This study is being done to determine the overall progression-free survival (PFS) in
patients with advanced or metastatic (Stage IIIB - pleural effusion/IV), non-squamous
histology NSCLC treated with metronomic chemotherapy plus Avastin. Also, currently there are
no defined markers that predict for clinical benefit to Avastin. Preliminary studies show
that there are several observations that support the concept of metronomic chemotherapy with
or without the combination of an anti-angiogenic agent. The metronomic chemotherapy with
Avastin was shown to enhance the clinical endpoints of the study (response rate and
progressive-free survival). Proof of metronomic scheduling requires the development of
appropriate intermediate surrogate markers. Several markers will be assessed.
This is a non-randomized, open-label, pilot Phase II study of metronomic chemotherapy plus
Avastin in chemo naïve subjects with advanced non-squamous, non-small cell carcinoma of the
lung. The primary endpoint of this study is to assess the overall progression-free survival.
Subjects will be treated with metronomic chemotherapy with paclitaxel and gemcitabine weekly
for 3 out of 4 weeks, and Avastin will be administered every 2 weeks. Treatment with
metronomic chemotherapy will be expressed as a 4-week cycle. Tumor response to treatment
will be evaluated every 8 weeks.
Treatment with metronomic chemotherapy and Avastin will continue for a total of 6 cycles
unless there is evidence of disease progression, intolerable toxicity, or withdrawal of
consent. Maintenance therapy with Avastin will then continue until disease progression,
intolerable toxicity or withdrawal of consent.
Potential biologic parameters to monitor anti-tumor activity of metronomic chemotherapy will
be evaluated in 10 subjects. These biomarkers include: sequential determination of blood
levels of VEGF, VEGFR2, thrombospondin-1, E-selectin, ICAM-1, and circulating endothelial
cells and endothelial precursor cells.
Inclusion Neutrophil Count greater than or equal to 1500/μL
- Platelet Count greater than or equal to 100,000/μL
- Hemoglobin greater than or equal to 9.0g/dL
- Total Bilirubin ≤ 1.5mg/dL
- Transaminases ≤ 2.5 x ULN
- Serum Creatinine ≤ 1.5 x ULN
- Proteinuria: Urine protein: creatinine (UPC) ratio < 1.0 at screening OR Urine
dipstick for proteinuria < 2+ (patients discovered to have ≥2+ proteinuria on
dipstick urinalysis at baseline should undergo a 24 hour urine collection and must
demonstrate ≤ 1g of protein in 24 hours to be eligible).
INR ≤ 1.5 and a PTT no greater than the ULN
- Subjects must be 19 years or older.
- Subjects with a history of hypertension must be well-controlled (< 150/100) on a
stable regimen of anti-hypertensive therapy.
- Subjects must not have serious non-healing wound ulcer, or bone fracture, or major
surgical procedure within 28 days prior to starting treatment.
- Subjects must not have radiation therapy within 3 weeks prior to initiation of
- Female subjects must be postmenopausal, surgically sterile, or using effective
contraception. All females of childbearing potential must have a negative serum
pregnancy test within 7 days prior to the initiation of treatment.
- Informed consent must be obtained in writing prior to the initiation of treatment.
- Inability to comply with study and/or follow-up procedures
- Life expectancy of less than 12 weeks
- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than a Genentech-sponsored Avastin
- Active malignancy, other than superficial basal cell and superficial squamous (skin)
cell, or carcinoma in situ of the cervix within last five years
- Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
and/or diastolic blood pressure > 100 mmHg)
- Prior history of hypertensive crisis or hypertensive encephalopathy
- New York Heart Association (NYHA) Grade II or greater congestive heart failure
- History of myocardial infarction or unstable angina within 6 months prior to Day 1
- History of stroke or transient ischemic attack within 6 months prior to Day 1
- Known CNS disease, except for treated brain metastasis Treated brain metastases are
defined as having no evidence of progression or hemorrhage after treatment and no
ongoing requirement for dexamethasone, as ascertained by clinical examination and
brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose)
are allowed. Treatment for brain metastases may include whole brain radiotherapy
(WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as
deemed appropriate by the treating physician. Patients with CNS metastases treated by
neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will
- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1
- History of hemoptysis (greater than or equal to 1/2 teaspoon of bright red blood per
episode) within 1 month prior to Day 1
- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1 or anticipation of need for major surgical procedure during the course
of the study
- Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to Day 1
- History of abdominal fistula or gastrointestinal perforation within 6 months prior to
- Serious, non-healing wound, active ulcer, or untreated bone fracture
- Proteinuria as demonstrated by a UPC ratio greater than or equal to 1.0 at screening
- Known hypersensitivity Criteria:
- Pathological-proven NSCLC except squamous cell carcinoma as the predominant
- Advanced NSCLC: Stage IIIB with pleural effusion or Stage IV or recurrent disease.
- Measurable or non-measurable disease as defined by solid tumor response criteria
- ECOG Performance Status 0 to 1.
- No prior systemic chemotherapy or biologic therapy.
- Required laboratories (obtained ≤ 1 week prior to the initiation of treatment)
- Absolutely any component of Avastin
- Pregnancy (positive pregnancy test) or lactation. Use of effective means of
contraception (men and women) in patients of child-bearing potential
- Intrathoracic lung carcinoma of squamous cell histology Mixed tumors will be
categorized by the predominant cell type unless small cell elements are present, in
which case the patient is ineligible; sputum cytology alone is acceptable. Patients
with extrathoracic-only squamous cell NSCLC are eligible. Patients with only
peripheral lung lesions (of any NSCLC histology) will also be eligible (a peripheral
lesion is defined as a lesion in which the epicenter of the tumor is less than or
equal to 2 cm from the costal or diaphragmatic pleura in a three-dimensional
orientation based on each lobe of the lung and is greater than 2 cm from the trachea,
main, and lobar bronchi).