Soft Tissue SarcomaPhase 1/2NCT00864032
Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients With Soft Tissue Sarcoma of the Extremity and Body Wall
A Phase 1/2 study testing Sorafenib in people with Soft Tissue Sarcoma, run by University of California, Davis at 1 site in United States.
Trial summary
Patients will receive neoadjuvant sorafenib (investigational agent) in combination with preoperative external beam conformal radiotherapy (50 Gy in 25 fractions) for localized, large soft tissue sarcomas of the extremity and body wall prior to resection with curative intent. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Soft Tissue Sarcoma
- What is being tested?
- Sorafenib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2009to Aug 2011
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed soft-tissue sarcoma located on the extremity or body wall.
- Intermediate or High grade (NCI grade 2 or 3/3-tier system), > 5 cm in maximal dimension.
- Low grade (NCI grade 1/3-tier system), > 8 cm in maximal dimension.
- No evidence of regional or distant metastatic disease.
- Patient must be 18 years of age or older.
- Patient must have an ECOG performance status of ≤ 2.
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- Patient must have a histologic diagnosis of soft tissue sarcoma.
- Patient must have adequate bone marrow, liver, and renal function as assessed by the following:
- Hemoglobin ≥ 9.0 g/dl
- Absolute neutrophil count (ANC) ≥ 1,500/mm3
- Platelets ≥ 100,000/mm3.
- Total bilirubin ≤ 1.5 mg/dL. NOTE: Patients with elevated bilirubin secondary to Gilbert's syndrome are eligible to participate in the study.
- AST and ALT ≤ 2.5 times the institution upper limit of normal (ULN).
- Creatinine ≤ 1.5 times ULN.
- Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to the start of treatment . NOTE: Postmenopausal women must be amenorrheic for at least 12 months to be deemed not of reproductive potential.
- Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib.
- Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
- INR < 1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.
Who cannot join
- Patient is receiving additional cancer-directed therapy at time of entry into trial.
- Patient has received or is receiving preoperative investigational treatment.
- Patient has congestive heart failure > class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
- Patient has history of cardiac ventricular arrhythmia requiring ongoing anti-arrhythmic therapy.
- Patient has uncontrolled hypertension, defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
- Patient has known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
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- Patient has active clinically serious infection > CTCAE Grade 2.
- Patient has thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
- Patient has history of pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug.
- Patient has history of any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug.
- Patient has history of clinical or laboratory evidence of bleeding diathesis or coagulopathy.
- Patient has history of major surgery or significant traumatic injury within 4 weeks of first study drug.
- Patient has concomitant use of St. John's Wort or rifampin (rifampicin).
- Patient has known or suspected allergy to sorafenib or any agent given in the course of this trial.
- Patient has any condition that impairs his or her ability to swallow whole pills.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of california, Davis Medical Center
Sacramento, California, 95817
About this study
Official title: Phase I/II Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients With Soft Tissue Sarcoma of the Extremity and Body Wall
Patients will receive neoadjuvant sorafenib (investigational agent) in combination with preoperative external beam conformal radiotherapy (50 Gy in 25 fractions) for localized, large soft tissue sarcomas of the extremity and body wall prior to resection with curative intent. Sorafenib is an FDA-approved targeted agent for patients with renal cell carcinoma and hepatocellular carcinoma. Preliminary data suggest activity for sorafenib against soft tissue sarcoma in the metastatic setting. Limited data are available regarding the safety and efficacy of sorafenib in combination with radiotherapy.
The Phase I portion of the trial will seek to establish the safety of sorafenib and radiotherapy in the neoadjuvant setting for soft tissue sarcomas of the extremity and body wall. The Phase II portion of the trial will aim to determine the pathologic near-complete/complete response rate (≥ 95% tumor necrosis) of this multimodality therapy. Molecular and dynamic contrast-enhanced MRI studies will seek to establish correlative biological and imaging markers of response and/or resistance to this therapy.
Read the detailed description
Patients will receive neoadjuvant sorafenib (investigational agent) in combination with preoperative external beam conformal radiotherapy (50 Gy in 25 fractions) for localized, large soft tissue sarcomas of the extremity and body wall prior to resection with curative intent. Sorafenib is an FDA-approved targeted agent for patients with renal cell carcinoma and hepatocellular carcinoma. Preliminary data suggest activity for sorafenib against soft tissue sarcoma in the metastatic setting. Limited data are available regarding the safety and efficacy of sorafenib in combination with radiotherapy.
