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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Genentech
Information provided by (Responsible Party):
Francisco Robert,MD, University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT00655850
First received: April 4, 2008
Last updated: January 16, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Non-Small Cell Lung Cancer
Drug: Paclitaxel
Drug: Gemcitabine
Biological: Avastin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot Phase II Study of Metronomic Chemotherapy in Combination With Avastin in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer

Resource links provided by NLM:


Further study details as provided by University of Alabama at Birmingham:

Primary Outcome 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Assessment of circulating endothelial progenitor cells (CEPs) 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 ] [ Designated as 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. ] [ Designated as safety issue: Yes ]
  • To determine blood levels of VEGF before and during therapy and explore possible correlations with clinical outcome. [ Time Frame: Prior to and during therapy ] [ Designated as safety issue: No ]
  • Assessment of 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 ] [ Designated as safety issue: No ]
  • To determine blood levels of soluble VEGFR2 during therapy and explore possible correlations with clinical outcome. [ Time Frame: Prior to and during therapy ] [ Designated as safety issue: No ]
  • To determine blood levels of thrombospondin-1 before and during therapy and explore possible correlations with clinical outcome. [ Time Frame: Prior to and during therapy ] [ Designated as safety issue: No ]
  • To determine blood levels of E-selectin before and during therapy and explore possible correlations with clinical outcome. [ Time Frame: Prior to and during therapy ] [ Designated as safety issue: No ]
  • To determine blood levels of ICAM-1 before and during therapy and explore possible correlations with clinical outcome. [ Time Frame: Prior to and during therapy ] [ Designated as safety issue: No ]

Estimated Enrollment: 35
Study Start Date: March 2008
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Paclitaxel and Gemcitabine + Avastin
Patients will be treated with metronomic chemotherapy with paclitaxel and gemcitabine weekly for 3 out of 4 weeks which constitutes one cycle (4 weeks). Avastin will be administered every 2 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 continue until disease progression, intolerable toxicity, or withdrawal of consent.
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
Other Name: Taxol
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
Other Name: Gemzar
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.
Other Name: Anti-VEGF

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

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00655850

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294 - 0104
Sponsors and Collaborators
University of Alabama at Birmingham
Genentech
Investigators
Principal Investigator: Francisco Robert, M.D. University of Alabama at Birmingham
  More Information

No publications provided

Responsible Party: Francisco Robert,MD, Professor, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT00655850     History of Changes
Other Study ID Numbers: F070727010, UAB 0709
Study First Received: April 4, 2008
Last Updated: January 16, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Alabama at Birmingham:
Lung Cancer
Non-Small Cell Lung Cancer
Metronomic Chemotherapy

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Gemcitabine
Bevacizumab
Paclitaxel
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on July 23, 2014