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

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

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.

Study Overview

• Status: Completed
• Conditions: Osteosarcoma; Malignant Fibrous Histiocytoma (MFH) of Bone
• Intervention / Treatment: Drug: Methotrexate; Drug: Doxorubicin; Drug: etoposide; Biological: Bevacizumab; Drug: Cisplatin; Procedure: Surgery; Drug: Ifosfamide; Radiation: Radiotherapy

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital and Health Center
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins - Sidney Kimmel Comprehensive Cancer Center
    • Bethesda, Maryland, United States, 20892
      • NCI/NIH - Pediatric Oncology Branch
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St Jude Children's Research Hospital
  • Texas
    • Houston, Texas, United States, 77030-4009
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 30 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Localized Resectable Disease (Stratum A); 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.	Drug: Methotrexate; Given IV.; Other Names: MTX; Drug: Doxorubicin; Given IV.; Other Names: Adriamycin®; Biological: Bevacizumab; Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).; Other Names: rhuMAb VEGF; Avastin®; Drug: Cisplatin; Given IV.; Other Names: Platinol-AQ®; Procedure: Surgery; Participants undergo definitive surgery and assessment of histologic response at week 10.
Experimental: Metastatic Disease (Stratum B); 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.	Drug: Methotrexate; Given IV.; Other Names: MTX; Drug: Doxorubicin; Given IV.; Other Names: Adriamycin®; Drug: etoposide; Given IV.; Other Names: VP-16; Vepesid®; Biological: Bevacizumab; Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).; Other Names: rhuMAb VEGF; Avastin®; Drug: Cisplatin; Given IV.; Other Names: Platinol-AQ®; Procedure: Surgery; Participants undergo definitive surgery and assessment of histologic response at week 10.; Drug: Ifosfamide; Given IV.; Other Names: Ifex®; Radiation: Radiotherapy; Radiation therapy delivered for positive margins or intralesional resections.
Experimental: Unresectable Disease (Stratum C); 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.	Drug: Methotrexate; Given IV.; Other Names: MTX; Drug: Doxorubicin; Given IV.; Other Names: Adriamycin®; Drug: etoposide; Given IV.; Other Names: VP-16; Vepesid®; Biological: Bevacizumab; Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).; Other Names: rhuMAb VEGF; Avastin®; Drug: Cisplatin; Given IV.; Other Names: Platinol-AQ®; Procedure: Surgery; Participants undergo definitive surgery and assessment of histologic response at week 10.; Drug: Ifosfamide; Given IV.; Other Names: Ifex®; Radiation: Radiotherapy; Radiation therapy delivered for positive margins or intralesional resections.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Collaborators: Genentech, Inc.
• Investigators: Principal Investigator: Michael Bishop, MD, St. Jude Children's Research Hospital

Publications and helpful links

General Publications

• Turner DC, Navid F, Daw NC, Mao S, Wu J, Santana VM, Neel M, Rao B, Willert JR, Loeb DM, Harstead KE, Throm SL, Freeman BB 3rd, Stewart CF. Population pharmacokinetics of bevacizumab in children with osteosarcoma: implications for dosing. Clin Cancer Res. 2014 May 15;20(10):2783-92. doi: 10.1158/1078-0432.CCR-13-2364. Epub 2014 Mar 17.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2008
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: April 24, 2008
• First Submitted That Met QC Criteria: April 25, 2008
• First Posted (Estimated): April 28, 2008

Study Record Updates

• Last Update Posted (Actual): August 7, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Neoplasms, Fibrous Tissue; Osteosarcoma; Histiocytoma, Malignant Fibrous; Histiocytoma; Histiocytoma, Benign Fibrous; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Etoposide; Ifosfamide; Bevacizumab; Doxorubicin; Methotrexate
• Other Study ID Numbers: OS2008; GENENTECH PHARM (Other Identifier: Genentech Pharmaceuticals); NCI-2009-00846 (Registry Identifier: NCI Clinical Trial Registration Program)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No