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SarcomaPhase 1NCT00822848

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

A Phase 1 study testing epirubicin hydrochloride, ifosfamide and sorafenib tosylate in people with Sarcoma, run by OHSU Knight Cancer Institute at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 15 to 120 years
Conditions the study is for
Sarcoma
What is being tested?
epirubicin hydrochloride, ifosfamide and sorafenib tosylate
Could I receive a placebo?
No, everyone receives an active treatment
How many people
18 participants
Where
1 siteUnited States
Study dates
Feb 2009to 30 Apr 2013
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 15 to 120 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • OHSU Knight Cancer Institute

    Portland, Oregon, 97239-3098

Other trials in United States

About this study

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

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.

Read the 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.

Conditions
Sarcoma
Being tested
epirubicin hydrochloride, ifosfamide, sorafenib tosylate, immunoenzyme technique, immunohistochemistry staining method
Keywords
stage II adult soft tissue sarcoma, stage III adult soft tissue sarcoma
Medical subject headings
Sarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • epirubicin hydrochlorideDrug

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

  • ifosfamideDrug

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

  • sorafenib tosylateDrug

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

  • immunoenzyme techniqueOther

  • immunohistochemistry staining methodOther

  • laboratory biomarker analysisOther

  • adjuvant therapyProcedure or surgery

    Also called Adjuvant radiotherapy, Adjuvant chemotherapy

    Preoperative administration has been the preference at our institution.

  • neoadjuvant therapyProcedure or surgery

    Also called Neoadjuvant chemoradiotherapy

  • therapeutic conventional surgeryProcedure or surgery

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

  • hypofractionated radiation therapyRadiation

    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.

Study groups in NCT00822848
Study groupRoleWhat they receive
Sorafenib, Epirubicin, IfosfamideExperimentalNot described
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

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

  2. 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).

    Measured: As necessary and at the discretion of the principal investigator

Secondary outcomes (7)

  1. Time to local recurrence

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

    Measured: From surgical resection of the primary tumor until local recurrence

  2. 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.

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

  3. 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.

    Measured: Registration to progressive disease (per RECIST)

  4. Overall survival

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

    Measured: Registration until death from any cause.

  5. Histologic necrosis rate of ≥ 95%

    Measured: Examined for pathologic response at the time of surgery.

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

    Measured: Baseline, during, and after treatment with sorafenib plus chemoradiotherapy

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

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Jan 2009 (estimated)
  2. Study startFeb 2009
  3. Primary completionSep 2012
  4. Study completion30 Apr 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
18 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00822848
Sponsor's protocol ID
IRB00004653
Other IDs
P30CA069533, OHSU-4653, 4653, OHSU-SOL-08080-L, BAYER-OHSU-4653, CDR0000631580, NCI-2011-03738
Status last verified
Sep 2018
First submitted
14 Jan 2009
Last updated
7 Sep 2018
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing epirubicin hydrochloride, ifosfamide and sorafenib tosylate in people with Sarcoma, run by OHSU Knight Cancer Institute at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00822848.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Sep 2018.

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