Sorafenib Tosylate, Combination Chemotherapy, Radiation Therapy, and Surgery in Treating Patients With High-Risk Stage IIB-IV Soft Tissue Sarcoma

• Sponsor: OHSU Knight Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02050919
• Collaborator: Bayer (Industry), Oregon Health and Science University (Other)
• Enrollment: 20
• Location: 1
• Arm: 1
• Actual Duration (Months): 84.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial studies how well sorafenib tosylate, combination chemotherapy, radiation therapy, and surgery work in treating patients with high-risk stage IIB-IV soft tissue sarcoma. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as epirubicin hydrochloride and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x rays to kill tumor cells. Giving sorafenib tosylate, combination chemotherapy, radiation therapy, and surgery may be an effective treatment for soft tissue sarcoma.

Condition or Disease	Intervention/Treatment	Phase
Pleomorphic Rhabdomyosarcoma; Stage IIB Adult Soft Tissue Sarcoma AJCC v7; Stage III Adult Soft Tissue Sarcoma AJCC v7; Stage IV Adult Soft Tissue Sarcoma AJCC v7	Drug: Epirubicin Hydrochloride; Radiation: External Beam Radiation Therapy; Drug: Ifosfamide; Other: Laboratory Biomarker Analysis; Drug: Sorafenib Tosylate; Procedure: Therapeutic Conventional Surgery	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the pathologic response rate (>= 95% necrosis) after preoperative treatment with sorafenib (sorafenib tosylate), epirubicin (epirubicin hydrochloride), ifosfamide, and hypofractionated radiation for high risk soft tissue sarcomas of the extremities or body wall.

SECONDARY OBJECTIVES:

1. To further characterize the safety of sorafenib plus chemoradiotherapy, including wound complication rate.

2. To estimate time-to-event rates, including overall survival, overall disease-free survival, distant disease-free survival, and local disease-free survival in patients with high risk soft tissue sarcomas of the extremities or body wall treated with preoperative sorafenib plus chemoradiotherapy and postoperative sorafenib plus chemotherapy.

OUTLINE:

Patients receive sorafenib tosylate orally (PO) once daily (QD) on days 1-71 and 85-155, epirubicin hydrochloride intravenously (IV) over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo external beam radiation therapy (EBRT) on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98.

After completion of study treatment, patients are followed up every 4 months for 2 years, every 6 months for 1 year, and then yearly for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Sorafenib With Chemotherapy, Radiation, and Surgery for High-Risk Soft Tissue Sarcomas
• Actual Study Start Date: Dec 3, 2013
• Actual Primary Completion Date: May 7, 2018
• Actual Study Completion Date: Dec 31, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (sorafenib, chemotherapy, radiation, surgery) Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98.

Drug: Epirubicin Hydrochloride; Given IV; Other Names: Ellence IMI-28 Pharmorubicin PFS ; Radiation: External Beam Radiation Therapy; Undergo EBRT; Other Names: Definitive Radiation Therapy EBRT External Beam Radiotherapy External Beam RT external radiation External Radiation Therapy external-beam radiation ; Drug: Ifosfamide; Given IV; Other Names: Asta Z 4942 Asta Z-4942 Cyfos Holoxan Holoxane Ifex IFO IFO-Cell Ifolem Ifomida Ifomide Ifosfamidum Ifoxan IFX Iphosphamid Iphosphamide Iso-Endoxan Isoendoxan Isophosphamide Mitoxana MJF 9325 MJF-9325 Naxamide Seromida Tronoxal Z 4942 Z-4942 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Sorafenib Tosylate; Given PO; Other Names: BAY 43-9006 Tosylate BAY 54-9085 Nexavar sorafenib ; Procedure: Therapeutic Conventional Surgery; Undergo surgical resection

Outcome Measures

Primary Outcome Measures

1. Pathologic Response Rate, Defined as the Percentage of Participants With Greater Than or Equal to 95% Necrosis. [Assessed at surgical resection]

   Descriptive statistical analysis will be conducted. The proportion with 95% confidence interval will be summarized.

Secondary Outcome Measures

1. Number of Grade 3-4 Adverse Events [Up to 5 years]

   Measured as the number of Grade 3-4 Adverse Events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0

2. Number of Participants With Wound Complications [At least 120 days]

   Wound complication rate, including 1) any secondary operation for wound repair, or 2) wound management without secondary operation including invasive procedures without general or regional anesthesia, readmission for wound care, or persistent deep packing for 120 days or longer.

