A Phase II Study of Neo-Adjuvant Gemcitabine, Cisplatin and Bevacizumab in Stage IIIA (N2) Non-Squamous Cell Non-Small Cell Lung Cancer
Condition: NSCLC; Stage IIIA (N2)
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Gemcitabine; Cisplatin; Bevacizumab; Surgery; Etoposide
Intervention description: 1250 mg/m^2 dose for two doses on days 1 and 8; 80 mg/m^2 on day 1; 7.5 mg/m^2 on day 1 every 21 days for first two cycles only; thoracotomy with lobectomy/pneumonectomy and mediastinal lymph node dissection 4-6 weeks post completion of last cycle of cisplatin; 100 mg/m^2 intravenous per day for consecutive 3 days on days 1 to 3 every 3 weeks for 4 cycles.
Intervention MeSH terms: Bevacizumab; Gemcitabine; Etoposide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Neoadjuvant; Stage IIIA (N2); Cisplatin; Gemcitabine; Bevacizumab; Non-Small Cell Lung Cancer; NSCLC

Summary:

      Background:

        -  Surgical resection is the treatment of choice for patients with lung cancer, and cure
           after resection generally depends on whether lymph nodes are involved. A patient with
           Stage IIIA (N2) lung cancer has cancer in the lymph nodes involving the center of the
           chest (mediastinum).

        -  Studies have shown that surgery alone as a treatment for Stage IIIA (N2) lung cancer is
           not as effective as chemotherapy followed by surgery.

        -  Giving chemotherapy upfront may prevent the spread of Stage IIIA (N2) lung cancer
           tumors, and may shrink the tumors to allow adequate surgery to be performed. It is also
           thought that chemotherapy is usually better tolerated before major surgery than after,
           so higher doses can be given.

      Objectives:

        -  To determine the effectiveness of the combination of three anti-cancer drugs
           (gemcitabine, cisplatin, and bevacizumab) given before surgery.

        -  To find out what effects this drug combination may have on the patient and the cancer.

        -  To determine if the combination of all three drugs given prior to surgery is more
           effective and as safe, safer, or less safe than other drug combinations given before
           surgery.

      Eligibility:

        -  Patients with Stage IIIA (N2) lung cancer who have not had chemotherapy, radiation, or
           surgery to treat the cancer.

      Design:

        -  Evaluations before the treatment period to determine eligibility:

        -  Physical examination, including vital signs and body weight checks, and pregnancy test
           for women who can become pregnant.

        -  Tests to evaluate heart and lung function, such as an echocardiogram.

        -  Blood and urine tests.

        -  Disease evaluation with computed tomography (CT), chest X-ray, positron emission
           tomography (PET) scans, and bronchoscopy/mediastinoscopy (examinations of the inside of
           the chest and lungs).

        -  Treatment with intravenous gemcitabine, cisplatin, and bevacizumab for three 21-day
           cycles.

        -  Cycles 1 and 2 - Gemcitabine on day 1 and day 8, cisplatin on day 1, bevacizumab on day
           1.

        -  Cycle 3 - Gemcitabine on day 1 and day 8, cisplatin on day 1 (no bevacizumab).

        -  Physical examinations and tests will be conducted throughout each cycle.

        -  Surgery will take place 4 to 6 weeks after the last cycle if heart and lung functions
           are satisfactory and if the cancer remains stable.

        -  Chemotherapy (four 21-day cycles of cisplatin and etoposide treatments), further
           evaluations and examinations, and followup studies will take place 4 to 8 weeks after
           the surgery.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Histologically or cytologically documented non squamous cell non-small cell lung
             cancer and confirmed by the pathological laboratories at participating centers.

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded) as
             greater than 20 mm with conventional techniques or as greater than 10 mm with spiral
             computed tomography (CT) scan.

          -  Stage IIIA (N2) disease. All patients will require a baseline mediastinoscopy to
             ensure histological proof of N2 disease.

          -  No prior treatment for lung cancer including chemotherapy, radiotherapy, surgery or
             biological therapy.

          -  Age greater than or equal to 18 years (males or non-pregnant females).

          -  Life expectancy of greater than 3 months.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky greater
             than 60 percent).

          -  Adequate pulmonary and cardiovascular function to tolerate planned surgical resection:

               -  Pulmonary Function criteria:

                    -  Partial pressure of oxygen (paO2) greater than 65 mmHg, partial pressure of
                       carbon dioxide (paCO2) less than 45 mmHg on room air arterial blood gas
                       (ABG).

                    -  Anticipated post-op forced expiratory volume 1 (FEV1) greater than or equal
                       to 40 percent predicted.

                    -  Anticipated post-op carbon monoxide diffusing capacity (DLCO) greater than
                       or equal to 40 percent predicted.

                    -  If anticipated post-op FEV1 or DLCO less than percent predicted, must have
                       volume of oxygen (VO2) greater than 15ml/kg on oxygen consumption study.

