Sorafenib in Treating Patients With Soft Tissue Sarcomas (Extremity Sarcoma Closed to Entry as of 5/30/07)

A Phase II Clinical and Correlative Study of BAY 43-9006 (Sorafenib) IND 69,896 in Sarcoma

This phase II trial is studying how well sorafenib works in treating patients with soft tissue sarcoma. Sorafenib may stop the growth of soft tissue sarcoma by blocking blood flow to the tumor and blocking some of the enzymes needed for tumor cell growth

Study Overview

• Status: Completed
• Conditions: Recurrent Osteosarcoma; Metastatic Osteosarcoma; Recurrent Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: therapeutic conventional surgery; Procedure: computed tomography; Drug: sorafenib tosylate; Procedure: dynamic contrast-enhanced magnetic resonance imaging

Detailed Description

PRIMARY OBJECTIVES:

I. To determine if the combined vascular endothelial growth factor receptor 2 (VEGF-R2)/platelet-derived growth factor receptor (PDGFR)-beta inhibitor BAY 43-9006/ sorafenib can decrease interstitial fluid pressure (IFP) in soft tissue sarcomas.

II. To investigate the effects of BAY 43-9006/sorafenib on tumor blood flow, circulating endothelial cells, vascular density and pericyte coverage.

III. To characterize the pharmacokinetics of BAY 43-9006/sorafenib in sarcoma patients.

SECONDARY OBJECTIVES:

I. To describe any preliminary evidence of anti-tumor activity. II. Assess whether there are any significant relationships between systemic drug exposure and drug-related toxicity or biological effect.

OUTLINE: This is a multicenter study. Patients are assigned to one of two groups (group 1 closed to accrual as of 5/30/07).

GROUP I (SARCOMAS OF THE EXTREMITY) (CLOSED TO ACCRUAL AS OF 5/30/07): Patients receive oral sorafenib twice daily on days 1-14. Patients undergo surgical resection of the tumor on approximately day 15. Once patients recover from surgery (and radiotherapy if indicated), patients who demonstrate a clinically and pathologically significant response (≥ 25% reduction in tumor size or ≥ 25% necrosis in the surgical specimen) may continue sorafenib as above for a maximum of 6 months in the absence of disease progression or unacceptable toxicity and at the discretion of the principal investigator. Biopsy tissue and blood samples are examined for biomarkers and interstitial fluid pressure (IFP) is measured at baseline and immediately before surgery.

GROUP II (METASTATIC OR INOPERABLE SARCOMAS): Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days for 2 courses. Patients with responding or stable disease may continue sorafenib in the absence of disease progression or unacceptable toxicity. Biopsy tissue and blood samples are examined for biomarkers and IFP is measured at baseline and on days 28 and 56.

In both groups, blood samples are drawn periodically for pharmacological studies.

After completion of study therapy, patients are followed monthly until all study-related toxicities are resolved and then at the discretion of the investigator.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• There are two groups of patients eligible for this study; treatment group 1 consists of patients with extremity sarcomas other than potentially curable osteosarcoma or Ewing's sarcoma who are candidates for potentially curative surgery; treatment group 2 consists of patients with metastatic or inoperable sarcoma, for which there is no known curative or survival prolonging palliative therapy, or failure of these therapies; patients must have at least one site of measurable disease by radiologic imaging techniques; patients must have at least one palpable tumor mass with no overlying viscera which is amenable to biopsy; the tumor mass should be approximately 2 cm or greater in diameter; patients with smaller palpable tumors are eligible if participation is approved by the treating surgeon after discussion with the study chairperson

  • As of 5/30/07, no subjects will accrue to Treatment Group I
• Life expectancy >= 2 months
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Pretreatment laboratory data, obtained within 14 days of study entry, must meet the following criteria:
• Absolute Neutrophil Count (ANC) >= 1,500/mm^3
• Platelets >= 100,000/mm^3
• Serum glutamic oxaloacetic transaminase (SGOT) =< 2.5-times the upper limit of normal (ULN)
• Serum glutamic-pyruvic transaminase (SGPT)=< 2.5-times ULN
• Total Bilirubin =< ULN
• Serum creatinine =< 1.5-times ULN
• >= 3 weeks since major surgery unrelated to study disease (sarcoma)
• >= 3 weeks since chemotherapy or radiation therapy (6 weeks for nitrosourea or mitomycin C chemotherapy)
• No prior treatment with sorafenib (BAY 43-9006) or specific inhibitors of mitogen-activated protein kinase (MAPK) pathways are permitted; a previously irradiated tumor site cannot be used for clinical or correlative measurements, although irradiation to sites other than a measurable site is permitted; there are no limitations on the extent or type of prior therapy received by the patient other than the time intervals indicated in the above and demonstrating complete recovery from any adverse effects associated by satisfying all relevant eligibility criteria
• Patients who are on warfarin anticoagulation are allowed to participate as long as they are converted to a low molecular weight heparin (e.g. lovenox) from study entry until at least day 56
• Women of childbearing potential must not be pregnant or lactating; all women of childbearing potential (age < 50, last menstrual period [LMP] < 12 months ago) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L of beta-HCG) within 72 hr prior to receiving the study medication; BAY43-9006 has antiproliferative effects, which may be harmful to the developing fetus or nursing infant
• Fertile males and females must use adequate contraception
• Signed informed consent