3. Overall Survival at 2 Years [Time from registration until death from any cause]

   Percentage of patients alive at 2 years, Method of Kaplan-Meier used.

4. Overall Disease-free Survival (Stage IIB-III Patients) [Time from surgical resection to local recurrence, distant metastatic disease, or death, whichever occurs first, assessed up to 2 years]

   Time from surgical resection to local recurrence, distant metastatic disease or death, subjects with stage IV disease excluded. Method of Kaplan-Meier \used.

5. Distant Disease-free Survival (Stage IIB-III Patients) [Time from registration until development of distant metastatic disease or death, whichever occurs first, assessed up to 2 years]

   Time from registration to development of distant metastatic disease or death, subjects with stage IV disease excluded. Method of Kaplan-Meier used.

6. Number of Participants With Local Recurrence [Time from surgical resection until primary analysis ( Median follow-up for local recurrence 17.11 months, range 6.18 - 42.8 months)]

   Number of patients with local recurrence after surgical resection of the primary tumor

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed, soft-tissue sarcoma: excluding rhabdomyosarcoma (pleomorphic rhabdomyosarcoma patients are eligible), Ewing's, primitive neuroectodermal tumor (PNET), osteosarcoma, or gastrointestinal stromal tumor

• American Joint Committee on Cancer (AJCC) (7th edition) stage IIb, III, or IV patients planned for resection of the primary tumor

• 5 cm in greatest dimension

• Intermediate or high-grade

• Superficial or deep

• Sarcoma located on upper (includes shoulder) or lower (includes hip) extremities or on body wall

• Intermediate or high-grade: grades 2 or 3 on scale of 1-3

• Left ventricular ejection fraction (LVEF) >= 50%

• Absolute neutrophil count (ANC) >= 1500/uL

• Hemoglobin (Hgb) >= 9.0 g/dL

• Platelets >= 100,000/uL

• Creatinine =< 1.5 x upper limit of normal (ULN)

• Bilirubin =< 1.5 mg/dL

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 x ULN

• International normalized ratio (INR) < 1.5 or a prothrombin time (PT)/partial thromboplastin time (PTT) within normal limits; patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate; for patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable

• No prior chemotherapy, radiation, or biotherapy

• No major surgery within 4 weeks prior to study entry

• No contraindications to limb-sparing surgery; patient should be evaluated by a surgeon who specializes in sarcoma resections prior to study enrollment to ensure patient (pt) is a candidate for limb-sparing surgery

• No severe peripheral vascular disease

• Adequate contraception must be used and patients must not be pregnant or breastfeeding; women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation; men and women should use adequate birth control for at least thirty days after the last administration of sorafenib

• Women of childbearing potential must have negative serum pregnancy test performed within 7-days prior to registration

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

• Patient must sign a study-specific consent form prior to registration

• Ability to understand and the willingness to sign a written informed consent; a signed informed consent must be obtained prior to any study specific procedures

Exclusion Criteria:

• Patients with known brain metastases; patients with neurological symptoms must undergo a computed tomography (CT) scan/magnetic resonance imaging (MRI) of the brain to exclude brain metastases

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection > Common Terminology Criteria for Adverse Events (CTCAE) grade 2, symptomatic congestive heart failure, unstable angina pectoris, cardiac ventricular arrhythmia requiring anti-arrhythmic therapy, or psychiatric illness/social situations that would limit compliance with study requirements; patients must not have unstable angina (angina symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months

• Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management

• Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C

• Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months

• Pulmonary hemorrhage/bleeding event >= CTCAE grade 2 within 4 weeks of first dose of study drug

• Any other hemorrhage/bleeding event >= CTCAE grade 3 within 4 weeks of first dose of study drug

• Serious non-healing wound, ulcer, or bone fracture

• Evidence or history of bleeding diathesis or coagulopathy

• Major surgery or significant traumatic injury within 4 weeks of first study drug

• Use of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers

• Known or suspected allergy to sorafenib or any agent given in the course of this trial

• Any condition that impairs patient's ability to swallow whole pills

• Any malabsorption problem

• Pregnant or lactating women are excluded from this study

• Patients with a "currently active" second malignancy other than non-melanoma skin cancers are not to be registered; patients are not considered to have a "currently active" malignancy if they have completed therapy and considered by their physician to be at less than 30% risk of relapse

• Any uncontrolled thyroid disease

• Requirement for hemodialysis or peritoneal dialysis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	OHSU Knight Cancer Institute	Portland	Oregon	United States	97239

Sponsors and Collaborators

• OHSU Knight Cancer Institute
• Bayer
• Oregon Health and Science University

Investigators

• Principal Investigator: Christopher Ryan, OHSU Knight Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 15, 2016

More Information

Publications

None provided.

