopping the growth of tumor cells in the body. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Adding cabozantinib to standard chemotherapy may work better in treating newly diagnosed osteosarcoma.
Detailed Description: PRIMARY OBJECTIVES: I. To determine the feasibility of adding cabozantinib S-malate (cabozantinib) to standard MAP (high dose methotrexate, doxorubicin hydrochloride \[doxorubicin\], and cisplatin) chemotherapy in patients with newly diagnosed metastatic osteosarcoma with a resectable primary tumor. II. To determine whether MAP chemotherapy plus cabozantinib results in more favorable event-free survival (EFS) than MAP chemotherapy alone in patients with localized, resectable osteosarcoma. III. To determine whether MAP chemotherapy plus cabozantinib results in more favorable event-free survival (EFS) than MAP chemotherapy alone in patients with metastatic, pelvic and unresectable osteosarcoma. SECONDARY OBJECTIVES: I. To determine whether MAP chemotherapy plus cabozantinib results in more favorable overall survival (OS) than MAP chemotherapy alone in patients with localized, resectable osteosarcoma. II. To determine whether MAP chemotherapy plus cabozantinib results in more favorable overall survival (OS) than MAP chemotherapy alone in patients with metastatic, pelvic and unresectable osteosarcoma. EXPLORATORY OBJECTIVES: I. To determine the rate of good histologic response (\> 90%) of resected primary tumor specimens following neoadjuvant chemotherapy with MAP plus cabozantinib and compare with response rates for MAP chemotherapy alone. II. To describe the toxicities of the addition of cabozantinib to MAP chemotherapy in patients with newly diagnosed osteosarcoma. III. To describe frequency of application of local control methods (surgery, hypofractionated stereotactic body radiotherapy, or radiofrequency ablation) for extrapulmonary metastatic osteosarcoma. IV. To compare total cumulative delivered doses of MAP chemotherapy agents between standard and experimental arms across multiple phases of therapy. V. To assess the pharmacokinetics of cabozantinib when administered concomitantly with standard chemotherapy agents during feasibility. VI. To collect pulmonary metastatic lesions, paired primary tumor tissue, and serial blood samples for tumor profiling, liquid biopsies, and future testing of correlative biology studies. OUTLINE: This is a dose-escalation study of cabozantinib (Feasibility Phase) followed by a randomized phase II/III study (Efficacy Phase). FEASIBILITY PHASE: Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. EFFICACY PHASE: Patients with standard risk osteosarcoma are randomized to Arm A or Arm B. Patients with high risk osteosarcoma are randomized to Arm C or Arm D. ARM A: Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. ARM B: Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. ARM C: High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles. ARM D: High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. All patients also undergo X-ray, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.
Minimum Age:
Eligible Ages: CHILD, ADULT
Sex: ALL
Healthy Volunteers: No
Children's Hospital of Alabama, Birmingham, Alabama, United States
Arkansas Children's Hospital, Little Rock, Arkansas, United States
City of Hope Comprehensive Cancer Center, Duarte, California, United States
Loma Linda University Medical Center, Loma Linda, California, United States
Miller Children's and Women's Hospital Long Beach, Long Beach, California, United States
Valley Children's Hospital, Madera, California, United States
UCSF Benioff Children's Hospital Oakland, Oakland, California, United States
Kaiser Permanente-Oakland, Oakland, California, United States
Children's Hospital of Orange County, Orange, California, United States
Lucile Packard Children's Hospital Stanford University, Palo Alto, California, United States
Rady Children's Hospital - San Diego, San Diego, California, United States
UCSF Medical Center-Mission Bay, San Francisco, California, United States
Alfred I duPont Hospital for Children, Wilmington, Delaware, United States
Golisano Children's Hospital of Southwest Florida, Fort Myers, Florida, United States
University of Florida Health Science Center - Gainesville, Gainesville, Florida, United States
Nemours Children's Clinic-Jacksonville, Jacksonville, Florida, United States
Nicklaus Children's Hospital, Miami, Florida, United States
AdventHealth Orlando, Orlando, Florida, United States
Kapiolani Medical Center for Women and Children, Honolulu, Hawaii, United States
Lurie Children's Hospital-Chicago, Chicago, Illinois, United States
Northwestern University, Chicago, Illinois, United States
Riley Hospital for Children, Indianapolis, Indiana, United States