The Phase I portion of the trial will seek to establish the safety of sorafenib and radiotherapy in the neoadjuvant setting for soft tissue sarcomas of the extremity and body wall. The Phase II portion of the trial will aim to determine the pathologic near-complete/complete response rate (≥ 95% tumor necrosis) of this multimodality therapy. Molecular and dynamic contrast-enhanced MRI studies will seek to establish correlative biological and imaging markers of response and/or resistance to this therapy.
Significant challenges exist in the treatment of patients with soft tissue sarcoma (STS) of the extremity and body wall. Major therapeutic goals for all patients include local disease-control, maximization of limb function, and avoidance of therapeutic morbidity. The standard approach for patients with STS has been based on radical resection with wide margins in combination with external beam radiation. Although local control rates in this setting range from 85 to 90%, patients remain at risk for substantial morbidity from this multimodality therapy. Furthermore, despite effective local therapy with surgery and radiation, approximately 50% of patients with high grade STS will die of disease within 5 years of diagnosis.
Experimental data and experience from other solid tumors suggest a significant synergistic effect when anti-angiogenic targeted therapies, such as sorafenib, are combined with radiotherapy (RT). Overproduction of angiogenic factors in the tumor vasculature leads to disordered/poorly regulated tumor perfusion which appears to normalize following delivery of anti-angiogenic agents. This, in turn, allows improved delivery of and susceptibility to cytotoxic agents, which is particularly important with RT since hypoxia is a key mechanism of resistance to this modality. Preliminary clinical data in rectal cancer and malignant brain tumors have demonstrated promising results from the combination of anti-angiogenic agents and RT with respect to downstaging of the primary tumor, local tumor control, and improved progression-free survival. Angiogenic factors are upregulated in patients with STS, and anti-angiogenic agents demonstrate activity against STS in the metastatic setting.
Consequently, we propose to evaluate preoperative combined modality sorafenib and conformal RT in patients with STS of the extremity and body wall in a prospective Phase I/II clinical trial. Key endpoints will be safety and toxicity in the Phase I trial and pathological response in the Phase II trial. Additional endpoints will include molecular and functional imaging correlative studies of biomarkers of response and resistance to treatment.
We hypothesize that this combination will be safe and will increase pathologic necrosis within the primary tumor at the time of surgical resection, translating into reduced volume of resected tissue, improved local disease-control, and ultimately improved disease-free survival. Functional imaging studies (dynamic contrast-enhanced MRI) and molecular examination of pre- and post-treatment tumor tissue and serum will allow correlation of changes in tumor blood flow, hypoxia transcription factors, phosphorylated ERK, and angiogenic markers to the degree of tumor necrosis following treatment with preoperative sorafenib and radiotherapy.
- Conditions
- Soft Tissue Sarcoma
- Being tested
- Sorafenib
- Keywords
- Soft tissue sarcoma of the extremity and body wall
- Medical subject headings
- Sarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SorafenibDrug
Also called Nexavar
400mg twice daily
| Study group | Role | What they receive |
|---|---|---|
| Phase I | Experimental | Not described Receives: Drug: Sorafenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Dose Limiting Toxicities
Number of dose limiting toxicities and number with adverse events.
Dose-escalation schedule comprising 6 to 12 patients (see schema). This sample size is based on a traditional 3+3 cohort design with escalating doses of sorafenib in combination with 50 Gy of conformal radiotherapy delivered in 25 fractions (200 cGy per fraction). Based on preclinical data regarding the radiobiology of sorafenib,33, 36 sorafenib will be initiated at a dose of 200 mg twice daily, followed by 200 mg Q AM/400 mg Q PM for the 2nd cohort, followed by 400 mg bid for the 3rd cohort. Since 400 mg bid is the well established MTD for sorafenib monotherapy in patients with renal cell carcinoma and hepatocellular carcinoma, the dose will not be escalated above this level even if DLT is not observed. Dose level escalation will be determined based on DLTs observed from initiation of sorafenib/RT until time of surgery.
Measured: Approximately 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Mar 2009 (estimated)
- Study startMar 2009
- Primary completionAug 2011
- Study completionAug 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Soft Tissue SarcomaStudies of the same condition, open and under way.