• Responsible Party: Christopher Ryan, Principal Investigator, OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT02050919
• Other Study ID Numbers: IRB00009464; NCI-2013-02414; IRB00009464
• First Posted: Jan 31, 2014
• Last Update Posted: Mar 21, 2022
• Last Verified: Feb 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Sarcoma; Rhabdomyosarcoma; Sorafenib; Epirubicin; Ifosfamide; Isophosphamide mustard

Study Results

Participant Flow

Arm/Group Title	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
Arm/Group Description	Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98. Epirubicin Hydrochloride: Given IV External Beam Radiation Therapy: Undergo EBRT Ifosfamide: Given IV Laboratory Biomarker Analysis: Correlative studies Sorafenib Tosylate: Given PO Therapeutic Conventional Surgery: Undergo surgical resection
Period Title: Overall Study
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
Arm/Group Description	Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98. Epirubicin Hydrochloride: Given IV External Beam Radiation Therapy: Undergo EBRT Ifosfamide: Given IV Laboratory Biomarker Analysis: Correlative studies Sorafenib Tosylate: Given PO Therapeutic Conventional Surgery: Undergo surgical resection
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	17 85%
>=65 years	3 15%
Sex: Female, Male (Count of Participants)
Female	11 55%
Male	9 45%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5%
Not Hispanic or Latino	18 90%
Unknown or Not Reported	1 5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	1 5%
Black or African American	0 0%
White	18 90%
More than one race	0 0%
Unknown or Not Reported	1 5%
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Pathologic Response Rate, Defined as the Percentage of Participants With Greater Than or Equal to 95% Necrosis.
Description	Descriptive statistical analysis will be conducted. The proportion with 95% confidence interval will be summarized.
Time Frame	Assessed at surgical resection

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
Arm/Group Description	Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98. Epirubicin Hydrochloride: Given IV External Beam Radiation Therapy: Undergo EBRT Ifosfamide: Given IV Laboratory Biomarker Analysis: Correlative studies Sorafenib Tosylate: Given PO Therapeutic Conventional Surgery: Undergo surgical resection
Measure Participants	20
Number (95% Confidence Interval) [% of participants]	20 100%

2. Secondary Outcome

Title	Number of Grade 3-4 Adverse Events
Description	Measured as the number of Grade 3-4 Adverse Events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
Arm/Group Description	Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98. Epirubicin Hydrochloride: Given IV External Beam Radiation Therapy: Undergo EBRT Ifosfamide: Given IV Laboratory Biomarker Analysis: Correlative studies Sorafenib Tosylate: Given PO Therapeutic Conventional Surgery: Undergo surgical resection
Measure Participants	20
Number [Grade 3-4 Adverse Events]	86

3. Secondary Outcome

Title	Number of Participants With Wound Complications
Description	Wound complication rate, including 1) any secondary operation for wound repair, or 2) wound management without secondary operation including invasive procedures without general or regional anesthesia, readmission for wound care, or persistent deep packing for 120 days or longer.
Time Frame	At least 120 days

Outcome Measure Data

Analysis Population Description

Patients who had surgery.

Arm/Group Title	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
Arm/Group Description	Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98. Epirubicin Hydrochloride: Given IV External Beam Radiation Therapy: Undergo EBRT Ifosfamide: Given IV Laboratory Biomarker Analysis: Correlative studies Sorafenib Tosylate: Given PO Therapeutic Conventional Surgery: Undergo surgical resection
Measure Participants	20
Count of Participants [Participants]	10 50%

4. Secondary Outcome

Title	Overall Survival at 2 Years
Description	Percentage of patients alive at 2 years, Method of Kaplan-Meier used.
Time Frame	Time from registration until death from any cause

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
Arm/Group Description	Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98. Epirubicin Hydrochloride: Given IV External Beam Radiation Therapy: Undergo EBRT Ifosfamide: Given IV Laboratory Biomarker Analysis: Correlative studies Sorafenib Tosylate: Given PO Therapeutic Conventional Surgery: Undergo surgical resection
Measure Participants	20
Number (95% Confidence Interval) [percentage of patients]	82

5. Secondary Outcome

Title	Overall Disease-free Survival (Stage IIB-III Patients)
Description	Time from surgical resection to local recurrence, distant metastatic disease or death, subjects with stage IV disease excluded. Method of Kaplan-Meier \used.
Time Frame	Time from surgical resection to local recurrence, distant metastatic disease, or death, whichever occurs first, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

15 of the 20 patients enrolled on the trial were evaluable for DFS. Four patients were metastatic at baseline, and 1 developed metastatic disease during preoperative treatment.