               -  Cardiac criteria:

                    -  Left ventricular ejection fraction (LVEF) greater than 40 percent.

                    -  No pulmonary hypertension or right ventricular (RV) dysfunction.

                    -  No unstable angina.

          -  Serum Creatinine less than or equal to 1.5mg/dl

          -  Hemoglobin (baseline) greater than or equal to 10.0g/dl

          -  Absolute neutrophil count greater than or equal to 1,500/m^3 and platelets greater
             than or equal to 100,000/m^3.

          -  aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and
             alanine aminotransferase (ALT)/ serum glutamic pyruvic transaminase (SGPT) less than
             or equal to 2.5 times the upper limit of normal (ULN), total bilirubin less than or
             equal to 1.5 times the ULN (In patients with evidence of Gilberts disease, elevated
             bilirubin should not be related to tumor or other liver diseases and should be less
             than or equal 2 times the upper limit of normal).

          -  The ability to understand and the willingness to sign a written informed consent
             document and the ability to comply with the requirements of the protocol.

          -  Women of childbearing potential must have a negative pregnancy test and both men and
             women must be willing to consent to using effective contraception while on treatment
             and for at least 3 months thereafter.

        EXCLUSION CRITERIA:

          -  Squamous cell cancer or mixed tumors with small cell elements.

          -  Tumor of any histology in close proximity to a major vessel or cavitation. (Any tumor
             abutting an interlobar, main pulmonary artery, vena cava or major vein will be
             excluded).

          -  History of hemoptysis (bright red blood of one-half teaspoon or more [greater than or
             equal to 2.5 mL] unrelated to any diagnostic procedure. (Patients who have a history
             of hemoptysis that occurred greater than 3 months prior to study entry and that is
             assessed not to be related to tumor may be eligible).

          -  Patients with metastatic disease.

          -  History of uncontrolled or labile hypertension, defined as blood pressure greater than
             150/100mmHg (National Cancer Institute (NCI) Common Terminology Criteria for Adverse
             Events (CTCAE) v.3.0 grade greater than or equal to 2), systolic blood pressure
             greater than 180 mm Hg if diastolic blood pressure less than 90 mm Hg, or diastolic
             blood pressure greater than 90 mm Hg, on at least 2 repeated determinations on
             separate days within 3 months prior to study enrollment. Patients who have medication
             controlled hypertension are eligible for the study.

          -  Any of the following within 6 months prior to study enrollment: myocardial infarction,
             severe/unstable angina pectoris or uncontrolled angina pectoris, coronary/peripheral
             artery bypass graft, New York Heart Association (NYHA) class III or IV congestive
             heart failure, clinically significant peripheral vascular disease (Grade II or
             greater).

          -  Psychiatric or neurologic illness that would limit compliance with study requirements.

          -  Patients with serious illness or medical condition.

          -  Active infection within 14 days before beginning treatment.

          -  Patients may not be receiving any other investigational agents.

          -  History of a malignancy in the last five years other than in situ carcinoma of the
             cervix, or non-melanomatous skin cancers.

          -  Patients must not be on therapeutic anticoagulation or chronic daily treatment with
             aspirin 325mg/day within 10 days prior to day 1 on study. Prophylactic anticoagulation
             during perioperative period is acceptable. Full dose aspirin post surgical resection
             is acceptable. Low dose aspirin 81mg/day and anticoagulation for line protection are
             allowed in the perioperative period and the adjuvant setting.

          -  Women who are breast feeding.

          -  History of stroke or transient ischemic attack within 6 months.

          -  History of pulmonary embolism, deep venous thrombosis or other thrombo-embolic event
             within 6 months prior to study.

          -  Patients with a history of severe hypersensitivity reaction to compounds of similar
             chemical or biologic composition to cisplatin, gemcitabine, bevacizumab, etoposide or
             other agents used in the study.

          -  History of a major surgical procedure, open biopsy, or a significant traumatic injury
             within 35 days prior to commencing treatment, or the anticipation of the need for a
             major surgical procedure during the course of the study prior to the predetermined
             date of tumor excision. Fine needle aspirations, core biopsies or mediastinoscopies
             within 7 days prior to commencing treatment.

          -  History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or
             tracheo-esophageal fistula.

          -  Non-healing wound or ulcer

          -  Evidence of coagulopathic disorder or hemorrhagic diathesis. International normalized
             ratio (INR) greater than 1.5.

          -  Patients with existing ototoxicity.

          -  Pregnancy (positive pregnancy test).

          -  Urine protein: creatinine ratio greater than or equal to 1.0 at screening.

          -  Patients known to be human immunodeficiency virus (HIV)-positive or have active
             hepatitis B/C (due to possible interaction between chemotherapy and highly active
             antiretroviral therapy (HAART) and antiviral medications used for treatment of active
             hepatitis B/C).

          -  Serious illness that may preclude adherence to the protocol.