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

NCT00822848 | Completed Phase 1 DMC

• 8 other identifiers: IRB00004653P30CA069533OHSU-46534653OHSU-SOL-08080-LBAYER-OHSU-4653CDR0000631580NCI-2011-03738
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

Conditions

Sarcoma

Keywords

stage II adult soft tissue sarcoma; stage III adult soft tissue sarcoma

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• Time to local recurrence

  From surgical resection of the primary tumor until local recurrence

• Distant disease-free survival

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

• Progression-free survival

  Registration to progressive disease (per RECIST)

• Overall survival

  Registration until death from any cause.

• Histologic necrosis rate of ≥ 95%

  Examined for pathologic response at the time of surgery.

Study Arms (1)

Sorafenib, Epirubicin, Ifosfamide

EXPERIMENTAL

Drug: epirubicin hydrochloride; Drug: ifosfamide; Drug: sorafenib tosylate; Other: immunoenzyme technique; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Procedure: adjuvant therapy; Procedure: neoadjuvant therapy; Procedure: therapeutic conventional surgery; Radiation: hypofractionated radiation therapy

Interventions

epirubicin hydrochloride DRUG

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

Sorafenib, Epirubicin, Ifosfamide

ifosfamide DRUG

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

Sorafenib, Epirubicin, Ifosfamide

sorafenib tosylate DRUG

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

Sorafenib, Epirubicin, Ifosfamide

immunoenzyme technique OTHER

Sorafenib, Epirubicin, Ifosfamide

immunohistochemistry staining method OTHER

Sorafenib, Epirubicin, Ifosfamide

laboratory biomarker analysis OTHER

Sorafenib, Epirubicin, Ifosfamide

adjuvant therapy PROCEDURE

Preoperative administration has been the preference at our institution.

Also known as: Adjuvant radiotherapy, Adjuvant chemotherapy

Sorafenib, Epirubicin, Ifosfamide

neoadjuvant therapy PROCEDURE

Also known as: Neoadjuvant chemoradiotherapy

Sorafenib, Epirubicin, Ifosfamide

therapeutic conventional surgery PROCEDURE

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

Sorafenib, Epirubicin, Ifosfamide

hypofractionated radiation therapy RADIATION

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.

Sorafenib, Epirubicin, Ifosfamide

Eligibility Criteria

• Age: 15 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

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

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• OHSU Knight Cancer Institute: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

OHSU Knight Cancer Institute

Portland, Oregon, 97239-3098, United States

Location

Related Links

• NCBI PubMed Central (PMC)

MeSH Terms

Conditions

Sarcoma

Interventions

Epirubicin; Ifosfamide; Sorafenib; Immunoenzyme Techniques; Immunohistochemistry; Chemotherapy, Adjuvant; Radiotherapy, Adjuvant; Neoadjuvant Therapy

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Doxorubicin; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Cyclophosphamide; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenylurea Compounds; Urea; Amides; Benzene Derivatives; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Pyridines; Immunoassay; Immunologic Techniques; Investigative Techniques; Molecular Probe Techniques; Histocytochemistry; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Histological Techniques; Combined Modality Therapy; Therapeutics; Drug Therapy; Radiotherapy

Study Officials

• Christopher W. Ryan, MD

  OHSU Knight Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 14, 2009
• First Posted: January 15, 2009
• Study Start: February 1, 2009
• Primary Completion: September 1, 2012
• Study Completion: April 30, 2013
• Last Updated: September 7, 2018

Record last verified: 2018-09

Locations

US (1)