A Study to Test the Addition of the Drug Cabozantinib to Chemotherapy in Patients With Newly Diagnosed Osteosarcoma
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| ClinicalTrials.gov Identifier: NCT05691478 |
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Recruitment Status :
Suspended
(Scheduled Interim Monitoring)
First Posted : January 20, 2023
Last Update Posted : May 8, 2024
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
- Study Details
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| High Grade Osteosarcoma Localized Osteosarcoma Metastatic Osteosarcoma Secondary Osteosarcoma | 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 | Phase 2 Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 1122 participants |
| Allocation: | Randomized |
| Intervention Model: | Sequential Assignment |
| Intervention Model Description: | Single-arm Feasibility Phase study followed by a randomized, parallel 4-arm Efficacy Phase study |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | March 3, 2023 |
| Estimated Primary Completion Date : | March 20, 2030 |
| Estimated Study Completion Date : | March 20, 2030 |
Resource links provided by the National Library of Medicine
Drug Information
available for:
Cabozantinib
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: 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 additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.
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Procedure: Bone Scan
Undergo bone scintography
Other Name: Bone Scintigraphy Drug: Cisplatin Given IV
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Drug: Methotrexate Given IV
Other Names:
Procedure: Surgical Procedure Undergo surgery
Other Names:
Procedure: X-Ray Imaging Undergo X-ray
Other Names:
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Experimental: 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 "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.
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Procedure: Bone Scan
Undergo bone scintography
Other Name: Bone Scintigraphy Drug: Cabozantinib S-malate Given PO
Other Names:
Drug: Cisplatin Given IV
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Drug: Methotrexate Given IV
Other Names:
Procedure: Surgical Procedure Undergo surgery
Other Names:
Procedure: X-Ray Imaging Undergo X-ray
Other Names:
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Active Comparator: 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 additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.
|
Procedure: Bone Scan
Undergo bone scintography
Other Name: Bone Scintigraphy Drug: Cisplatin Given IV
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Drug: Methotrexate Given IV
Other Names:
Procedure: Surgical Procedure Undergo surgery
Other Names:
Procedure: X-Ray Imaging Undergo X-ray
Other Names:
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Experimental: 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 "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles. Patients also undergo X-ray, CT, MRI, and PET or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.
|
Procedure: Bone Scan
Undergo bone scintography
Other Name: Bone Scintigraphy Drug: Cabozantinib S-malate Given PO
Other Names:
Drug: Cisplatin Given IV
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Drug: Methotrexate Given IV
Other Names:
Procedure: X-Ray Imaging Undergo X-ray
Other Names:
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Experimental: Feasibility phase (cabozantinib, MAP)
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.
|
Procedure: Bone Scan
Undergo bone scintography
Other Name: Bone Scintigraphy Drug: Cabozantinib S-malate Given PO
Other Names:
Drug: Cisplatin Given IV
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Drug: Methotrexate Given IV
Other Names:
Procedure: Surgical Procedure Undergo surgery
Other Names:
Procedure: X-Ray Imaging Undergo X-ray
Other Names:
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Primary Outcome Measures :
- Occurrence of dose-limiting toxicity (DLT) (Feasibility) [ Time Frame: Baseline up to 6 weeks ]Only patients with high risk osteosarcoma who have a primary tumor considered resectable at the time of enrollment will be enrolled to this part of the trial. If a feasible dose cannot be established, the study committee will consult with Children's Oncology Group (COG) leadership and National Cancer Institute Cancer Therapy Evaluation Program (NCI CTEP) regarding possible modifications of the regimen and subsequent protocol amendment.
- Event-free survival (EFS) (Phase II) [ Time Frame: From randomization until disease progression, relapse, diagnosis of a second malignant neoplasm, death or last contact, whichever occurs first, assessed up to 5 years after completion of study treatment ]The randomization and analysis will be stratified according to risk group. An assessment of the reduction in risk for EFS-event at the designated landmark time will be used to determine whether the trial continues to part 3. If the study proceeds to part 3, patients enrolled to part 2 of the trial will contribute to the primary analyses for part 3 of the study. If the interim criterion for continuation is not obtained, accrual will be closed with the conclusion that cabozantinib does not reduce sufficiently the risk for EFS-event for patients with newly-diagnosed osteosarcoma.
- Event-free survival (EFS) (Phase III) [ Time Frame: From randomization until disease progression, relapse, diagnosis of a second malignant neoplasm, death or last contact, whichever occurs first, assessed up to 5 years after completion of study treatment ]Will consist of two randomized phase 3 sub-studies ('Phase 3'). One will be conducted in standard risk patients and one will be conducted in high risk patients.
- Overall survival (OS) [ Time Frame: From randomization until death or last contact, whichever occurs first, assessed up to 5 years after completion of study treatment ]
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| Ages Eligible for Study: | up to 40 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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.
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Bone metastases: Areas suspicious for bone metastasis based on fludeoxyglucose F-18 (18F-FDG)-positron emission tomography (PET) scan (or whole body technetium-99 bone scan if 18F-FDG-PET is unavailable at the treating institution) require confirmatory biopsy or supportive anatomic imaging of at least one suspicious site with either magnetic resonance imaging (MRI) or computed tomography (CT) (whole body 18F-FDG-PET/CT or 18F-FDG-PET/MR scans are acceptable).
- Efficacy Phases (Phase 2/3)
Patients with both localized and metastatic disease are eligible for the efficacy phase, regardless of resectability. Patients will be enrolled to two separate cohorts:
- Cohort 1 (Standard Risk): Patients with non-pelvic primary osteosarcoma deemed to be resectable at the time of diagnosis by the institutional multidisciplinary team, without evidence of metastatic lesions.
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Cohort 2 (High-Risk): Patients with a primary pelvic tumor, a primary tumor designated as unresectable by the institutional multidisciplinary team, AND/OR radiographic evidence of metastatic lesions.
- A serum creatinine based on age/gender as follows (within 7 days prior to enrollment unless otherwise indicated):
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(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
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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).
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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)
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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
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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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05691478
Locations
Show 92 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Michael W Bishop | Children's Oncology Group |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT05691478 |
| Obsolete Identifiers: | NCT05683197 |
| Other Study ID Numbers: |
NCI-2022-08567 NCI-2022-08567 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) AOST2032 ( Other Identifier: Children's Oncology Group ) AOST2032 ( Other Identifier: CTEP ) U10CA180886 ( U.S. NIH Grant/Contract ) |
| First Posted: | January 20, 2023 Key Record Dates |
| Last Update Posted: | May 8, 2024 |
| Last Verified: | May 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | 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. |
| URL: | https://grants.nih.gov/policy/sharing.htm |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | No |
Additional relevant MeSH terms:
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Osteosarcoma Neoplasms, Bone Tissue Neoplasms, Connective Tissue Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Neoplasms Sarcoma Cisplatin Doxorubicin Liposomal doxorubicin Methotrexate Antineoplastic Agents Antibiotics, Antineoplastic Topoisomerase II Inhibitors Topoisomerase Inhibitors |
Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents Physiological Effects of Drugs Antimetabolites, Antineoplastic Antimetabolites Dermatologic Agents Folic Acid Antagonists Immunosuppressive Agents Immunologic Factors Antirheumatic Agents Nucleic Acid Synthesis Inhibitors |