Ignite Creation Date:
2025-12-24 @ 9:58 PM
Ignite Modification Date:
2026-03-06 @ 1:35 PM
Study NCT ID:
NCT00864032
Status:
COMPLETED
Last Update Posted:
2013-04-10
First Post:
2009-03-17
Is Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients With Soft Tissue Sarcoma of the Extremity and Body Wall
Sponsor:
University of California, Davis
Organization:
Study Overview
Official Title:
Phase I/II Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients With Soft Tissue Sarcoma of the Extremity and Body Wall
Status:
COMPLETED
Status Verified Date:
2013-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Patients will receive neoadjuvant sorafenib (investigational agent) in combination with preoperative external beam conformal radiotherapy (50 Gy in 25 fractions) for localized, large soft tissue sarcomas of the extremity and body wall prior to resection with curative intent. Sorafenib is an FDA-approved targeted agent for patients with renal cell carcinoma and hepatocellular carcinoma. Preliminary data suggest activity for sorafenib against soft tissue sarcoma in the metastatic setting. Limited data are available regarding the safety and efficacy of sorafenib in combination with radiotherapy.
The Phase I portion of the trial will seek to establish the safety of sorafenib and radiotherapy in the neoadjuvant setting for soft tissue sarcomas of the extremity and body wall. The Phase II portion of the trial will aim to determine the pathologic near-complete/complete response rate (≥ 95% tumor necrosis) of this multimodality therapy. Molecular and dynamic contrast-enhanced MRI studies will seek to establish correlative biological and imaging markers of response and/or resistance to this therapy.
The Phase I portion of the trial will seek to establish the safety of sorafenib and radiotherapy in the neoadjuvant setting for soft tissue sarcomas of the extremity and body wall. The Phase II portion of the trial will aim to determine the pathologic near-complete/complete response rate (≥ 95% tumor necrosis) of this multimodality therapy. Molecular and dynamic contrast-enhanced MRI studies will seek to establish correlative biological and imaging markers of response and/or resistance to this therapy.
Detailed Description:
Patients will receive neoadjuvant sorafenib (investigational agent) in combination with preoperative external beam conformal radiotherapy (50 Gy in 25 fractions) for localized, large soft tissue sarcomas of the extremity and body wall prior to resection with curative intent. Sorafenib is an FDA-approved targeted agent for patients with renal cell carcinoma and hepatocellular carcinoma. Preliminary data suggest activity for sorafenib against soft tissue sarcoma in the metastatic setting. Limited data are available regarding the safety and efficacy of sorafenib in combination with radiotherapy.
The Phase I portion of the trial will seek to establish the safety of sorafenib and radiotherapy in the neoadjuvant setting for soft tissue sarcomas of the extremity and body wall. The Phase II portion of the trial will aim to determine the pathologic near-complete/complete response rate (≥ 95% tumor necrosis) of this multimodality therapy. Molecular and dynamic contrast-enhanced MRI studies will seek to establish correlative biological and imaging markers of response and/or resistance to this therapy.
Significant challenges exist in the treatment of patients with soft tissue sarcoma (STS) of the extremity and body wall. Major therapeutic goals for all patients include local disease-control, maximization of limb function, and avoidance of therapeutic morbidity. The standard approach for patients with STS has been based on radical resection with wide margins in combination with external beam radiation. Although local control rates in this setting range from 85 to 90%, patients remain at risk for substantial morbidity from this multimodality therapy. Furthermore, despite effective local therapy with surgery and radiation, approximately 50% of patients with high grade STS will die of disease within 5 years of diagnosis.
Experimental data and experience from other solid tumors suggest a significant synergistic effect when anti-angiogenic targeted therapies, such as sorafenib, are combined with radiotherapy (RT). Overproduction of angiogenic factors in the tumor vasculature leads to disordered/poorly regulated tumor perfusion which appears to normalize following delivery of anti-angiogenic agents. This, in turn, allows improved delivery of and susceptibility to cytotoxic agents, which is particularly important with RT since hypoxia is a key mechanism of resistance to this modality. Preliminary clinical data in rectal cancer and malignant brain tumors have demonstrated promising results from the combination of anti-angiogenic agents and RT with respect to downstaging of the primary tumor, local tumor control, and improved progression-free survival. Angiogenic factors are upregulated in patients with STS, and anti-angiogenic agents demonstrate activity against STS in the metastatic setting.