University of Iowa/Holden Comprehensive Cancer Center, Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center, Lexington, Kentucky, United States
Norton Children's Hospital, Louisville, Kentucky, United States
Ochsner Medical Center Jefferson, New Orleans, Louisiana, United States
Maine Children's Cancer Program, Scarborough, Maine, United States
Sinai Hospital of Baltimore, Baltimore, Maryland, United States
Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Children's Hospital of Michigan, Detroit, Michigan, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital, Grand Rapids, Michigan, United States
University of Minnesota/Masonic Cancer Center, Minneapolis, Minnesota, United States
University of Mississippi Medical Center, Jackson, Mississippi, United States
Children's Mercy Hospitals and Clinics, Kansas City, Missouri, United States
Washington University School of Medicine, Saint Louis, Missouri, United States
Children's Hospital and Medical Center of Omaha, Omaha, Nebraska, United States
University of Nebraska Medical Center, Omaha, Nebraska, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation, Las Vegas, Nevada, United States
Summerlin Hospital Medical Center, Las Vegas, Nevada, United States
Hackensack University Medical Center, Hackensack, New Jersey, United States
Morristown Medical Center, Morristown, New Jersey, United States
Newark Beth Israel Medical Center, Newark, New Jersey, United States
Saint Joseph's Regional Medical Center, Paterson, New Jersey, United States
Albany Medical Center, Albany, New York, United States
Montefiore Medical Center - Moses Campus, Bronx, New York, United States
Roswell Park Cancer Institute, Buffalo, New York, United States
NYU Langone Hospital - Long Island, Mineola, New York, United States
Stony Brook University Medical Center, Stony Brook, New York, United States
State University of New York Upstate Medical University, Syracuse, New York, United States
New York Medical College, Valhalla, New York, United States
Duke University Medical Center, Durham, North Carolina, United States
East Carolina University, Greenville, North Carolina, United States
Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Rainbow Babies and Childrens Hospital, Cleveland, Ohio, United States
Cleveland Clinic Foundation, Cleveland, Ohio, United States
Dayton Children's Hospital, Dayton, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital, Toledo, Ohio, United States
University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Oregon Health and Science University, Portland, Oregon, United States
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
Saint Christopher's Hospital for Children, Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States
Prisma Health Richland Hospital, Columbia, South Carolina, United States
Saint Francis Hospital, Greenville, South Carolina, United States
BI-LO Charities Children's Cancer Center, Greenville, South Carolina, United States
Saint Francis Cancer Center, Greenville, South Carolina, United States
Sanford USD Medical Center - Sioux Falls, Sioux Falls, South Dakota, United States
Saint Jude Children's Research Hospital, Memphis, Tennessee, United States
The Children's Hospital at TriStar Centennial, Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center, Nashville, Tennessee, United States
Dell Children's Medical Center of Central Texas, Austin, Texas, United States
Medical City Dallas Hospital, Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas, Dallas, Texas, United States
El Paso Children's Hospital, El Paso, Texas, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center, Houston, Texas, United States
M D Anderson Cancer Center, Houston, Texas, United States
Covenant Children's Hospital, Lubbock, Texas, United States
UMC Cancer Center / UMC Health System, Lubbock, Texas, United States
Children's Hospital of San Antonio, San Antonio, Texas, United States
Methodist Children's Hospital of South Texas, San Antonio, Texas, United States
University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Primary Children's Hospital, Salt Lake City, Utah, United States
University of Virginia Cancer Center, Charlottesville, Virginia, United States
Children's Hospital of The King's Daughters, Norfolk, Virginia, United States
VCU Massey Cancer Center at Stony Point, Richmond, Virginia, United States
Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia, United States
Seattle Children's Hospital, Seattle, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital, Spokane, Washington, United States
Mary Bridge Children's Hospital and Health Center, Tacoma, Washington, United States
Madigan Army Medical Center, Tacoma, Washington, United States
Marshfield Medical Center-Marshfield, Marshfield, Wisconsin, United States
Name: Michael W Bishop
Affiliation: Children's Oncology Group
Role: PRINCIPAL_INVESTIGATOR