A Study of Bevacizumab in Combination With Chemotherapy for Treatment of Osteosarcoma

Study Overview
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Brief Summary
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This study adopts a novel strategy for first-line treatment of osteosarcoma by combining chemotherapy with anti-angiogenic therapy using bevacizumab (Avastin®), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Chemotherapy for localized disease comprises a 3-drug regimen (cisplatin, doxorubicin, and high-dose methotrexate). Chemotherapy for metastatic or unresectable disease comprises a cisplatin-based regimen that includes high-dose methotrexate, doxorubicin, ifosfamide, and etoposide.

Detailed Description
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This is a comprehensive study that uses a novel agent that targets angiogenesis (bevacizumab) in combination with conventional chemotherapy for the treatment of osteosarcoma. Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), has been shown to stop the growth of new blood vessels of tumors, both in the laboratory and in patients with other types of cancers. Bevacizumab has improved the effect of chemotherapy in adult patients with different types of cancer by increasing tumor response and increasing the chances of survival. This study has two main goals: To find out if bevacizumab can be combined safely with chemotherapy for osteosarcoma To find out if adding bevacizumab to chemotherapy will be beneficial in treating osteosarcoma. The chemotherapy drugs used in this study are commonly used to treat osteosarcoma. Patients with non-metastatic and resectable tumors receive bevacizumab and chemotherapy comprised of cisplatin, doxorubicin and high-dose methotrexate. Patients with metastatic tumors or tumors that cannot be removed by surgery receive bevacizumab and chemotherapy comprised of cisplatin, doxorubicin and high-dose methotrexate, ifosfamide and etoposide. If the tumor can be removed by surgery, surgery will be performed after 10 weeks of chemotherapy and will be followed by additional chemotherapy. After completion of active therapy, patient's response to therapy will be followed for approximately 5 years.

Official Title
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A Study of Bevacizumab, a Humanized Monoclonal Antibody Against Vascular Endothelial Growth Factor (VEGF), in Combination With Chemotherapy for Treatment of Osteosarcoma

Conditions
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Osteosarcoma, Malignant Fibrous Histiocytoma (MFH) of Bone

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Cisplatin
* Drug: Doxorubicin
* Drug: Methotrexate
* Drug: Ifosfamide
* Drug: etoposide
* Procedure: Surgery
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have newly diagnosed high-grade, biopsy proven, osteosarcoma or malignant fibrous histiocytoma (MFH) of bone with no history of prior chemotherapy or radiation; Participant is able to perform tasks and daily activities as defined in the study guidelines Patient meets established guidelines for adequate function of the kidney, liver, heart and bone marrow Participants meets other requirements defined in the eligibility portion of the study Exclusion Criteria: recent major surgical procedure or injury Known bleeding diathesis, platelet disorder or coagulopathy Thrombosis Cardiac disease or hypertension Significant proteinuria Central nervous system disease Gastrointestinal perforation/abdominal fistula Osteosarcoma or MFH of bone as second malignancy

