Lower Dose Chemotherapy Given More Frequent With Avastin to Treat Advanced Non-Squamous Non-Small Cell Lung Cancer
Condition: Non-Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Paclitaxel; Gemcitabine; Avastin
Intervention description: Prior to receiving paclitaxel, all patients will receive the following premedications one hour before the infusion:
Dexamethasone 20mg, intravenously (IV)
Diphenhydramine 50 mg IV
Ranitidine 50 mg IV
Paclitaxel will be administered after the gemcitabine infusion as a 1 hour (IV) infusion.
The initial dose of paclitaxel is 80 mg/m2/weekly for 3 out of 4 weeks (Day 1, 8, 15)
Paclitaxel Dose Levels:
Dose Level 1 ________80 mg/m2/weekly
Dose Level -1 ________70 mg/m2/weekly; Premedication
Prophylactic antiemetics: 5-HT3-receptor antagonist prior to infusion with gemcitabine.
Prior to receiving paclitaxel chemotherapy
Gemcitabine will be given at the initial dose of 200mg/m2/week (Dose Level 1) for 3 out of 4 weeks (Day 1, 8, 15), as a 30 minute (IV) infusion.
The dose of gemcitabine can be escalated to 300mg/m2/weekly (Dose Level 2) after the first cycle of treatment if no significant toxicity is experienced.
Gemcitabine Dose Levels:
Dose Level 2 ________300 mg/m2/weekly
Dose Level 1 ________200 mg/m2/weekly
Dose Level -1 ________150 mg/m2/weekly; The dose of Avastin is 10 mg/kg IV every 2 weeks
It will be administered following the administration of chemotherapy
The first infusion will be administered over 90 minutes; if well tolerated, the second and subsequent doses will be administered as a 60-minute and 30-minute infusion, respectively.
It should not be administered or mixed with dextrose solutions.
Intervention MeSH terms: Paclitaxel; Gemcitabine; Bevacizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 39.0
Sex: All
Minimum age: 19 Years
Healthy volunteers: No
Keywords: Lung Cancer; Non-Small Cell Lung Cancer; Metronomic Chemotherapy

Summary:

      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.
    

Eligibility criteria:

        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
             treatment.

          -  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.

        Exclusion Criteria

          -  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
             cancer study

          -  Active malignancy, other than superficial basal cell and superficial squamous (skin)
             cell, or carcinoma in situ of the cervix within last five years

        Avastin-Specific Exclusions

          -  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
             be excluded

          -  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
             therapeutic anticoagulation)

          -  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
             Day 1

          -  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 histology.

          -  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
             (RECIST)

          -  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).