Exclusion Criteria:

• Ewing's sarcoma or osteosarcoma that is potentially curable with surgery, chemotherapy, and/or radiation therapy
• Active brain metastases including evidence of cerebral edema by CT scan or MRI, or progression from prior imaging study, any requirements for steroids, or enzyme-inducing anti-convulsant agents, or clinical symptoms of/from brain metastases; patients with treated and/or stable brain metastasis who are asymptomatic can be enrolled, if otherwise eligible
• Any uncontrolled serious medical or psychiatric illness; particular note is given to uncontrolled hypertension (discretion left to investigators) and significant proteinuria > 1 gm/24 hr (does not require quantitation in absence of clinical indication)
• Patients receiving other investigational agents
• Human immunodeficiency virus (HIV) patients receiving combination anti-retroviral therapy are excluded because of potential pharmacokinetic interactions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group I (sarcomas of extremity, closed accrual as of 5/30/07); Patients receive oral sorafenib twice daily on days 1-14. Patients undergo surgical resection of the tumor on approximately day 15. Once patients recover from surgery (and radiotherapy if indicated), patients who demonstrate a clinically and pathologically significant response (≥ 25% reduction in tumor size or ≥ 25% necrosis in the surgical specimen) may continue sorafenib as above for a maximum of 6 months in the absence of disease progression or unacceptable toxicity and at the discretion of the principal investigator. Biopsy tissue and blood samples are examined for biomarkers and interstitial fluid pressure (IFP) is measured at baseline and immediately before surgery.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Procedure: therapeutic conventional surgery; Undergo surgery; Procedure: computed tomography; Correlative studies; Other Names: tomography, computed; Drug: sorafenib tosylate; Given PO; Other Names: BAY 43-9006; BAY 43-9006 Tosylate Salt; BAY 54-9085; Nexavar; SFN; Procedure: dynamic contrast-enhanced magnetic resonance imaging; Correlative studies; Other Names: DCE-MRI
Experimental: Group II (metastatic or inoperable sarcomas); Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days for 2 courses. Patients with responding or stable disease may continue sorafenib in the absence of disease progression or unacceptable toxicity. Biopsy tissue and blood samples are examined for biomarkers and IFP is measured at baseline and on days 28 and 56.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Procedure: computed tomography; Correlative studies; Other Names: tomography, computed; Drug: sorafenib tosylate; Given PO; Other Names: BAY 43-9006; BAY 43-9006 Tosylate Salt; BAY 54-9085; Nexavar; SFN; Procedure: dynamic contrast-enhanced magnetic resonance imaging; Correlative studies; Other Names: DCE-MRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Fludeoxyglucose (FDG) Uptake (Maximal Standardized Uptake Value, or SUVmax)	Paired comparison made using a Wilcoxon signed rank test with one-sided type I error of 5%.	Baseline to up to 1 month post-treatment
Change in Interstitial Fluid Pressure (IFP)	Paired comparison made using a Wilcoxon signed rank test with one-sided type I error of 5%.	Baseline to up to 1 month post-treatment
Change in White Blood Cell Count (WBC)	Paired comparison made using a Wilcoxon signed rank test with one-sided type I error of 5%.	Baseline to up to 1 month post-treatment
Change in Pericyte Coverage of Endothelial Cells (Alpha-SMA)	Paired comparison made using a Wilcoxon signed rank test with one-sided type I error of 5%.	Baseline to up to 1 month post-treatment
Clinical Benefit as Measured by 50% Reduction in IFP		Baseline to surgery
Clinical Benefit, Measured by Any Reduction in Tumor Dimensions on CT Scan as Measured by RECIST Criteria		Up to 1 month
Incidence of Adverse Events		Up to 1 month

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jeffrey Morgan, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• Raut CP, Boucher Y, Duda DG, Morgan JA, Quek R, Ancukiewicz M, Lahdenranta J, Eder JP, Demetri GD, Jain RK. Effects of sorafenib on intra-tumoral interstitial fluid pressure and circulating biomarkers in patients with refractory sarcomas (NCI protocol 6948). PLoS One. 2012;7(2):e26331. doi: 10.1371/journal.pone.0026331. Epub 2012 Feb 7.

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): December 1, 2007
• Study Completion (Actual): July 1, 2008

Study Registration Dates

• First Submitted: May 25, 2006
• First Submitted That Met QC Criteria: May 25, 2006
• First Posted (Estimate): May 26, 2006

Study Record Updates

• Last Update Posted (Estimate): April 30, 2014
• Last Update Submitted That Met QC Criteria: April 1, 2014
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Recurrence; Sarcoma, Ewing; Osteosarcoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: NCI-2012-03122; U01CA062490 (U.S. NIH Grant/Contract); 05-033