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

Osteosarcoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00667342
• Other study ID #: OS2008
• Secondary ID: GENENTECH PHARMN
• Status: Completed
• Phase: Phase 2
• Start date: June 3, 2008
• Est. completion date: August 2017

Study information

• Verified date: May 2019
• Source: St. Jude Children's Research Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: August 2017
• Est. primary completion date: August 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 30 Years

Eligibility

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

Related Conditions & MeSH terms

• Histiocytoma
• Histiocytoma, Malignant Fibrous
• Malignant Fibrous Histiocytoma (MFH) of Bone
• Osteosarcoma

Intervention

Biological:
• Bevacizumab
Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).

Drug:
• Cisplatin
Given IV.
• Doxorubicin
Given IV.
• Methotrexate
Given IV.
• Ifosfamide
Given IV.
• etoposide
Given IV.

Procedure:
• Surgery
Participants undergo definitive surgery and assessment of histologic response at week 10.

Radiation:
• Radiotherapy
Radiation therapy delivered for positive margins or intralesional resections.

Locations

Country	Name	City	State
United States	Johns Hopkins - Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	NCI/NIH - Pediatric Oncology Branch	Bethesda	Maryland
United States	MD Anderson Cancer Center	Houston	Texas
United States	St Jude Children's Research Hospital	Memphis	Tennessee
United States	Rady Children's Hospital and Health Center	San Diego	California

Sponsors (2)

Lead Sponsor	Collaborator
St. Jude Children's Research Hospital	Genentech, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Neuropathic Pain (NP) Following Surgery	Of the 43 participants enrolled on this trial, 37 met criteria for evaluation of neuropathic pain (NP) following definitive surgery. The 37 participants underwent 38 surgeries: one participant had a limb-sparing surgery followed by an amputation surgery. Six of 43 participants were excluded from evaluation for NP: 1 due to deep vein thrombosis, 2 removed from study prior to surgery, 1 removed immediately after surgery to receive radiation therapy, 1 had non-extremity osteosarcoma, and 1 patient had a fibula resection. Patients were followed for neuropathic pain daily for the first week postoperatively and weekly for up to 6 months postoperatively.	Up to 6 months postoperatively
Other	Median Duration of Neuropathic Pain	Thirty participants who underwent surgery (31 surgeries) were determined to have neuropathic pain. Four participants received only opioids for NP and 26 participants (for 27 surgeries) were treated with NP specific medications including gabapentin, tricyclic antidepressant, methadone. One participant had 2 different surgical procedures and was analyzed both in the limb sparing group and in the amputation group.	From surgery until resolution of NP symptoms, up to 6 months
Other	Mean Duration of Neuropathic Pain	Thirty participants who underwent surgery (31 surgeries) were determined to have neuropathic pain (NP). Four participants received only opioids for NP and 26 participants (for 27 surgeries) were treated with NP specific medications including gabapentin, tricyclic antidepressant, methadone. One participant had 2 different surgical procedures and was analyzed both in the limb sparing group and in the amputation group.	From surgery until resolution of NP symptoms, up to 6 months
Other	Median Duration of Neuropathic Pain Medication	Thirty participants who underwent surgery (31 surgeries) were determined to have neuropathic pain (NP). Four participants received only opioids for NP and 26 participants (for 27 surgeries) were treated with NP specific medications including gabapentin, tricyclic antidepressant, methadone. One participant had 2 different surgical procedures and was analyzed both in the limb sparing group and in the amputation group.	From surgery until resolution of NP symptoms, up to 6 months
Other	Mean Duration of Neuropathic Pain Medication	Thirty participants who underwent surgery (31 surgeries) were determined to have neuropathic pain. Four participants received only opioids for NP and 26 participants (for 27 surgeries) were treated with NP specific medications including gabapentin, tricyclic antidepressant, methadone. One participant had 2 different surgical procedures and was analyzed both in the limb sparing group and in the amputation group.	From surgery until resolution of NP symptoms, up to 6 months
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Clinical Trials Open at St. Jude
•   St. Jude Children's Research Hospital