Arm/Group Title	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
Arm/Group Description	Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98. Epirubicin Hydrochloride: Given IV External Beam Radiation Therapy: Undergo EBRT Ifosfamide: Given IV Laboratory Biomarker Analysis: Correlative studies Sorafenib Tosylate: Given PO Therapeutic Conventional Surgery: Undergo surgical resection
Measure Participants	15
Median (95% Confidence Interval) [Months]	13.3

6. Secondary Outcome

Title	Distant Disease-free Survival (Stage IIB-III Patients)
Description	Time from registration to development of distant metastatic disease or death, subjects with stage IV disease excluded. Method of Kaplan-Meier used.
Time Frame	Time from registration until development of distant metastatic disease or death, whichever occurs first, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

Four patients were metastatic at baseline, and thus excluded from the distant disease-free survival evaluation.

Arm/Group Title	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
Arm/Group Description	Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98. Epirubicin Hydrochloride: Given IV External Beam Radiation Therapy: Undergo EBRT Ifosfamide: Given IV Laboratory Biomarker Analysis: Correlative studies Sorafenib Tosylate: Given PO Therapeutic Conventional Surgery: Undergo surgical resection
Measure Participants	16
Median (95% Confidence Interval) [Months]	16.4

7. Secondary Outcome

Title	Number of Participants With Local Recurrence
Description	Number of patients with local recurrence after surgical resection of the primary tumor
Time Frame	Time from surgical resection until primary analysis ( Median follow-up for local recurrence 17.11 months, range 6.18 - 42.8 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
Arm/Group Description	Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98. Epirubicin Hydrochloride: Given IV External Beam Radiation Therapy: Undergo EBRT Ifosfamide: Given IV Laboratory Biomarker Analysis: Correlative studies Sorafenib Tosylate: Given PO Therapeutic Conventional Surgery: Undergo surgical resection
Measure Participants	16
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	Toxicity measure through follow up, every 4 months until patient death or withdrawal, a median of 34.5 months.
Adverse Event Reporting Description	Adverse events will be using the NCI Common Toxicity Criteria for Adverse Events v4.0. Assessment of study drug attribution will be made by an Investigator. Acute and long-term radiation toxicity will be assessed for the following CTCAE categories: 1) Injury, poisoning and procedural complications: Dermatitis radiation 2) Musculoskeletal and connective tissue disorders: Fibrosis 3) other appropriate Musculoskeletal and connective tissue disorders AEs appropriate to limb function.
Arm/Group Title	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
Arm/Group Description	Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98. Epirubicin Hydrochloride: Given IV External Beam Radiation Therapy: Undergo EBRT Ifosfamide: Given IV Laboratory Biomarker Analysis: Correlative studies Sorafenib Tosylate: Given PO Therapeutic Conventional Surgery: Undergo surgical resection
All Cause Mortality
	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
	Affected / at Risk (%)	# Events
Total	5/20 (25%)
Serious Adverse Events
	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
	Affected / at Risk (%)	# Events
Total	18/20 (90%)
Blood and lymphatic system disorders
Febrile Neutropenia	12/20 (60%)
Gastrointestinal disorders
Constipation	1/20 (5%)
Diarrhea	1/20 (5%)
Infections and infestations
Catheter Related infection	1/20 (5%)
enterocolitis infectious	1/20 (5%)
Sepsis	3/20 (15%)
Soft tissue infection	1/20 (5%)