- More trials run by University of California, DavisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, Davis
- Sponsor type
- University, hospital or other
- Collaborators
- Bayer
- Responsible party
- Principal investigator, Robert J. Canter, MD, University of California, Davis
- Investigators
- Robert Canter, MD, Principal investigator, U C Davis Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00864032
- Sponsor's protocol ID
- STS Sorafenib
- Status last verified
- Apr 2013
- First submitted
- 17 Mar 2009
- Last updated
- 10 Apr 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Canter RJ, Borys D, Olusanya A, Li CS, Lee LY, Boutin RD, Christensen SD, Tamurian RM, Monjazeb AM. Phase I trial of neoadjuvant conformal radiotherapy plus sorafenib for patients with locally advanced soft tissue sarcoma of the extremity. Ann Surg Oncol. 2014 May;21(5):1616-23. doi: 10.1245/s10434-014-3543-7. Epub 2014 Feb 20.
PubMed 24554062
Study at a glance
From the registry record, last updated by the sponsor on 10 Apr 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients With Soft Tissue Sarcoma of the Extremity and Body Wall
- ClinicalTrials.gov ID
- NCT00864032
- Acronym / sponsor ID
- STS Sorafenib
- Conditions
- Soft Tissue Sarcoma
- Keywords
- Soft tissue sarcoma of the extremity and body wall
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- University of California, DavisUniversity, hospital or other
- Collaborators
- Bayer
- Study start
- Mar 2009
- Primary completion
- Aug 2011 (actual)
- Study completion
- Aug 2011 (actual)
- First posted
- 18 Mar 2009 (estimated)
- Results
- Posted 10 Apr 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Patients will receive neoadjuvant sorafenib (investigational agent) in combination with preoperative external beam conformal radiotherapy (50 Gy in 25 fractions) for localized, large soft tissue sarcomas of the extremity and body wall prior to resection with curative intent. Sorafenib is an FDA-approved targeted agent for patients with renal cell carcinoma and hepatocellular carcinoma. Preliminary data suggest activity for sorafenib against soft tissue sarcoma in the metastatic setting. Limited data are available regarding the safety and efficacy of sorafenib in combination with radiotherapy.
The Phase I portion of the trial will seek to establish the safety of sorafenib and radiotherapy in the neoadjuvant setting for soft tissue sarcomas of the extremity and body wall. The Phase II portion of the trial will aim to determine the pathologic near-complete/complete response rate (≥ 95% tumor necrosis) of this multimodality therapy. Molecular and dynamic contrast-enhanced MRI studies will seek to establish correlative biological and imaging markers of response and/or resistance to this therapy.
Detailed description
Patients will receive neoadjuvant sorafenib (investigational agent) in combination with preoperative external beam conformal radiotherapy (50 Gy in 25 fractions) for localized, large soft tissue sarcomas of the extremity and body wall prior to resection with curative intent. Sorafenib is an FDA-approved targeted agent for patients with renal cell carcinoma and hepatocellular carcinoma. Preliminary data suggest activity for sorafenib against soft tissue sarcoma in the metastatic setting. Limited data are available regarding the safety and efficacy of sorafenib in combination with radiotherapy.
The Phase I portion of the trial will seek to establish the safety of sorafenib and radiotherapy in the neoadjuvant setting for soft tissue sarcomas of the extremity and body wall. The Phase II portion of the trial will aim to determine the pathologic near-complete/complete response rate (≥ 95% tumor necrosis) of this multimodality therapy. Molecular and dynamic contrast-enhanced MRI studies will seek to establish correlative biological and imaging markers of response and/or resistance to this therapy.
Significant challenges exist in the treatment of patients with soft tissue sarcoma (STS) of the extremity and body wall. Major therapeutic goals for all patients include local disease-control, maximization of limb function, and avoidance of therapeutic morbidity. The standard approach for patients with STS has been based on radical resection with wide margins in combination with external beam radiation. Although local control rates in this setting range from 85 to 90%, patients remain at risk for substantial morbidity from this multimodality therapy. Furthermore, despite effective local therapy with surgery and radiation, approximately 50% of patients with high grade STS will die of disease within 5 years of diagnosis.
