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Sorafenib, Epirubicin, Ifosfamide, and Radiation Therapy Followed By Surgery in Treating Patients With High-Risk Stage II or Stage III Soft Tissue Sarcoma

Primary Purpose

Sarcoma

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

epirubicin hydrochloride

ifosfamide

sorafenib tosylate

immunoenzyme technique

immunohistochemistry staining method

laboratory biomarker analysis

adjuvant therapy

neoadjuvant therapy

therapeutic conventional surgery

hypofractionated radiation therapy

About this trial

This is an interventional treatment trial for Sarcoma focused on measuring stage II adult soft tissue sarcoma, stage III adult soft tissue sarcoma

Eligibility Criteria

15 Years - 120 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

DISEASE CHARACTERISTICS:

Histologically confirmed soft tissue sarcoma of the upper (including shoulder) or lower (including hip) extremities or body wall
Stage II or III disease, as defined by the following:
- Tumor dimension > 5 cm
- Superficial or deep tumor
- Intermediate or high-grade disease
- No regional lymph node involvement
- No distant metastases
No rhabdomyosarcoma, Ewing sarcoma, primitive neuroectodermal tumor (PNET), osteosarcoma, or gastrointestinal stromal tumor
- Pleomorphic rhabdomyosarcoma allowed
No known metastases
- Patients with neurological symptoms must undergo a CT scan or MRI of the brain to exclude brain metastases

PATIENT CHARACTERISTICS:

Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Absolute Neutrophil Count (ANC) ≥ 1,500/μL
Hemoglobin ≥ 9.0 g/dL
Platelet count ≥ 100,000/μL
International Normalized Ratio (INR) < 1.5 or Prothrombin Time/Partial Thromboplastin Time (PT/PTT) normal
Creatinine ≤ 1.5 times upper limit of normal (ULN)
Bilirubin ≤ 1.5 mg/dL
Aspartate Aminotransferase/Alanine Aminotransferase (AST/ALT) ≤ 1.5 times ULN
Left Ventricular Ejection Fraction (LVEF) ≥ 50%
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception (male patients must use effective contraception for ≥ 3 months after completion of study treatment)
No contraindications to limb-sparing surgery
No severe peripheral vascular disease
No concurrent uncontrolled illness including, but not limited to, the following:
- Ongoing or active serious infection > Common Toxicity Criteria for Adverse Effects (CTCAE) grade 2
- Symptomatic congestive heart failure
- Unstable angina pectoris (i.e., angina symptoms at rest) or new onset angina within the past 3 months
- Myocardial infarction within the past 6 months
- Cardiac ventricular arrhythmia requiring anti-arrhythmic therapy
- Psychiatric illness/social situation that would limit compliance with study requirements
No uncontrolled hypertension (defined as systolic blood pressure > 150 mm Hg or diastolic blood pressure > 90 mm Hg, despite optimal medical management)
No known HIV infection or chronic hepatitis B or C infection
No thrombolic or embolic events (e.g., cerebrovascular accident, including transient ischemic attacks) within the past 6 months
No pulmonary hemorrhage or bleeding event ≥ CTCAE grade 2 within the past 4 weeks
No other hemorrhage or bleeding event ≥ CTCAE grade 3 within the past 4 weeks
No serious non-healing wound, ulcer, or bone fracture
No evidence or history of bleeding diathesis or coagulopathy
No significant traumatic injury within the past 4 weeks
No known or suspected allergy to sorafenib tosylate or any agent given in the study
No condition that would impair the ability to swallow whole pills
No malabsorption problem
No "currently active" second malignancy other than non-melanoma skin cancer
- Not considered to have a "currently active" malignancy if patient completed therapy AND has a < 30% risk of relapse

PRIOR CONCURRENT THERAPY:

No prior chemotherapy, radiotherapy, or biotherapy
More than 4 weeks since prior major surgery
No concurrent St. John's wort or rifampin
No other concurrent investigational or anticancer therapy
Concurrent anticoagulation with warfarin or heparin allowed

Sites / Locations

OHSU Knight Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sorafenib, Epirubicin, Ifosfamide

Arm Description

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD) of sorafenib tosylate when combined with chemoradiotherapy

The MTD is defined as the dose that produces dose limiting toxicity (DLT) in 33% of patients. Dose level escalation will be determined based on DLTs observed through the first 8 weeks of therapy, but DLTs will be monitored throughout the entire 22 week treatment course and dose de-escalation may occur if excess late DLTs are observed.

