Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients With Soft Tissue Sarcoma of the Extremity and Body Wall

NCT00864032 | Completed Phase 1 Results DMC

• 1 other identifier: STS Sorafenib
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Soft Tissue Sarcoma

Keywords

Soft tissue sarcoma of the extremity and body wall

Outcome Measures

Primary Outcomes (1)

• 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.

  Approximately 12 weeks

Study Arms (1)

Phase I

EXPERIMENTAL

Drug: Sorafenib

Interventions

Sorafenib DRUG

400mg twice daily

Also known as: Nexavar

Phase I

Eligibility Criteria

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

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• University of California, Davis: lead
• Bayer: collaborator

Study Sites (1)

University of california, Davis Medical Center

Sacramento, California, 95817, United States

Location

Related Publications (1)

• 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.

  PMID: 24554062 DERIVED

MeSH Terms

Conditions

Sarcoma

Interventions

Sorafenib

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Dr. Robert J. Canter
• Organization: University of California Davis Comprehensive Cancer Center

robert.canter@ucdmc.ucdavis.edu

916-734-5907

Study Officials

• Robert Canter, MD

  U C Davis Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: March 17, 2009
• First Posted: March 18, 2009
• Study Start: March 1, 2009
• Primary Completion: August 1, 2011
• Study Completion: August 1, 2011
• Last Updated: April 10, 2013
• Results First Posted: April 10, 2013

Record last verified: 2013-04

Locations

US (1)