Metastatic Osteosarcoma Clinical Trial
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
Verified date | May 2024 |
Source | National Cancer Institute (NCI) |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Suspended |
Enrollment | 1122 |
Est. completion date | March 20, 2030 |
Est. primary completion date | March 20, 2030 |
Accepts healthy volunteers | No |
Gender | All |
Age group | N/A to 40 Years |
Eligibility | 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: 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) 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/gender as follows (within 7 days prior to enrollment unless otherwise indicated): - (Age: Maximum Serum Creatinine [mg/dL]; Gender) - 1 month to < 6 months: 0.4 (male); 0.4 (female) - 6 months to < 1 year: 0.5 (male); 0.5 (female) - 1 to < 2 years: 0.6 (male); 0.6 (female) - 2 to < 6 years: 0.8 (male); 0.8 (female) - 6 to < 10 years: 1 (male); 1 (female) - 10 to < 13 years: 1.2 (male); 1.2 (female) - 13 to < 16 years: 1.5 (male); 1.4 (female) - >= 16 years: 1.7 (male); 1.4 (female) - OR - a 24 hour urine creatinine clearance >= 70 mL/min/1.73 m^2 - OR - a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard). - Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility. - Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment unless otherwise indicated) - Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment unless otherwise indicated) - Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L - No history of congenital prolonged corrected QT (QTc) syndrome, New York Heart Association (NYHA) Class III or IV congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias or - Shortening fraction of >= 27%, or - Ejection fraction of >= 50%, or - Corrected QT interval by Fridericia (QTcF) < 480 msec on electrocardiogram. Patients with Grade 1 prolonged QTc (450-480 msec) at time of study enrollment should have correctable causes of prolonged QTc addressed if possible (i.e., electrolytes, medications). - Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment unless otherwise indicated) - Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to enrollment) (within 7 days prior to enrollment unless otherwise indicated) - Hemoglobin >= 8.0 g/dL (within 7 days prior to enrollment unless otherwise indicated) - International normalized ratio (INR) =< 1.5 (within 7 days prior to enrollment unless otherwise indicated) - Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible as long as they are NOT receiving anti-retroviral agents that are strong inhibitors or inducers of CYP3A4, CYP2D6, and/or MRP2 transporter protein. - All patients and/or their parents or legal guardians must sign a written informed consent. - All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met. 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 gender for patients < 18 years and > 140/90 mmHg for patients >= 18 years requiring medication for blood pressure control. - Patients who are receiving drugs that prolong QTc. - Patients receiving anticoagulation with oral coumarin agents (eg warfarin), direct thrombin inhibitors (eg dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (eg, clopidogrel). Low dose aspirin for cardioprotection (per local applicable guidelines) and low dose, low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH and direct factor Xa inhibitors rivaroxaban or apixaban are allowed in subjects who are on a stable dose for at least 6 weeks before the first dose of study treatment, and who have had no complications from a thromboembolic event or the anticoagulation regimen. - Patients receiving strong CYP3A4 inducers or strong CYP3A4 inhibitors. - Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential. - Lactating females who plan to breastfeed their infants. - Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of protocol therapy. |
Country | Name | City | State |
---|---|---|---|
United States | Albany Medical Center | Albany | New York |
United States | Dell Children's Medical Center of Central Texas | Austin | Texas |
United States | Sinai Hospital of Baltimore | Baltimore | Maryland |
United States | Children's Hospital of Alabama | Birmingham | Alabama |
United States | Dana-Farber Cancer Institute | Boston | Massachusetts |
United States | Montefiore Medical Center - Moses Campus | Bronx | New York |
United States | Roswell Park Cancer Institute | Buffalo | New York |
United States | University of Virginia Cancer Center | Charlottesville | Virginia |
United States | Lurie Children's Hospital-Chicago | Chicago | Illinois |
United States | Northwestern University | Chicago | Illinois |
United States | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio |
United States | Cleveland Clinic Foundation | Cleveland | Ohio |
United States | Rainbow Babies and Childrens Hospital | Cleveland | Ohio |
United States | Prisma Health Richland Hospital | Columbia | South Carolina |
United States | Medical City Dallas Hospital | Dallas | Texas |
United States | UT Southwestern/Simmons Cancer Center-Dallas | Dallas | Texas |
United States | Dayton Children's Hospital | Dayton | Ohio |
United States | Children's Hospital of Michigan | Detroit | Michigan |
United States | City of Hope Comprehensive Cancer Center | Duarte | California |
United States | Duke University Medical Center | Durham | North Carolina |
United States | El Paso Children's Hospital | El Paso | Texas |
