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

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

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.

Study Overview

• Status: Completed
• Conditions: Sarcoma
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: immunoenzyme technique; Procedure: neoadjuvant therapy; Other: immunohistochemistry staining method; Drug: epirubicin hydrochloride; Drug: ifosfamide; Drug: sorafenib tosylate; Procedure: adjuvant therapy; Procedure: therapeutic conventional surgery; Radiation: hypofractionated radiation therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • OHSU Knight Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 120 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Sorafenib, Epirubicin, Ifosfamide

Other: laboratory biomarker analysis; Other: immunoenzyme technique; Procedure: neoadjuvant therapy; Other Names: Neoadjuvant chemoradiotherapy; Other: immunohistochemistry staining method; Drug: epirubicin hydrochloride; I.V., days 1-3 of each cycle. Epirubicin to be omitted during cycle 2 (concomitant chemoradiation); Drug: ifosfamide; Over 90 minutes I.V., days 1-3 of each cycle. Administered with hydration and Mesna.; Drug: sorafenib tosylate; P.O. daily beginning 2 weeks before first chemotherapy cycle, held 1 week before and after surgery.; Procedure: adjuvant therapy; Preoperative administration has been the preference at our institution.; Other Names: Adjuvant radiotherapy; Adjuvant chemotherapy; Procedure: therapeutic conventional surgery; Surgery should be planned for 2-4 weeks after the initiation of chemotherapy for cycle 3.; Radiation: hypofractionated radiation therapy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	The first 8 weeks of therapy, but dose limiting toxicity (DLTs) will be monitored throughout the entire 22 week treatment
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).	As necessary and at the discretion of the principal investigator

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to local recurrence	Defined as the duration of time from surgical resection of the primary tumor until local recurrence (amputated patients excluded).	From surgical resection of the primary tumor until local recurrence
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.	Registration until development of distant metastatic disease or death, whichever occurs first.
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.	Registration to progressive disease (per RECIST)
Overall survival	Defined as the interval of time from registration until death from any cause.	Registration until death from any cause.
Histologic necrosis rate of ≥ 95%		Examined for pathologic response at the time of surgery.
Levels of tumorigenic and angiogenic markers, including p-ERK, VEGF, sVEGFR-2, bFGF, in plasma and tumor tissue samples as measured by ELISA		Baseline, during, and after treatment with sorafenib plus chemoradiotherapy
Expression of tumor proliferation and angiogenic factors, including p-ERK, VEGFR2 and PDGFR, in tumor tissue samples as measured by IHC		baseline, week 2 (after sorafenib run-in), and then every 3 weeks through completion of treatment.

Collaborators and Investigators

• Sponsor: OHSU Knight Cancer Institute
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NCBI PubMed Central (PMC)

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (ACTUAL): September 1, 2012
• Study Completion (ACTUAL): April 30, 2013

Study Registration Dates

• First Submitted: January 14, 2009
• First Submitted That Met QC Criteria: January 14, 2009
• First Posted (ESTIMATE): January 15, 2009

Study Record Updates

• Last Update Posted (ACTUAL): September 7, 2018
• Last Update Submitted That Met QC Criteria: September 5, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: stage III adult soft tissue sarcoma; stage II adult soft tissue sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Sorafenib; Epirubicin; Ifosfamide
• Other Study ID Numbers: IRB00004653; P30CA069533 (U.S. NIH Grant/Contract); OHSU-4653; 4653; OHSU-SOL-08080-L; BAYER-OHSU-4653; CDR0000631580 (OTHER: NCI PDQ); NCI-2011-03738 (REGISTRY: CTRP (Clinical Trial Reporting Program))