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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier:
NCT00822848
First received: January 14, 2009
Last updated: July 2, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Sarcoma
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
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by OHSU Knight Cancer Institute:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of sorafenib tosylate when combined with chemoradiotherapy [ Time Frame: The first 8 weeks of therapy, but dose limiting toxicity (DLTs) will be monitored throughout the entire 22 week treatment ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: As necessary and at the discretion of the principal investigator ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: From surgical resection of the primary tumor until local recurrence ] [ Designated as safety issue: No ]
    Defined as the duration of time from surgical resection of the primary tumor until local recurrence (amputated patients excluded).

  • Distant disease-free survival [ Time Frame: Registration until development of distant metastatic disease or death, whichever occurs first. ] [ Designated as safety issue: No ]
    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 [ Time Frame: Registration to progressive disease (per RECIST) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Registration until death from any cause. ] [ Designated as safety issue: No ]
    Defined as the interval of time from registration until death from any cause.

  • Histologic necrosis rate of ≥ 95% [ Time Frame: Examined for pathologic response at the time of surgery. ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]

Estimated Enrollment: 18
Study Start Date: February 2009
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sorafenib, Epirubicin, Ifosfamide 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.
Other: immunoenzyme technique Other: immunohistochemistry staining method Other: laboratory biomarker analysis Procedure: adjuvant therapy
Preoperative administration has been the preference at our institution.
Other Names:
  • Adjuvant radiotherapy
  • Adjuvant chemotherapy
Procedure: neoadjuvant therapy
Other Name: Neoadjuvant chemoradiotherapy
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.

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.

  Eligibility

Ages Eligible for Study:   15 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00822848

Locations
United States, Oregon
OHSU Knight Cancer Institute
Portland, Oregon, United States, 97239-3098
Sponsors and Collaborators
OHSU Knight Cancer Institute
Investigators
Principal Investigator: Christopher W. Ryan, MD OHSU Knight Cancer Institute
  More Information

Additional Information:
No publications provided

Responsible Party: OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT00822848     History of Changes
Other Study ID Numbers: CDR0000631580, P30CA069533, OHSU-4653, 4653, OHSU-SOL-08080-L, BAYER-OHSU-4653
Study First Received: January 14, 2009
Last Updated: July 2, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by OHSU Knight Cancer Institute:
stage II adult soft tissue sarcoma
stage III adult soft tissue sarcoma

Additional relevant MeSH terms:
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Epirubicin
Isophosphamide mustard
Sorafenib
Ifosfamide
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 28, 2014