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 | Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital | Grand Rapids | Michigan |
United States | BI-LO Charities Children's Cancer Center | Greenville | South Carolina |
United States | East Carolina University | Greenville | North Carolina |
United States | Saint Francis Cancer Center | Greenville | South Carolina |
United States | Saint Francis Hospital | Greenville | South Carolina |
United States | Hackensack University Medical Center | Hackensack | New Jersey |
United States | Kapiolani Medical Center for Women and Children | Honolulu | Hawaii |
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 | Riley Hospital for Children | Indianapolis | Indiana |
United States | University of Iowa/Holden Comprehensive Cancer Center | Iowa City | Iowa |
United States | University of Mississippi Medical Center | Jackson | Mississippi |
United States | Nemours Children's Clinic-Jacksonville | Jacksonville | Florida |
United States | Children's Mercy Hospitals and Clinics | Kansas City | Missouri |
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 | University of Kentucky/Markey Cancer Center | Lexington | Kentucky |
United States | Arkansas Children's Hospital | Little Rock | Arkansas |
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 | Norton Children's Hospital | Louisville | Kentucky |
United States | Covenant Children's Hospital | Lubbock | Texas |
United States | UMC Cancer Center / UMC Health System | Lubbock | Texas |
United States | Valley Children's Hospital | Madera | California |
United States | Marshfield Medical Center-Marshfield | Marshfield | Wisconsin |
United States | Saint Jude Children's Research Hospital | Memphis | Tennessee |
United States | Nicklaus Children's Hospital | Miami | Florida |
United States | NYU Langone Hospital - Long Island | Mineola | New York |
United States | University of Minnesota/Masonic Cancer Center | Minneapolis | Minnesota |
United States | Morristown Medical Center | Morristown | New Jersey |
United States | The Children's Hospital at TriStar Centennial | Nashville | Tennessee |
United States | Vanderbilt University/Ingram Cancer Center | Nashville | Tennessee |
United States | Ochsner Medical Center Jefferson | New Orleans | Louisiana |
United States | Newark Beth Israel Medical Center | Newark | New Jersey |
United States | Children's Hospital of The King's Daughters | Norfolk | Virginia |
United States | Kaiser Permanente-Oakland | Oakland | California |
United States | UCSF Benioff Children's Hospital Oakland | Oakland | California |
United States | University of Oklahoma Health Sciences Center | Oklahoma City | Oklahoma |
United States | Children's Hospital and Medical Center of Omaha | Omaha | Nebraska |
United States | University of Nebraska Medical Center | Omaha | Nebraska |
United States | Children's Hospital of Orange County | Orange | California |
United States | AdventHealth Orlando | Orlando | Florida |
United States | Lucile Packard Children's Hospital Stanford University | Palo Alto | California |
United States | Saint Joseph's Regional Medical Center | Paterson | New Jersey |
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 | Oregon Health and Science University | Portland | Oregon |
United States | VCU Massey Cancer Center at Stony Point | Richmond | Virginia |
United States | Virginia Commonwealth University/Massey Cancer Center | Richmond | Virginia |
United States | Washington University School of Medicine | Saint Louis | Missouri |
United States | Primary Children's Hospital | Salt Lake City | Utah |
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 | Rady Children's Hospital - San Diego | San Diego | California |
United States | UCSF Medical Center-Mission Bay | San Francisco | California |
United States | Maine Children's Cancer Program | Scarborough | Maine |
United States | Seattle Children's Hospital | Seattle | Washington |
United States | Sanford USD Medical Center - Sioux Falls | Sioux Falls | South Dakota |
United States | Providence Sacred Heart Medical Center and Children's Hospital | Spokane | Washington |
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 | Madigan Army Medical Center | Tacoma | Washington |
United States | Mary Bridge Children's Hospital and Health Center | Tacoma | Washington |
United States | ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital | Toledo | Ohio |
United States | New York Medical College | Valhalla | New York |
United States | Alfred I duPont Hospital for Children | Wilmington | Delaware |
United States | Wake Forest University Health Sciences | Winston-Salem | North Carolina |
Lead Sponsor | Collaborator |
---|---|
National Cancer Institute (NCI) |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Occurrence of dose-limiting toxicity (DLT) (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 (COG) leadership and National Cancer Institute Cancer Therapy Evaluation Program (NCI CTEP) regarding possible modifications of the regimen and subsequent protocol amendment. | Baseline up to 6 weeks | |
Primary | 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. | 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 | |
Primary | Event-free survival (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. | 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 | |
Primary | Overall survival (OS) | From randomization until death or last contact, whichever occurs first, assessed up to 5 years after completion of study treatment |
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