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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

Phase 2
19 Years
Not Enrolling
Non Squamous Cell Lung Cancer, Non Small Cell Lung Cancer

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Trial Information

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

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 maximum tolerated dose (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.

Inclusion Criteria:

- Pathologic-proven non-squamous cell-NSCLC

- Advanced non-squamous-NSCLC: Stage IIIB with pleural effusion or stage IV, or
recurrent disease

- Eastern Cooperative Oncology Group (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

- 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 upper limit of normal (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.

- International normalized ratio (INR) less than or equal to 1.5 or a prothrombin
time/partial prothrombin time (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 New York Heart
Association (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 Common Terminology Criteria for
Adverse Events (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

- 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

- Women who are breast-feeding.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

2-month Progression-free Survival

Outcome Description:

Evaluation of the 2-month progression-free survival in poor performance status patients with non-squamous non-small cell lung cancer with the goal to improve 2-month progression free survival from 50% to 70%.

Outcome Time Frame:

2 months

Safety Issue:


Principal Investigator

Francisco Robert, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Alabama at Birmingham


United States: Institutional Review Board

Study ID:




Start Date:

January 2008

Completion Date:

March 2011

Related Keywords:

  • Non Squamous Cell Lung Cancer
  • Non Small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



University of Alabama at Birmingham Birmingham, Alabama  35294-3300