Experimental data and experience from other solid tumors suggest a significant synergistic effect when anti-angiogenic targeted therapies, such as sorafenib, are combined with radiotherapy (RT). Overproduction of angiogenic factors in the tumor vasculature leads to disordered/poorly regulated tumor perfusion which appears to normalize following delivery of anti-angiogenic agents. This, in turn, allows improved delivery of and susceptibility to cytotoxic agents, which is particularly important with RT since hypoxia is a key mechanism of resistance to this modality. Preliminary clinical data in rectal cancer and malignant brain tumors have demonstrated promising results from the combination of anti-angiogenic agents and RT with respect to downstaging of the primary tumor, local tumor control, and improved progression-free survival. Angiogenic factors are upregulated in patients with STS, and anti-angiogenic agents demonstrate activity against STS in the metastatic setting.
Consequently, we propose to evaluate preoperative combined modality sorafenib and conformal RT in patients with STS of the extremity and body wall in a prospective Phase I/II clinical trial. Key endpoints will be safety and toxicity in the Phase I trial and pathological response in the Phase II trial. Additional endpoints will include molecular and functional imaging correlative studies of biomarkers of response and resistance to treatment.
We hypothesize that this combination will be safe and will increase pathologic necrosis within the primary tumor at the time of surgical resection, translating into reduced volume of resected tissue, improved local disease-control, and ultimately improved disease-free survival. Functional imaging studies (dynamic contrast-enhanced MRI) and molecular examination of pre- and post-treatment tumor tissue and serum will allow correlation of changes in tumor blood flow, hypoxia transcription factors, phosphorylated ERK, and angiogenic markers to the degree of tumor necrosis following treatment with preoperative sorafenib and radiotherapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Phase I | Experimental | Drug: Sorafenib |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- Histologically confirmed soft-tissue sarcoma located on the extremity or body wall.
- Patient must have adequate bone marrow, liver, and renal function as assessed by the following:
- Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to the start of treatment . NOTE: Postmenopausal women must be amenorrheic for at least 12 months to be deemed not of reproductive potential.
- Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib.
- Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
Key exclusion criteria (15 listed)
- Patient is receiving additional cancer-directed therapy at time of entry into trial.
- Patient has received or is receiving preoperative investigational treatment.
- Patient has congestive heart failure > class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
- Patient has history of cardiac ventricular arrhythmia requiring ongoing anti-arrhythmic therapy.
- Patient has uncontrolled hypertension, defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SorafenibAlso: Nexavar400mg twice daily | Drug | Phase I |
Primary outcome
Number of Dose Limiting Toxicities
Time frame: Approximately 12 weeks
Number of dose limiting toxicities and number with adverse events. Dose-escalation schedule comprising 6 to 12 patients (see schema). This sample size is based on a traditional 3+3 cohort design with escalating doses of sorafenib in combination with 50 Gy of conformal radiotherapy delivered in 25 fractions (200 cGy per fraction). Based on preclinical data regarding the radiobiology of sorafenib,33, 36 sorafenib will be initiated at a dose of 200 mg twice daily, followed by 200 mg Q AM/400 mg Q PM for the 2nd cohort, followed by 400 mg bid for the 3rd cohort. Since 400 mg bid is the well established MTD for sorafenib monotherapy in patients with renal cell carcinoma and hepatocellular carcinoma, the dose will not be escalated above this level even if DLT is not observed. Dose level escalation will be determined based on DLTs observed from initiation of sorafenib/RT until time of surgery.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Apr 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 24554062Canter RJ, Borys D, Olusanya A, Li CS, Lee LY, Boutin RD, Christensen SD, Tamurian RM, Monjazeb AM. Phase I trial of neoadjuvant conformal radiotherapy plus sorafenib for patients with locally advanced soft tissue sarcoma of the extremity. Ann Surg Oncol. 2014 May;21(5):1616-23. doi: 10.1245/s10434-014-3543-7. Epub 2014 Feb 20.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert Canter, MD principal investigator
U C Davis Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Sorafenib in people with Soft Tissue Sarcoma, run by University of California, Davis 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?
The sponsor lists 18 inclusion and 15 exclusion criteria. 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 10 Apr 2013. 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 combined 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.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Apr 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Number of Dose Limiting Toxicities (time frame: Approximately 12 weeks). 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 NCT00864032, which also lists 1 linked publication.
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 10 Apr 2013.