Consequently, we propose to evaluate preoperative combined modality sorafenib and conformal RT in patients with STS of the extremity and body wall in a prospective Phase I/II clinical trial. Key endpoints will be safety and toxicity in the Phase I trial and pathological response in the Phase II trial. Additional endpoints will include molecular and functional imaging correlative studies of biomarkers of response and resistance to treatment.
We hypothesize that this combination will be safe and will increase pathologic necrosis within the primary tumor at the time of surgical resection, translating into reduced volume of resected tissue, improved local disease-control, and ultimately improved disease-free survival. Functional imaging studies (dynamic contrast-enhanced MRI) and molecular examination of pre- and post-treatment tumor tissue and serum will allow correlation of changes in tumor blood flow, hypoxia transcription factors, phosphorylated ERK, and angiogenic markers to the degree of tumor necrosis following treatment with preoperative sorafenib and radiotherapy.
The Phase I portion of the trial will seek to establish the safety of sorafenib and radiotherapy in the neoadjuvant setting for soft tissue sarcomas of the extremity and body wall. The Phase II portion of the trial will aim to determine the pathologic near-complete/complete response rate (≥ 95% tumor necrosis) of this multimodality therapy. Molecular and dynamic contrast-enhanced MRI studies will seek to establish correlative biological and imaging markers of response and/or resistance to this therapy.
Significant challenges exist in the treatment of patients with soft tissue sarcoma (STS) of the extremity and body wall. Major therapeutic goals for all patients include local disease-control, maximization of limb function, and avoidance of therapeutic morbidity. The standard approach for patients with STS has been based on radical resection with wide margins in combination with external beam radiation. Although local control rates in this setting range from 85 to 90%, patients remain at risk for substantial morbidity from this multimodality therapy. Furthermore, despite effective local therapy with surgery and radiation, approximately 50% of patients with high grade STS will die of disease within 5 years of diagnosis.
Experimental data and experience from other solid tumors suggest a significant synergistic effect when anti-angiogenic targeted therapies, such as sorafenib, are combined with radiotherapy (RT). Overproduction of angiogenic factors in the tumor vasculature leads to disordered/poorly regulated tumor perfusion which appears to normalize following delivery of anti-angiogenic agents. This, in turn, allows improved delivery of and susceptibility to cytotoxic agents, which is particularly important with RT since hypoxia is a key mechanism of resistance to this modality. Preliminary clinical data in rectal cancer and malignant brain tumors have demonstrated promising results from the combination of anti-angiogenic agents and RT with respect to downstaging of the primary tumor, local tumor control, and improved progression-free survival. Angiogenic factors are upregulated in patients with STS, and anti-angiogenic agents demonstrate activity against STS in the metastatic setting.
Consequently, we propose to evaluate preoperative combined modality sorafenib and conformal RT in patients with STS of the extremity and body wall in a prospective Phase I/II clinical trial. Key endpoints will be safety and toxicity in the Phase I trial and pathological response in the Phase II trial. Additional endpoints will include molecular and functional imaging correlative studies of biomarkers of response and resistance to treatment.
We hypothesize that this combination will be safe and will increase pathologic necrosis within the primary tumor at the time of surgical resection, translating into reduced volume of resected tissue, improved local disease-control, and ultimately improved disease-free survival. Functional imaging studies (dynamic contrast-enhanced MRI) and molecular examination of pre- and post-treatment tumor tissue and serum will allow correlation of changes in tumor blood flow, hypoxia transcription factors, phosphorylated ERK, and angiogenic markers to the degree of tumor necrosis following treatment with preoperative sorafenib and radiotherapy.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: