Clinical Trial: A Study of Bevacizumab in Combination With Chemotherapy for Treatment of Osteosarcoma

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

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

Brief Summary: 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 Summary:

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.

Sponsor: St. Jude Children's Research Hospital

Current Primary Outcome:

• Number of Participants With Unacceptable Toxicity [ Time Frame: After all patients have completed therapy, up to 1 year after last patient is enrolled ]

  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.

• 3-Year Event Free Survival [ Time Frame: After all patients have completed therapy, up to 4 years after last patient is enrolled ]
  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.

Original Primary Outcome:

• Feasibility [ Time Frame: 5 years ]
• Event Free Survival [ Time Frame: 7 years ]

Current Secondary Outcome:

• Histologic Response by Stratum [ Time Frame: After 6 cycles of chemotherapy, up to 1 year after the start of therapy ]

  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.

• 2-Year Event Free Survival (EFS) of Patients With Osteosarcoma [ Time Frame: After all patients have completed therapy, up to 2 years after last patient is enrolled ]
  Kaplan-Meier method was used to estimate the EFS of patients with osteosarcoma treated with chemotherapy and Bevacizumab.
• 2-Year Overall Survival (OS) of Patients With Osteosarcoma [ Time Frame: After all patients have completed therapy, up to 2 years after last patient is enrolled ]
  Kaplan-Meier method was used to estimate the OS of patients with osteosarcoma treated with chemotherapy and Bevacizumab.
• 2-Year Event Free Survival (EFS) in Patients With Localized Resectable Disease Compared to St. Jude OS99 Protocol. [ Time Frame: After all patients have completed therapy, up to 2 years after last patient is enrolled ]
  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.
• 2-Year Overall Survival (OS) in Patients With Localized Resectable Disease Compared to OS99 Protocol. [ Time Frame: After all patients have completed therapy, up to 2 years after last patient is enrolled ]
  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.
• Mean Ktrans [ Time Frame: Baseline through Week 10 ]
  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.
• Mean Vp [ Time Frame: Baseline through Week 10 ]
  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.
• Mean Ve [ Time Frame: Baseline through Week 10 ]
  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.
• Histologic Response by Number of Participants [ Time Frame: at week 10 after start of therapy ]
  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%.
• Ktrans by Good and Poor Response [ Time Frame: at week 10 after start of therapy ]
  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 of Ktrans by Good and Poor Response [ Time Frame: at week 10 after start of therapy ]
  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.
• Difference Between Good and Poor Response by SUVmax [ Time Frame: at week 10 after start of therapy ]
  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%.

Original Secondary Outcome:

Information By: St. Jude Children's Research Hospital

Dates:
Date Received: April 24, 2008
Date Started: June 2008
Date Completion: April 2018
Last Updated: April 17, 2017
Last Verified: April 2017