wound infection	7/20 (35%)
Injury, poisoning and procedural complications
wound dehiscence	1/20 (5%)
Investigations
Lymphocyte count decreased	1/20 (5%)
Neutrophil Count decreased	1/20 (5%)
Platelet Count Decreased	2/20 (10%)
Metabolism and nutrition disorders
Hypokalemia	1/20 (5%)
Nervous system disorders
Encephalopathy	3/20 (15%)
syncope	1/20 (5%)
Psychiatric disorders
Delirium	1/20 (5%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	1/20 (5%)
Other (Not Including Serious) Adverse Events
	Treatment (Sorafenib, Chemotherapy, Radiation, Surgery)
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
Anemia	19/20 (95%)
Febrile Neutropenia	1/20 (5%)
Cardiac disorders
Atrial flutter	1/20 (5%)
Sinus Tachycardia	1/20 (5%)
Eye disorders
blurred vision	2/20 (10%)
Gastrointestinal disorders
Abdominal Pain	1/20 (5%)
anal fistula	1/20 (5%)
Bloating	1/20 (5%)
Constipation	8/20 (40%)
Diarrhea	8/20 (40%)
Dry mouth	1/20 (5%)
Dyspepsia	1/20 (5%)
Dysphagia	1/20 (5%)
Gastroesophageal reflux disease	4/20 (20%)
hemorrhoids	2/20 (10%)
mucositis oral	8/20 (40%)
nausea	13/20 (65%)
Pancreatitis	1/20 (5%)
Rectal Hemorrhage	1/20 (5%)
vomiting	10/20 (50%)
General disorders
Chills	1/20 (5%)
Edema limbs	3/20 (15%)
Fatigue	10/20 (50%)
fever	1/20 (5%)
non-cardiac chest pain	1/20 (5%)
pain	6/20 (30%)
Infections and infestations
anorectal infection	1/20 (5%)
Catheter Related Infection	1/20 (5%)
Lip Infection	1/20 (5%)
prostate infection	1/20 (5%)
Urinary tract infection	2/20 (10%)
wound infection	6/20 (30%)
Injury, poisoning and procedural complications
Burn	1/20 (5%)
Dermatitis radiation	6/20 (30%)
Fracture	1/20 (5%)
Postoperative hemorrhage	1/20 (5%)
wound dehiscence	3/20 (15%)
Investigations
Activated partial thromboplastin time prolonged	1/20 (5%)
Alanine aminotransferase increased	8/20 (40%)
Alkaline phosphatase increased	8/20 (40%)
Aspartate aminotransferase Increased	10/20 (50%)
Blood bilirubin increased	5/20 (25%)
Creatinine increased	6/20 (30%)
Ejection fraction decreased	1/20 (5%)
Lipase increased	1/20 (5%)
Lymphocyte count decreased	20/20 (100%)
Neutrophil Count Decreased	18/20 (90%)
Platelet count decreased	20/20 (100%)
weight loss	5/20 (25%)
White Blood Cell Decreased	18/20 (90%)
Metabolism and nutrition disorders
anorexia	6/20 (30%)
dehydration	3/20 (15%)
Hypercalcemia	2/20 (10%)
Hyperglycemia	11/20 (55%)
hyperkalemia	2/20 (10%)
hypermagnesemia	2/20 (10%)
Hypernatremia	3/20 (15%)
Hypoalbuminemia	16/20 (80%)
hypocalcemia	12/20 (60%)
Hypoglycemia	1/20 (5%)
Hypokalemia	11/20 (55%)
Hypomagnesemia	12/20 (60%)
Hyponatremia	8/20 (40%)
Hypophosphatemia	16/20 (80%)
Musculoskeletal and connective tissue disorders
Arthritis	2/20 (10%)
bone pain	1/20 (5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment Related Secondary Malignancy	1/20 (5%)
Nervous system disorders
akathisia	1/20 (5%)
Dizziness	2/20 (10%)
Dysgeusia	1/20 (5%)
encephalopathy	3/20 (15%)
Headache	1/20 (5%)
Paresthesia	1/20 (5%)
Peripheral Motor Neuropathy	3/20 (15%)
Tremor	1/20 (5%)
Psychiatric disorders
anxiety	3/20 (15%)
Confusion	1/20 (5%)
Insomnia	3/20 (15%)
Renal and urinary disorders
Acute Kidney Injury	2/20 (10%)
Hematuria	1/20 (5%)
Reproductive system and breast disorders
Vaginal hemorrhage	1/20 (5%)
Respiratory, thoracic and mediastinal disorders
cough	2/20 (10%)
Dyspnea	1/20 (5%)
Epistaxis	1/20 (5%)
hiccups	2/20 (10%)
Nasal congestion	1/20 (5%)
Sore Throat	1/20 (5%)
Skin and subcutaneous tissue disorders
alopecia	2/20 (10%)
dry skin	2/20 (10%)
Palmar-plantar erythrodysesthesia syndrome	5/20 (25%)
Pruritus	1/20 (5%)
Rash Acneiform	1/20 (5%)
Rash maculo-papular	10/20 (50%)
Vascular disorders
flushing	1/20 (5%)
Hot flashes	1/20 (5%)
Hypertension	8/20 (40%)
Hypotension	3/20 (15%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.