Safety

As necessary and at the discretion of the principal investigator, a given dose level may be expanded by 3-6 subjects to further explore the safety of that dose level upon prior written approval of the Institutional Review Board (IRB).

Secondary Outcome Measures

Time to local recurrence

Defined as the duration of time from surgical resection of the primary tumor until local recurrence (amputated patients excluded).

Distant disease-free survival

Defined as the duration of time from registration until development of distant metastatic disease or death, whichever occurs first. Subjects with stage IV disease will be censored from this analysis.

Progression-free survival

Defined as the duration of time from registration to progressive disease (per RECIST), local recurrence, distant metastatic disease (exclusive of stage IV subjects), or death, whichever occurs first.

Overall survival

Defined as the interval of time from registration until death from any cause.

Histologic necrosis rate of ≥ 95%

Levels of tumorigenic and angiogenic markers, including p-ERK, VEGF, sVEGFR-2, bFGF, in plasma and tumor tissue samples as measured by ELISA

Expression of tumor proliferation and angiogenic factors, including p-ERK, VEGFR2 and PDGFR, in tumor tissue samples as measured by IHC

Full Information

NCT ID

NCT00822848

First Posted

January 14, 2009

Last Updated

September 5, 2018

Sponsor

OHSU Knight Cancer Institute

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00822848

Brief Title

Sorafenib, Epirubicin, Ifosfamide, and Radiation Therapy Followed By Surgery in Treating Patients With High-Risk Stage II or Stage III Soft Tissue Sarcoma

Official Title

Antiangiogenic Potentiation of Preoperative Chemoradiotherapy for High Risk Extremity Soft Tissue Sarcomas: A Phase I Study of Sorafenib With Epirubicin, Ifosfamide, Hypofractionated Radiation, and Surgery

Study Type

Interventional

2. Study Status

Record Verification Date

September 2018

Overall Recruitment Status

Completed

Study Start Date

February 2009 (undefined)

Primary Completion Date

September 2012 (Actual)

Study Completion Date

April 30, 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

OHSU Knight Cancer Institute

Collaborators

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as epirubicin and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase I trial is studying the side effects and best dose of sorafenib when given together with epirubicin, ifosfamide, and radiation therapy followed by surgery in treating patients with high-risk stage II or stage III soft tissue sarcoma.

Detailed Description

OBJECTIVES: Primary To determine the maximum tolerated dose of sorafenib tosylate when combined with epirubicin hydrochloride, ifosfamide, and hypofractionated radiotherapy prior to surgery in patients with high-risk stage II or III soft tissue sarcoma of the extremity or body wall. Secondary To examine, preliminarily, the activity of this regimen, in terms of time to local recurrence, distant disease-free survival, progression-free survival, overall survival, and histologic necrosis rate of ≥ 95%, in these patients. To investigate levels of tumorigenic and angiogenic markers, including phosphorylated extracellular signal-regulated kinase (p-ERK), vascular endothelial growth factor (VEGF), serum vascular endothelial growth factor receptor-2 (sVEGFR-2), and basic fibroblast growth factor (bFGF), in plasma and tumor tissue samples at baseline and during and after treatment. To evaluate expression of tumor proliferation and angiogenic factors, including p-ERK, vascular endothelial growth factor receptor-2 (VEGFR2) and Platelet-derived growth factor receptor (PDGFR), in tumor tissue samples as measured by Immunohistochemistry (IHC). OUTLINE: This is a dose-escalation study of sorafenib tosylate. Patients receive oral sorafenib tosylate* once or twice daily beginning 2 weeks before the initiation of chemotherapy and continuing until the completion of chemotherapy. Patients also receive epirubicin hydrochloride** IV and ifosfamide IV over 90 minutes on days 1-3 and pegfilgrastim subcutaneously (SC) on day 4 or filgrastim (G-CSF) (SC) daily beginning on day 4 and continuing for up to 10 days or until blood counts recover. Chemotherapy repeats approximately every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. During course 2, patients also undergo 8 fractions of external beam radiotherapy once daily between days 1-10 for a total dose of 28 Gy. Between courses 3 and 4, patients undergo surgical resection. Beginning approximately 2 weeks after surgical resection, patients with positive surgical margins undergo 6 fractions of boost external beam radiotherapy once daily for a total dose of 12 Gy. NOTE: *Sorafenib is discontinued 1 week before surgery and resumed 1 week after surgery. NOTE: **Epirubicin is omitted during course 2. Plasma and tumor tissue samples are collected periodically for correlative laboratory studies. Plasma and tumor tissue samples are analyzed by ELISA for measurement of tumorigenic and angiogenic markers, including p-ERK, VEGF, sVEGFR-2, and bFGF. Tumor tissue samples are also analyzed by IHC for p-ERK, VEGFR2, phospho-VEGFR2, PDGFR, and phospho-PDGFR. After completion of study therapy, patients are followed periodically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sarcoma

