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

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.

Time frame: After all patients have completed therapy, up to 4 years 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.

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

Population: 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.

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.

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

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

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

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

Population: All the 42 evaluable participants were included in this analysis.

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.

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

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

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

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

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

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%.

Time frame: at week 10 after start of therapy

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

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%.

Time frame: at week 10 after start of therapy

Population: Two Stratum A participants with no histologic response were excluded.

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.

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

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

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%.

Time frame: at week 10 after start of therapy

Population: Two Stratum A participants with no histologic response were excluded.

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.

Time frame: Baseline through Week 10

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

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.

Time frame: Baseline through Week 10

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

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.

Time frame: Baseline through Week 10

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

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.

Time frame: at week 10 after start of therapy

Population: Two Stratum A participants with no histologic response were excluded.

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.

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

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

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.

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

Population: 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.

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.

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

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

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.

Time frame: Up to 6 months postoperatively