Study of Metronomic Chemotherapy With Taxotere (Docetaxel) Plus Nexavar (Sorafenib) as First-Line Therapy for Patients With Advanced Non-Squamous Cell Non-Small Cell Lung Cancer
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.
Non Squamous Cell Lung Cancer
Non Small Cell Lung Cancer
Drug: Taxotere and Nexavar
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Pilot Phase IIa Study of Metronomic Chemotherapy With Taxotere (Docetaxel) Plus Nexavar (Sorafenib) as First-Line Therapy in Performance Status-2 Patients With Advanced Non-Squamous Cell Non-Small Cell Lung Cancer|
- Evaluation of the 2-month progression-free survival and median performance status. [ Time Frame: 2 months ] [ Designated as safety issue: No ]
- Evaluation of the objective response rate. [ Time Frame: 2 months ] [ Designated as safety issue: No ]
|Study Start Date:||January 2008|
|Study Completion Date:||March 2011|
|Primary Completion Date:||October 2009 (Final data collection date for primary outcome measure)|
|Experimental: Metronomic Taxotere and Nexavar||
Drug: Taxotere and Nexavar
Subjects will be treated with metronomic chemotherapy with low dose docetaxel weekly for 3 out of 4 weeks, and sorafenib will be administered continuously 400 mg bid on a 28 day cycle. Treatment with metronomic chemotherapy will be expressed as a 4-week cycle. Tumor response to treatment will be evaluated after every 8 weeks. Treatment with metronomic chemotherapy and sorafenib will continue for a total of 6 cycles unless there is evidence of disease progression, intolerable toxicity, or withdrawal of consent. Maintenance therapy with sorafenib will then continue until disease progression, intolerable toxicity or withdrawal of consent.
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.
|United States, Alabama|
|University of Alabama at Birmingham|
|Birmingham, Alabama, United States, 35294 - 0104|
|Principal Investigator:||Francisco Robert, M.D.||University of Alabama at Birmingham|