Keywords

stage II adult soft tissue sarcoma, stage III adult soft tissue sarcoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sorafenib, Epirubicin, Ifosfamide

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

epirubicin hydrochloride

Intervention Description

I.V., days 1-3 of each cycle. Epirubicin to be omitted during cycle 2 (concomitant chemoradiation)

Intervention Type

Drug

Intervention Name(s)

ifosfamide

Intervention Description

Over 90 minutes I.V., days 1-3 of each cycle. Administered with hydration and Mesna.

Intervention Type

Drug

Intervention Name(s)

sorafenib tosylate

Intervention Description

P.O. daily beginning 2 weeks before first chemotherapy cycle, held 1 week before and after surgery.

Intervention Type

Other

Intervention Name(s)

immunoenzyme technique

Intervention Type

Other

Intervention Name(s)

immunohistochemistry staining method

Intervention Type

Other

Intervention Name(s)

laboratory biomarker analysis

Intervention Type

Procedure

Intervention Name(s)

adjuvant therapy

Other Intervention Name(s)

Adjuvant radiotherapy, Adjuvant chemotherapy

Intervention Description

Preoperative administration has been the preference at our institution.

Intervention Type

Procedure

Intervention Name(s)

neoadjuvant therapy

Other Intervention Name(s)

Neoadjuvant chemoradiotherapy

Intervention Type

Procedure

Intervention Name(s)

therapeutic conventional surgery

Intervention Description

Surgery should be planned for 2-4 weeks after the initiation of chemotherapy for cycle 3.

Intervention Type

Radiation

Intervention Name(s)

hypofractionated radiation therapy

Intervention Description

28 Gy (350 centigray (cGy) x 8 fractions in 10 days) beginning at the start of cycle 2. *Boost: postoperative boost of 12 Gy (200 cGy x 6 fractions) for patients with positive surgical margins only.

Primary Outcome Measure Information:

Title

Maximum tolerated dose (MTD) of sorafenib tosylate when combined with chemoradiotherapy

Description

Time Frame

The first 8 weeks of therapy, but dose limiting toxicity (DLTs) will be monitored throughout the entire 22 week treatment

Title

Safety

Description

Time Frame

As necessary and at the discretion of the principal investigator

Secondary Outcome Measure Information:

Title

Time to local recurrence

Description

Defined as the duration of time from surgical resection of the primary tumor until local recurrence (amputated patients excluded).

Time Frame

From surgical resection of the primary tumor until local recurrence

Title

Distant disease-free survival

Description

Defined as the duration of time from registration until development of distant metastatic disease or death, whichever occurs first. Subjects with stage IV disease will be censored from this analysis.

Time Frame

Registration until development of distant metastatic disease or death, whichever occurs first.

Title

Progression-free survival

Description

Defined as the duration of time from registration to progressive disease (per RECIST), local recurrence, distant metastatic disease (exclusive of stage IV subjects), or death, whichever occurs first.

Time Frame

Registration to progressive disease (per RECIST)

Title

Overall survival

Description

Defined as the interval of time from registration until death from any cause.

Time Frame

Registration until death from any cause.

Title

Histologic necrosis rate of ≥ 95%

Time Frame

Examined for pathologic response at the time of surgery.

