Official Title: “Pilot Phase II Study of Metronomic Chemotherapy in Combination With Avastin in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer”

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.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Single Group Assignment, Efficacy Study

Study Primary Completion Date: March 2010

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, thrombespondin-1, E-selectin, ICAM-1, and circulating endothelial cells and endothelial precursor cells.

Intervention(s) in this Clinical Trial

• Drug: Paclitaxel
  • 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
• Drug: Gemcitabine
  • 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
• Biological: Avastin
  • 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.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1

Primary Measures

• To assess 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.
  • Time Frame: % of patients progression -free at 6 months
    Safety Issue?: No

Secondary Measures

• 2.2.4 Assessment of circulating endothelial progenitor cells (CEPs) and circulating endothelial cells (CECs) by flow cytometry as a surrogate marker of the anti-angiogenic effect of Avastin-based metronomic therapy.
  • Time Frame: Day 1, cycle 1; Day 1 cycle 3, 6
    Safety Issue?: No
• To assess toxicity in patients with advanced or metastatic (Stage IIB - pleural effusion/IV), non-squamous histology NSCLC treated with metronomic chemotherapy plus Avastin.
  • Time Frame: No time frame for toxicities experienced.
    Safety Issue?: Yes
• To determine blood levels of VEGF, soluble VEGFR2, thrombospondin-1, E-selectin and ICAM-1 before and during therapy, and explore possible correlations with clinical outcome.
  • Time Frame: Prior to and during therapy
    Safety Issue?: No

• 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)
• Absoluteto 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).

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 19 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Alabama at Birmingham

Overall Clinical Trial Officials and Contacts

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

Overall Contact: Francisco Robert, M.D. (205) 934-5077 francisco.robert@ccc.uab.edu

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00655850

Study ID Number: F070727010

ClinicalTrials.gov Identifier: NCT00655850

Health Authority: United States: Institutional Review Board