Ages Eligible for Study
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Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Localized Resectable Disease (Stratum A)<br>Participants with localized resectable disease receive Cycle 1 of bevacizumab 3 days before chemotherapy with cisplatin and doxorubicin. Subsequent cycles consist of bevacizumab on the first day of chemotherapy, then cisplatin, and doxorubicin, or methotrexate. If applicable, definitive surgery and assessment of histologic response will occur at week 10 followed by bevacizumab on the first day of chemotherapy with cisplatin and doxorubicin, or methotrexate. | Biological: Bevacizumab<br>* Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).<br>* Other names: Avastin®;Drug: Cisplatin<br>* Given IV.<br>* Other names: Platinol-AQ®;Drug: Doxorubicin<br>* Given IV.<br>* Other names: Adriamycin®;Drug: Methotrexate<br>* Given IV.<br>* Other names: MTX;Procedure: Surgery<br>* Participants undergo definitive surgery and assessment of histologic response at week 10.<br>|
| Experimental: Metastatic Disease (Stratum B)<br>Participants with metastatic disease (Stratum B) receive Cycle 1 of bevacizumab 3 days before chemotherapy with cisplatin and doxorubicin. Subsequent cycles consist of bevacizumab on the first day of chemotherapy, then cisplatin and doxorubicin, methotrexate or ifosfamide, and etoposide. If applicable, definitive surgery and assessment of histologic response will occur at week 10 followed by bevacizumab on the first day of chemotherapy with cisplatin and doxorubicin, methotrexate, or ifosfamide, and etoposide. Radiotherapy will be given post-operatively. | Biological: Bevacizumab<br>* Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).<br>* Other names: Avastin®;Drug: Cisplatin<br>* Given IV.<br>* Other names: Platinol-AQ®;Drug: Doxorubicin<br>* Given IV.<br>* Other names: Adriamycin®;Drug: Methotrexate<br>* Given IV.<br>* Other names: MTX;Drug: Ifosfamide<br>* Given IV.<br>* Other names: Ifex®;Drug: etoposide<br>* Given IV.<br>* Other names: Vepesid®;Procedure: Surgery<br>* Participants undergo definitive surgery and assessment of histologic response at week 10.<br>Radiation: Radiotherapy<br>* Radiation therapy delivered for positive margins or intralesional resections.<br>|
| Experimental: Unresectable Disease (Stratum C)<br>Participants with unresectable disease (Stratum C) receive treatment identical to Stratum B: Cycle 1 of bevacizumab 3 days before chemotherapy with cisplatin and doxorubicin. Subsequent cycles consist of bevacizumab on the first day of chemotherapy, then cisplatin and doxorubicin, methotrexate or ifosfamide, and etoposide. If applicable, definitive surgery and assessment of histologic response will occur at week 10 followed by bevacizumab on the first day of chemotherapy with cisplatin and doxorubicin, methotrexate, or ifosfamide, and etoposide. Radiotherapy will be given post-operatively. | Biological: Bevacizumab<br>* Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).<br>* Other names: Avastin®;Drug: Cisplatin<br>* Given IV.<br>* Other names: Platinol-AQ®;Drug: Doxorubicin<br>* Given IV.<br>* Other names: Adriamycin®;Drug: Methotrexate<br>* Given IV.<br>* Other names: MTX;Drug: Ifosfamide<br>* Given IV.<br>* Other names: Ifex®;Drug: etoposide<br>* Given IV.<br>* Other names: Vepesid®;Procedure: Surgery<br>* Participants undergo definitive surgery and assessment of histologic response at week 10.<br>Radiation: Radiotherapy<br>* Radiation therapy delivered for positive margins or intralesional resections.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Unacceptable Toxicity | Objective: To study the feasibility of combining: 1) bevacizumab with cisplatin, doxorubicin, and high-dose methotrexate (MAP) in patients with localized resectable osteosarcoma; and 2) bevacizumab with MAP and ifosfamide, and etoposide in patients with unresectable or metastatic osteosarcoma. The target unacceptable toxicity is defined as grade 4 hypertension, proteinuria, or bleeding excluding petechiae/purpura, grade 3/4 thrombosis/embolism excluding catheter-related thrombosis. The unacceptable toxicity for major wound complication is defined as grade 2, 3, or 4 major wound complications. A six-stage group sequential stopping rule was developed for monitoring unacceptable toxicity. | After all patients have completed therapy, up to 1 year after last patient is enrolled | 