Title

Levels of tumorigenic and angiogenic markers, including p-ERK, VEGF, sVEGFR-2, bFGF, in plasma and tumor tissue samples as measured by ELISA

Time Frame

Baseline, during, and after treatment with sorafenib plus chemoradiotherapy

Title

Expression of tumor proliferation and angiogenic factors, including p-ERK, VEGFR2 and PDGFR, in tumor tissue samples as measured by IHC

Time Frame

baseline, week 2 (after sorafenib run-in), and then every 3 weeks through completion of treatment.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

15 Years

Maximum Age & Unit of Time

120 Years

Accepts Healthy Volunteers

Eligibility Criteria

DISEASE CHARACTERISTICS: Histologically confirmed soft tissue sarcoma of the upper (including shoulder) or lower (including hip) extremities or body wall Stage II or III disease, as defined by the following: Tumor dimension > 5 cm Superficial or deep tumor Intermediate or high-grade disease No regional lymph node involvement No distant metastases No rhabdomyosarcoma, Ewing sarcoma, primitive neuroectodermal tumor (PNET), osteosarcoma, or gastrointestinal stromal tumor Pleomorphic rhabdomyosarcoma allowed No known metastases Patients with neurological symptoms must undergo a CT scan or MRI of the brain to exclude brain metastases PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Absolute Neutrophil Count (ANC) ≥ 1,500/μL Hemoglobin ≥ 9.0 g/dL Platelet count ≥ 100,000/μL International Normalized Ratio (INR) < 1.5 or Prothrombin Time/Partial Thromboplastin Time (PT/PTT) normal Creatinine ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 mg/dL Aspartate Aminotransferase/Alanine Aminotransferase (AST/ALT) ≤ 1.5 times ULN Left Ventricular Ejection Fraction (LVEF) ≥ 50% Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception (male patients must use effective contraception for ≥ 3 months after completion of study treatment) No contraindications to limb-sparing surgery No severe peripheral vascular disease No concurrent uncontrolled illness including, but not limited to, the following: Ongoing or active serious infection > Common Toxicity Criteria for Adverse Effects (CTCAE) grade 2 Symptomatic congestive heart failure Unstable angina pectoris (i.e., angina symptoms at rest) or new onset angina within the past 3 months Myocardial infarction within the past 6 months Cardiac ventricular arrhythmia requiring anti-arrhythmic therapy Psychiatric illness/social situation that would limit compliance with study requirements No uncontrolled hypertension (defined as systolic blood pressure > 150 mm Hg or diastolic blood pressure > 90 mm Hg, despite optimal medical management) No known HIV infection or chronic hepatitis B or C infection No thrombolic or embolic events (e.g., cerebrovascular accident, including transient ischemic attacks) within the past 6 months No pulmonary hemorrhage or bleeding event ≥ CTCAE grade 2 within the past 4 weeks No other hemorrhage or bleeding event ≥ CTCAE grade 3 within the past 4 weeks No serious non-healing wound, ulcer, or bone fracture No evidence or history of bleeding diathesis or coagulopathy No significant traumatic injury within the past 4 weeks No known or suspected allergy to sorafenib tosylate or any agent given in the study No condition that would impair the ability to swallow whole pills No malabsorption problem No "currently active" second malignancy other than non-melanoma skin cancer Not considered to have a "currently active" malignancy if patient completed therapy AND has a < 30% risk of relapse PRIOR CONCURRENT THERAPY: No prior chemotherapy, radiotherapy, or biotherapy More than 4 weeks since prior major surgery No concurrent St. John's wort or rifampin No other concurrent investigational or anticancer therapy Concurrent anticoagulation with warfarin or heparin allowed

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Christopher W. Ryan, MD

Organizational Affiliation

OHSU Knight Cancer Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

OHSU Knight Cancer Institute

City

Portland

State/Province

Oregon

ZIP/Postal Code

97239-3098

Country

United States

12. IPD Sharing Statement

Links:

URL

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869565/

Description

NCBI PubMed Central (PMC)

Learn more about this trial

Sorafenib, Epirubicin, Ifosfamide, and Radiation Therapy Followed By Surgery in Treating Patients With High-Risk Stage II or Stage III Soft Tissue Sarcoma

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