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OsteosarcomaPhase 2NCT00667342

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

A Phase 2 study testing Bevacizumab, Cisplatin and Doxorubicin in people with Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone, run by St. Jude Children's Research Hospital at 5 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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). Read more about this study

Who is it for?
Ages Up to 30 years
What is being tested?
Bevacizumab, Cisplatin and Doxorubicin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
43 participants
Where
5 sitesUnited States
Study dates
3 Jun 2008to Aug 2017
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 30 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

United States5 sites

  • Johns Hopkins - Sidney Kimmel Comprehensive Cancer Center

    Baltimore, Maryland, 21231

  • NCI/NIH - Pediatric Oncology Branch

    Bethesda, Maryland, 20892

  • MD Anderson Cancer Center

    Houston, Texas, 77030-4009

  • St Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • Rady Children's Hospital and Health Center

    San Diego, California, 92123

Other trials in United States

About this study

Official title: 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.

Read the 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.

Medical subject headings
Osteosarcoma, Histiocytoma, Malignant Fibrous

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BevacizumabBiological

    Also called rhuMAb VEGF, Avastin®

    Monoclonal Antibody against vascular endothelial growth factor (VEGF). Given intravenously (IV).

  • CisplatinDrug

    Also called Platinol-AQ®

    Given IV.

  • DoxorubicinDrug

    Also called Adriamycin®

    Given IV.

  • MethotrexateDrug

    Also called MTX

    Given IV.

  • IfosfamideDrug

    Also called Ifex®

    Given IV.

  • etoposideDrug

    Also called VP-16, Vepesid®

    Given IV.

  • SurgeryProcedure or surgery

    Participants undergo definitive surgery and assessment of histologic response at week 10.

  • RadiotherapyRadiation

    Radiation therapy delivered for positive margins or intralesional resections.

Study groups in NCT00667342
Study groupRoleWhat they receive
Localized Resectable Disease (Stratum A)ExperimentalParticipants 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.
Receives: Biological: Bevacizumab; Drug: Cisplatin; Drug: Doxorubicin; Drug: Methotrexate; Procedure: Surgery
Metastatic Disease (Stratum B)ExperimentalParticipants 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.
Receives: Biological: Bevacizumab; Drug: Cisplatin; Drug: Doxorubicin; Drug: Methotrexate; Drug: Ifosfamide; Drug: etoposide; Procedure: Surgery; Radiation: Radiotherapy
Unresectable Disease (Stratum C)ExperimentalParticipants 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.
Receives: Biological: Bevacizumab; Drug: Cisplatin; Drug: Doxorubicin; Drug: Methotrexate; Drug: Ifosfamide; Drug: etoposide; Procedure: Surgery; Radiation: Radiotherapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: After all patients have completed therapy, up to 1 year after last patient is enrolled

  2. 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.

    Measured: After all patients have completed therapy, up to 4 years after last patient is enrolled

Secondary outcomes (12)

  1. 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.

    Measured: After 6 cycles of chemotherapy, up to 1 year after the start of therapy

  2. 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.

    Measured: After all patients have completed therapy, up to 2 years after last patient is enrolled

  3. 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.

    Measured: After all patients have completed therapy, up to 2 years after last patient is enrolled

  4. 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.

    Measured: After all patients have completed therapy, up to 2 years after last patient is enrolled

  5. 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.

    Measured: After all patients have completed therapy, up to 2 years after last patient is enrolled

  6. 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.

    Measured: Baseline through Week 10

  7. 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.

    Measured: Baseline through Week 10

  8. 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.

    Measured: Baseline through Week 10

  9. 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%.

    Measured: at week 10 after start of therapy

  10. 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%.

    Measured: at week 10 after start of therapy

  11. 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.

    Measured: at week 10 after start of therapy

  12. 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%.

    Measured: at week 10 after start of therapy

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Apr 2008 (estimated)
  2. Study start3 Jun 2008
  3. Primary completionAug 2014
  4. Study completionAug 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
43 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00667342
Sponsor's protocol ID
OS2008
Other IDs
GENENTECH PHARM, NCI-2009-00846
Status last verified
May 2019
First submitted
24 Apr 2008
Last updated
7 Aug 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

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.

    PubMed 24637635

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Bevacizumab, Cisplatin and Doxorubicin in people with Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone, run by St. Jude Children's Research Hospital at 5 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 4 Aug 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Unacceptable Toxicity (time frame: After all patients have completed therapy, up to 1 year after last patient is enrolled). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00667342, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Aug 2023; AzTrials last refreshed its copy on 7 Nov 2026.

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