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

NCT00667342 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: OS2008GENENTECH PHARMNCI-2009-00846
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 5

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.

Conditions

Osteosarcoma; Malignant Fibrous Histiocytoma (MFH) of Bone

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (12)

• Histologic Response by Stratum

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

• 2-Year Event Free Survival (EFS) of Patients With Osteosarcoma

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

• 2-Year Overall Survival (OS) of Patients With Osteosarcoma

  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.

  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.

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

Other Outcomes (5)

• Number of Participants With Neuropathic Pain (NP) Following Surgery

  Up to 6 months postoperatively

• Median Duration of Neuropathic Pain

  From surgery until resolution of NP symptoms, up to 6 months

• Mean Duration of Neuropathic Pain

  From surgery until resolution of NP symptoms, up to 6 months

Study Arms (3)

Localized Resectable Disease (Stratum A)

EXPERIMENTAL

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.

Biological: Bevacizumab; Drug: Cisplatin; Drug: Doxorubicin; Drug: Methotrexate; Procedure: Surgery

Metastatic Disease (Stratum B)

EXPERIMENTAL

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.

Biological: Bevacizumab; Drug: Cisplatin; Drug: Doxorubicin; Drug: Methotrexate; Drug: Ifosfamide; Drug: etoposide; Procedure: Surgery; Radiation: Radiotherapy

Unresectable Disease (Stratum C)

EXPERIMENTAL

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; Drug: Cisplatin; Drug: Doxorubicin; Drug: Methotrexate; Drug: Ifosfamide; Drug: etoposide; Procedure: Surgery; Radiation: Radiotherapy

Interventions

Bevacizumab BIOLOGICAL

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

Also known as: rhuMAb VEGF, Avastin®

Localized Resectable Disease (Stratum A); Metastatic Disease (Stratum B); Unresectable Disease (Stratum C)

Cisplatin DRUG

Given IV.

Also known as: Platinol-AQ®

Localized Resectable Disease (Stratum A); Metastatic Disease (Stratum B); Unresectable Disease (Stratum C)

Doxorubicin DRUG

Given IV.

Also known as: Adriamycin®

Localized Resectable Disease (Stratum A); Metastatic Disease (Stratum B); Unresectable Disease (Stratum C)

Methotrexate DRUG

Given IV.

Also known as: MTX

Localized Resectable Disease (Stratum A); Metastatic Disease (Stratum B); Unresectable Disease (Stratum C)

Ifosfamide DRUG

Given IV.

Also known as: Ifex®

Metastatic Disease (Stratum B); Unresectable Disease (Stratum C)

etoposide DRUG

Given IV.

Also known as: VP-16, Vepesid®

Metastatic Disease (Stratum B); Unresectable Disease (Stratum C)

Surgery PROCEDURE

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

Localized Resectable Disease (Stratum A); Metastatic Disease (Stratum B); Unresectable Disease (Stratum C)

Radiotherapy RADIATION

Radiation therapy delivered for positive margins or intralesional resections.

Metastatic Disease (Stratum B); Unresectable Disease (Stratum C)

Eligibility Criteria

• Age: Up to 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Genentech, Inc.: collaborator

Study Sites (5)

Rady Children's Hospital and Health Center

San Diego, California, 92123, United States

Location

Johns Hopkins - Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21231, United States

Location

NCI/NIH - Pediatric Oncology Branch

Bethesda, Maryland, 20892, United States

Location

St Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

Related Publications (1)

• 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.

  PMID: 24637635 DERIVED

Related Links

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

MeSH Terms

Conditions

Osteosarcoma; Histiocytoma, Malignant Fibrous

Interventions

Bevacizumab; Cisplatin; Doxorubicin; Methotrexate; Ifosfamide; Etoposide; Surgical Procedures, Operative; Radiotherapy

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Histiocytoma; Neoplasms, Fibrous Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cyclophosphamide; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Oxazines; Heterocyclic Compounds, 1-Ring; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Therapeutics

Limitations and Caveats

Accrual to this study was stopped early after 4.5 years due to slow accrual of participants. No eligible participants were enrolled on Stratum B. All enrolled participants continue on study and results will be reported when available.

Results Point of Contact

• Title: Michael Bishop, MD
• Organization: St. Jude Children's Research Hospital

referralinfo@stjude.org

866-278-5833

Study Officials

• Michael Bishop, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 24, 2008
• First Posted: April 28, 2008
• Study Start: June 3, 2008
• Primary Completion: August 1, 2014
• Study Completion: August 1, 2017
• Last Updated: August 7, 2023
• Results First Posted: August 4, 2014

Record last verified: 2019-05

Locations

US (5)