| 3-Year Event Free Survival | To study the effect of adding bevacizumab to chemotherapy comprised of cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) on the event-free survival (EFS) in patients with localized resectable osteosarcoma. The Kaplan-Meier (K-M) method was used to estimate survival rate. | After all patients have completed therapy, up to 4 years after last patient is enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histologic Response by Stratum | The effect of adding bevacizumab to preoperative chemotherapy comprised of cisplatin, doxorubicin, and HDMTX on the histologic response in patients with localized resectable osteosarcoma compared to historical controls treated with preoperative cisplatin, doxorubicin, and HDMTX without bevacizumab on the Intergroup Study 0133. Histologic response at week 10 of therapy was evaluated by Huvos grading systems as grade I: tumor not responding to therapy, no effect identified; grade IIA: more than 50% viable tumor left; grade IIB: 5-50% viable tumor remaining; grade III: only scattered foci of viable tumor seen (less than 5% of tumor); grade IV: no viable tumor seen in extensive sampling (at least a full cross-section of the tumor). The study did not enroll an adequate number of participants, therefore, the comparison to Intergroup Study 0133 participants was not done. | After 6 cycles of chemotherapy, up to 1 year after the start of therapy | 
| 2-Year Event Free Survival (EFS) of Patients With Osteosarcoma | Kaplan-Meier method was used to estimate the EFS of patients with osteosarcoma treated with chemotherapy and Bevacizumab. | After all patients have completed therapy, up to 2 years after last patient is enrolled | 
| 2-Year Overall Survival (OS) of Patients With Osteosarcoma | Kaplan-Meier method was used to estimate the OS of patients with osteosarcoma treated with chemotherapy and Bevacizumab. | After all patients have completed therapy, up to 2 years after last patient is enrolled | 
| 2-Year Event Free Survival (EFS) in Patients With Localized Resectable Disease Compared to St. Jude OS99 Protocol. | The current protocol OS2008 (NCT00667342) was closed early due to slow accrual. Thus, with the limited number of patients, the comparison of EFS of OS20008 to that of OS99 (NCT00145639) participants was not done. The 2-year EFS of OS2008 participants is reported here. | After all patients have completed therapy, up to 2 years after last patient is enrolled | 
| 2-Year Overall Survival (OS) in Patients With Localized Resectable Disease Compared to OS99 Protocol. | The current protocol OS2008 (NCT00667342) was closed early due to slow accrual. Thus, with the limited number of patients, the comparison of EFS of OS2008 to that of OS99 (NCT00145639) participants was not done. The 2-year OS of OS2008 participants is reported here. | After all patients have completed therapy, up to 2 years after last patient is enrolled | 
| Mean Ktrans | The volume transfer constant (Ktrans) was used to evaluate clinical outcomes. The average for the distribution across the whole region of interest (ROI) was calculated as a summary measure for each data set. | Baseline through Week 10 | 
| Mean Vp | The fractional blood plasma volume (Vp) was used to evaluate clinical outcomes. The average for the distribution across the whole region of interest (ROI) was calculated as a summary measure for each data set. | Baseline through Week 10 | 
| Mean Ve | The fractional volume of extravascular extracellular space (Ve) was used to evaluate clinical outcomes. The average for the distribution across the whole region of interest (ROI) was calculated as a summary measure for each data set. | Baseline through Week 10 | 
| Histologic Response by Number of Participants | The association of interested variables with response was checked with the Wilcoxon rank-sum test. The response is based on the Huvos grade of histologic response for DCE-MRI comparisons and is defined as good for ≥90% necrosis and poor for less than 90%. | at week 10 after start of therapy | 
| Ktrans by Good and Poor Response | The response is based on the Huvos grade of histologic response for DCE-MRI comparisons and is defined as good for ≥90% necrosis and poor for less than 90%. | at week 10 after start of therapy | 
| P95 of Ktrans by Good and Poor Response | The response is based on the Huvos grade of histologic response for DCE-MRI comparisons and is defined as good for ≥90% necrosis and poor for less than 90%. P95 denotes the level of each kinetic parameter exceeding 95% of its values in each tumor. | at week 10 after start of therapy | 
| Difference Between Good and Poor Response by SUVmax | The response is based on the Huvos grade of histologic response for DCE-MRI comparisons and is defined as good for ≥90% necrosis and poor for less than 90%. | at week 10 after start of therapy |