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Lower Dose Chemotherapy Given More Frequent With Avastin to Treat Advanced Non-Squamous Non-Small Cell Lung Cancer

Information source: University of Alabama at Birmingham
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Non-Small Cell Lung Cancer

Intervention: Paclitaxel (Drug); Gemcitabine (Drug); Avastin (Biological)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: University of Alabama at Birmingham

Official(s) and/or principal investigator(s):
Francisco Robert, M.D., Principal Investigator, Affiliation: University of Alabama at Birmingham

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.

Clinical Details

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

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: 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.

Secondary outcome:

Assessment of circulating endothelial progenitor cells (CEPs) by flow cytometry as a surrogate marker of the anti-angiogenic effect of Avastin-based metronomic therapy.

To assess toxicity in patients with advanced or metastatic (Stage IIB - pleural effusion/IV), non-squamous histology NSCLC treated with metronomic chemotherapy plus Avastin.

To determine blood levels of VEGF before and during therapy and explore possible correlations with clinical outcome.

Assessment of circulating endothelial cells (CECs) by flow cytometry as a surrogate marker of the anti-angiogenic effect of Avastin-based metronomic therapy.

To determine blood levels of soluble VEGFR2 during therapy and explore possible correlations with clinical outcome.

To determine blood levels of thrombospondin-1 before and during therapy and explore possible correlations with clinical outcome.

To determine blood levels of E-selectin before and during therapy and explore possible correlations with clinical outcome.

To determine blood levels of ICAM-1 before and during therapy and explore possible correlations with clinical outcome.

Detailed description: 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.

Eligibility

Minimum age: 19 Years. Maximum age: N/A. Gender(s): Both.

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).

Locations and Contacts

University of Alabama at Birmingham, Birmingham, Alabama 35294 - 0104, United States
Additional Information

Starting date: March 2008
Last updated: February 22, 2015

Page last updated: August 20, 2015

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