Expired Study
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Birmingham, Alabama


Purpose:

To assess the 2-month progression-free survival in patients with advanced or metastatic, non-squamous cell lung cancer treated with weekly low dose docetaxel in combination with a b0006) is a potent oral multi kinase inhibitor of RAF1, a member of the RAF/MEK/ERK pathway in addition to inhibiting various kinases involved in neovascularization including VEGFR-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3 and c-KIT (35). These activities have been demonstrated in cancer cell lines and in human xenograft models of breast, colon and non small cell lung cancer. Its activity is attributable to combined effects of inhibition of the Raf/MEK/ERK/Ras pathway and kinases involved in angiogenesis like VEGF and PGDF. Sorafenib has been recently approved for use in metastatic renal cell carcinoma (RCC) and is actively being investigated for efficacy in other solid tumors including NSCLC.A phase II single agent sorafenib trial in patients with relapsed NSCLC showed that sorafenib was well tolerated at doses of 400 mg po bid continuously on 28 day cycle (36). Of the 5 evaluable patients, there was 1 partial response (PR) (remained in PR at week 28), 1 unconfirmed PR (at week 3), 2 stable disease (16 and 19 weeks, respectively) and 1 progressive disease after 8 weeks of treatment. A reappraisal of the best ways of administering chemotherapy is needed. Instead of using short bursts of toxic chemotherapy interspersed with long breaks, there is now a shift in thinking towards using more compressed or accelerated schedules of drug administration with smaller individual doses to reduce toxicities and perhaps improve antitumor effect.


Study summary:

The median survival of untreated advanced stage NSCLC is 5-6 months (2,3). Patients with poor performance status due to malignancy or co-morbidities have a poorer survival. This group of patients is underrepresented in clinical trials and may not receive chemotherapy due to fear of increased toxicities with systemic chemotherapy. The overall median survival of patients with advanced NSCLC treated with first-line platinum-based doublets is less than 12 months (8 10 months) with a 1-year and 2-year survival rate of 33% and 11%, respectively (4 6). No chemotherapy regimen has a significant advantage over the others in the treatment of advanced NSCLC. Agents targeting epidermal growth factor receptor, matrix metalloproteinase, farnesyl transferase, protein kinase C and retinoic X receptor have so far shown no survival benefit in combination with chemotherapy in advanced NSCLC (7-13). Docetaxel has activity in NSCLC in both first line and second line settings. In poor performance status patients or elderly patients, single agent chemotherapy is recommended. Weekly docetaxel administration is well tolerated and has lesser incidence of hematologic toxicity with no difference in overall survival when compared to patients receiving higher doses (75 mg/m2) q 3 weeks (14-18). There is an increased need for better strategies to improve survival as well as reduce regimen related toxicity for this large group of patients. The use of targeted therapy as well as low dose-protracted chemotherapy (metronomic chemotherapy) needs evaluation as such therapies have a better toxicity profile. Sorafenib (BAY 49-bursts of toxic MTD chemotherapy interspersed with long breaks, there is now a shift in thinking towards the view that more compressed or accelerated schedules of drug administration using much smaller individual doses than the MTD would be more effective; not only in terms of reducing certain toxicities, but perhaps even in improving antitumor effect as well. Moreover, some of these dosing/scheduling strategies are ideally suited to combining chemotherapeutic agents with many of the new targeted biologic drugs. The most recent refinement of this concept is called "metronomic" chemotherapy, which refers to the frequent administration of cytotoxic chemotherapeutic agents at doses significantly below the MTD, with no prolonged drug-free breaks.


Criteria:

Inclusion Criteria: - Pathologic-proven non-squamous cell-NSCLC - Advanced non-squamous-NSCLC: Stage IIIB with pleural effusion or stage IV, or recurrent disease - ECOG Performance Status 2: In bed less than 50% of the time, unable to work, but able to care for self - Measurable or non-measurable disease as defined by solid tumor response criteria (RECIST) - No prior systemic chemotherapy or biologic therapy - Age greater than or equal to 19 years old (Note: State of Alabama requirement) - Adequate bone marrow and renal function as assessed by the following: - Hemoglobin greater than or equal to 9.0 g/dL - Absolute neutrophil count (ANC)greater than or equal to 1500/mm3 - Platelet count greater than or equal to 100,000/mm3 - Creatinine less than or equal to 1.5 times ULN - Hepatic function requirements - Total bilirubin less than or equal to ULN - AST and ALT and alkaline phosphatase must be within the range allowing for eligibility. In determining eligibility the more abnormal of the two values (AST and ALT) should be used - Women of childbearing potential must have a negative serum pregnancy test performed within 72 hours prior to the start of treatment. 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 less than or equal to 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. Exclusion Criteria: - Predominant squamous cell histology will be excluded - Cardiac disease: Congestive heart failure greater than class II NYHA. Patents 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. - Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis. - Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. - Uncontrolled hypertension defined as systolic blood pressure >150 mmHg or diastolic pressure greater than 90 mmHg, despite optimal medical management. - Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. - Active clinically serious infection greater than CTCAE Grade 2. - Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months. - History of significant hemoptysis (defined as bright red blood of a ½ teaspoon or more). Patients with blood-tinged or blood-streaked sputum will be permitted on study if the hemoptysis amount to less than 5 mL of blood per episode and less than 10 mL of blood per 24 hour period. - Any other hemorrhage/bleeding event greater than or equal to CTCAE Grade 3 within 4 weeks of first dose of study drug. - Serious non-healing wound, ulcer or bone fracture. - Evidence or history of bleeding diathesis or coagulopathy. - Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug. - Use of St. John's Wort or rifampin (rifampicin). - Known or suspected allergy to sorafenib or any agent given in the course of this trial. - Any condition that impairs patient's ability to swallow whole pills. - Any malabsorption problem. - History of severe hypersensitivity reaction to any drugs formulated with polysorbate 80. - Women who are breast-feeding.


NCT ID:

NCT00801801


Primary Contact:

Principal Investigator
Francisco Robert, M.D.
University of Alabama at Birmingham


Backup Contact:

N/A


Location Contact:

Birmingham, Alabama
United States



There is no listed contact information for this specific location.

Site Status: N/A


Data Source: ClinicalTrials.gov

Date Processed: October 09, 2019

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