A Study of Bevacizumab in Combination With Chemotherapy for Treatment of Osteosarcoma
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| ClinicalTrials.gov Identifier: NCT00667342 |
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Recruitment Status :
Completed
First Posted : April 28, 2008
Results First Posted : August 4, 2014
Last Update Posted : June 28, 2019
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Sponsor:
St. Jude Children's Research Hospital
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Osteosarcoma Malignant Fibrous Histiocytoma (MFH) of Bone | Biological: Bevacizumab Drug: Cisplatin Drug: Doxorubicin Drug: Methotrexate Drug: Ifosfamide Drug: etoposide Procedure: Surgery Radiation: Radiotherapy | Phase 2 |
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 (Clinical Trial) |
| Actual Enrollment : | 43 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Study of Bevacizumab, a Humanized Monoclonal Antibody Against Vascular Endothelial Growth Factor (VEGF), in Combination With Chemotherapy for Treatment of Osteosarcoma |
| Actual Study Start Date : | June 3, 2008 |
| Actual Primary Completion Date : | August 2014 |
| Actual Study Completion Date : | August 2017 |
Resource links provided by the National Library of Medicine
Drug Information available for:
Bevacizumab
| Arm | Intervention/treatment |
|---|---|
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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.
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Biological: Bevacizumab
Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).
Other Names:
Drug: Cisplatin Given IV.
Other Name: Platinol-AQ® Drug: Doxorubicin Given IV.
Other Name: Adriamycin® Drug: Methotrexate Given IV.
Other Name: MTX Procedure: Surgery Participants undergo definitive surgery and assessment of histologic response at week 10. |
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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.
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Biological: Bevacizumab
Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).
Other Names:
Drug: Cisplatin Given IV.
Other Name: Platinol-AQ® Drug: Doxorubicin Given IV.
Other Name: Adriamycin® Drug: Methotrexate Given IV.
Other Name: MTX Drug: Ifosfamide Given IV.
Other Name: Ifex® Drug: etoposide Given IV.
Other Names:
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. |
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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.
|
Biological: Bevacizumab
Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).
Other Names:
Drug: Cisplatin Given IV.
Other Name: Platinol-AQ® Drug: Doxorubicin Given IV.
Other Name: Adriamycin® Drug: Methotrexate Given IV.
Other Name: MTX Drug: Ifosfamide Given IV.
Other Name: Ifex® Drug: etoposide Given IV.
Other Names:
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. |
Primary Outcome Measures :
- 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.
Secondary Outcome Measures :
- 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%.
Other Outcome Measures:
- Number of Participants With Neuropathic Pain (NP) Following Surgery [ Time Frame: Up to 6 months postoperatively ]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.
- Median Duration of Neuropathic Pain [ Time Frame: From surgery until resolution of NP symptoms, up to 6 months ]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.
- Mean Duration of Neuropathic Pain [ Time Frame: From surgery until resolution of NP symptoms, up to 6 months ]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.
- Median Duration of Neuropathic Pain Medication [ Time Frame: From surgery until resolution of NP symptoms, up to 6 months ]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.
- Mean Duration of Neuropathic Pain Medication [ Time Frame: From surgery until resolution of NP symptoms, up to 6 months ]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.
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| Ages Eligible for Study: | up to 30 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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
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): NCT00667342
Locations
| United States, California | |
| Rady Children's Hospital and Health Center | |
| San Diego, California, United States, 92123 | |
| United States, Maryland | |
| Johns Hopkins - Sidney Kimmel Comprehensive Cancer Center | |
| Baltimore, Maryland, United States, 21231 | |
| NCI/NIH - Pediatric Oncology Branch | |
| Bethesda, Maryland, United States, 20892 | |
| United States, Tennessee | |
| St Jude Children's Research Hospital | |
| Memphis, Tennessee, United States, 38105 | |
| United States, Texas | |
| MD Anderson Cancer Center | |
| Houston, Texas, United States, 77030-4009 | |
Sponsors and Collaborators
St. Jude Children's Research Hospital
Genentech, Inc.
Investigators
| Principal Investigator: | Michael Bishop, MD | St. Jude Children's Research Hospital |
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | St. Jude Children's Research Hospital |
| ClinicalTrials.gov Identifier: | NCT00667342 |
| Other Study ID Numbers: |
OS2008 GENENTECH PHARM ( Other Identifier: Genentech Pharmaceuticals ) NCI-2009-00846 ( Registry Identifier: NCI Clinical Trial Registration Program ) |
| First Posted: | April 28, 2008 Key Record Dates |
| Results First Posted: | August 4, 2014 |
| Last Update Posted: | June 28, 2019 |
| Last Verified: | May 2019 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Osteosarcoma Histiocytoma Histiocytoma, Benign Fibrous Histiocytoma, Malignant Fibrous Neoplasms, Bone Tissue Neoplasms, Connective Tissue Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Neoplasms Sarcoma Neoplasms, Fibrous Tissue Bevacizumab Doxorubicin Methotrexate Etoposide |
Ifosfamide Antineoplastic Agents, Immunological Antineoplastic Agents Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors Antibiotics, Antineoplastic Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Abortifacient Agents, Nonsteroidal Abortifacient Agents |