Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Osteosarcoma

Histiocytoma, Malignant Fibrous

Histiocytoma

Histiocytoma, Benign Fibrous

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Sarcoma

Neoplasms, Fibrous Tissue

Undifferentiated Pleomorphic Sarcoma

Soft Tissue Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Anti-Infective Agents

Micronutrients

Hematinics

Vitamins

Bevacizumab

Antibodies

Antibodies, Monoclonal

Etoposide

Doxorubicin

Liposomal doxorubicin

Methotrexate

Cisplatin

Ifosfamide

Etoposide phosphate

Immunoglobulins

Endothelial Growth Factors

Mitogens

Isophosphamide mustard

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Antimetabolites

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Folinic Acid

Folate

Vitamin B9

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.

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.

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.

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

etoposide

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

Surgery

Radiation therapy delivered for positive margins or intralesional resections.

Radiotherapy

Michael Bishop, MD

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.

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.

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

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.

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.

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.

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.

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.

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.

Kaplan-Meier method was used to estimate the EFS of patients with osteosarcoma treated with chemotherapy and Bevacizumab.

Kaplan-Meier method was used to estimate the OS of patients with osteosarcoma treated with chemotherapy and Bevacizumab.

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.

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.

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.

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.

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.

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%.

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%.

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.

Genentech, Inc.

St. Jude Children's Research Hospital

Stratum A participants had primary tumors potentially resectable by aggressive surgery, such as limb-salvage surgery or amputation, and no evidence of metastasis.

A: Localized Resectable Disease

Stratum C participants had metastatic tumors.

C: Metastatic Tumors

Participants with localized unresectable primary tumors were to participate in Stratum B. No participants were enrolled to this stratum.

B: Localized Unresectable Disease

Total

Age, Continuous

Sex: Female, Male

Participants were eligible if they were ≤30 years of age on date of diagnostic biopsy confirmation of high-grade osteosarcoma or malignant fibrous histiocytoma (MFH) of bone. Participants had no previous chemotherapy or radiation therapy.

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.

Grade 4 Hypertension

Grade 4 Proteinuria

Grade 4 Bleeding

Grade 3/4 Thrombosis/Embolism

Grade 2, 3 or 4 Major Wound Complication

Due to slow accrual, the trial was closed to accrual early. Thus, only 31 stratum A patients and 12 stratum B or C patients were enrolled on the study. Therefore, based on the number of patients enrolled and the designed power for the study, we do not have confidence in making a conclusion regarding this feasibility objective.

Number of Participants With Unacceptable Toxicity

OS2008 Stratum A participants had primary tumors potentially resectable by aggressive surgery, such as limb-salvage surgery or amputation, and no evidence of metastasis.

3-Year Event Free Survival

Grade I

Grade IIA

Grade IIB

Grade III

All Stratum A participants were evaluated. The tumor sample for analysis was not obtained for one of the 12 Stratum C participants.

Histologic Response by Stratum

All the 42 evaluable participants in this study had osteosarcoma, of which 22 had events and 20 had no event.

All Participants

All the 42 evaluable participants were included in this analysis.

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

All 42 evaluable participants were included in this analysis

All the 42 evaluable participants in this study had osteosarcoma, of which 12 died and 20 were still alive as of 05/04/2015.

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

OS2008 Localized Resectable Disease group had 31 participants: 14 had events, 17 had no events.

2-Year Event Free Survival (EFS) in Patients With Localized Resectable Disease Compared to St. Jude OS99 Protocol.

OS2008 Localized Resectable Disease group had 31 participants: 7 were expired and 24 still alive

2-Year Overall Survival (OS) in Patients With Localized Resectable Disease Compared to OS99 Protocol.

Baseline

Day -2

Day 1

Day 5

Week 5

Week 10

The number analyzed at each time point differed due to missing observations at some of the time points

Mean Ktrans

Mean Vp

Mean Ve

All 42 evaluable participants in this study had osteosarcoma. This analysis includes 29 Stratum A participants who had primary tumors potentially resectable by aggressive surgery, such as limb-salvage surgery or amputation, and no evidence of metastasis, and 11 Stratum C participants who had metastatic tumors.

Two Stratum A participants with no histologic response were excluded.

Histologic Response by Number of Participants

Poor Response

Good Response

Ktrans by Good and Poor Response

P95 of Ktrans by Good and Poor Response

Thirty-two participants with osteosarcoma were evaluated in this study. The analysis for this outcome measure included 23 Stratum A participants who had primary tumors potentially resectable by aggressive surgery, such as limb-salvage surgery or amputation, and no evidence of metastasis, and 8 Stratum C participants who had metastatic tumors.

One participant with no histologic response but with evaluable imaging was excluded.

Difference Between Good and Poor Response by SUVmax

Participants had metastatic disease at diagnosis.

Amputation Group

Participants had localized disease at diagnosis. One participant had 2 surgeries.

Limb Sparing Group

Participants enrolled on the study who met the criteria for evaluation of neuropathic pain.

Entire Study Group

Number of Participants With Neuropathic Pain (NP) Following Surgery

All participants who met the criteria, had definitive surgery (either limb sparing or/and amputation), experienced neuropathic pain (NP) and were treated for NP until resolution of NP symptoms and off NP medications.

Median Duration of Neuropathic Pain

All participants who met the criteria, had surgery, experienced neuropathic pain and were treated with NP medication.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Bevacizumab in Combination With Chemotherapy for Treatment of Osteosarcoma	NCT00667342	Osteosarcoma Malignant Fibro...	Bevacizumab Cisplatin Doxorubicin Methotrexate Ifosfamide etoposide Surgery Radiotherapy	- 30 Years	St. Jude Children's Research Hospital
A Study of Bevacizumab in Combination With Chemotherapy for Treatment of Osteosarcoma	NCT00667342	Osteosarcoma Malignant Fibro...	Bevacizumab Cisplatin Doxorubicin Methotrexate Ifosfamide etoposide Surgery Radiotherapy	- 30 Years	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for malignant fibrous histiocytoma (mfh) of bone