Erlotinib Hydrochloride With or Without Bevacizumab in Treating Patients With Stage IV Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Mutations
Condition: EGFR Exon 19 Deletion Mutation; EGFR NP_005219.2:p.L858R; Lung Non-Squamous Non-Small Cell Carcinoma; Stage IV Lung Non-Small Cell Cancer AJCC v7
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Bevacizumab; Erlotinib; Erlotinib Hydrochloride; Laboratory Biomarker Analysis
Intervention description: Given IV; Given PO; Given PO; Correlative studies
Intervention MeSH terms: Bevacizumab; Antineoplastic Agents, Immunological; Erlotinib Hydrochloride; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 88.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well erlotinib hydrochloride (Tarceva) with or
      without bevacizumab (Avastin) works in treating patients with stage IV non-small cell lung
      cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Erlotinib
      hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for
      cell growth. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different
      ways by targeting certain cells. Bevacizumab may also stop the growth of NSCLC by blocking
      the growth of new blood vessels necessary for tumor growth. It is not yet known whether
      erlotinib hydrochloride is more effective when given alone or with bevacizumab in treating
      patients with NSCLC.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologic documentation of primary lung carcinoma, non-squamous histology with
             activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R
             mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory
             Improvement Amendments (CLIA) certified lab; either institutional or through a
             commercial laboratory (e.g. Genzyme, Response Genetics, etc); the laboratory report
             from the commercial laboratories report the specific mutations detected, and the
             method of detecting the exon 19 and exon 21 L858R point mutations must be available

          -  Stage IV disease according to the 7th Edition of the American Joint Committee on
             Cancer staging system

          -  Measurable disease

          -  Life expectancy of >= 12 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

          -  Absolute neutrophil count (ANC) >= 1,500/mm^3 obtained =< 14 days prior to
             randomization

          -  Platelet count >= 100,000/mm^3 obtained =< 14 days prior to randomization

          -  Hemoglobin >= 9.0 g/dL obtained =< 14 days prior to randomization

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) obtained =< 14 days prior to
             randomization

          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
             serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
             ULN in patients without liver or bone metastases; < 5 x ULN in patients with liver or
             bone metastases obtained =< 14 days prior to randomization

          -  Cockcroft-Gault calculated creatinine clearance of >= 45 ml/min or creatinine =< 1.5 x
             ULN obtained =< 14 days prior to randomization

          -  Urine dipstick proteinuria < 2+ or urine protein/creatinine (UPC) ratio =< 1.0
             obtained =< 14 days prior to randomization

               -  Note: patients discovered to have >= 2 + proteinuria on dipstick urinalysis at
                  baseline should undergo a 24-hour urine collection and must demonstrate =< 1 g of
                  protein in 24 hours

          -  Negative pregnancy test done =< 7 days prior to randomization, for women of
             childbearing potential only

          -  Provide informed written consent

          -  Willing to return to Academic and Community Cancer Research United (ACCRU) enrolling
             institution for follow-up

          -  Willing to provide tissue and blood samples for correlative research purposes

        Exclusion Criteria:

          -  Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a
             predominant squamous component

          -  Prior chemotherapy or treatment for metastatic non-small cell lung cancer

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens

          -  Immunocompromised patients (other than that related to the use of corticosteroids)
             including patients known to be human immunodeficiency virus (HIV) positive, per
             medical doctor (MD) discretion

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, or psychiatric illness/social situations, or any other medical condition
             that would limit compliance with study requirements

          -  Receiving any other investigational agent which would be considered as a treatment for
             the primary neoplasm

          -  Other active malignancy =< 3 years prior to randomization; EXCEPTIONS: non melanotic
             skin cancer or carcinoma-in-situ of the cervix; Note: if there is a history of prior
             malignancy, they must not be receiving other specific treatment (i.e. hormonal
             therapy) for their cancer

          -  History of myocardial infarction or other evidence of arterial thrombotic disease
             (angina), symptomatic congestive heart failure (New York Heart Association >= grade
             2), unstable angina pectoris, or cardiac arrhythmia; Note: allowed only if patient has
             no evidence of active disease for at least 6 months prior to randomization

          -  History of cerebral vascular accident (CVA) or transient ischemic attack (TIA) =< 6
             months prior to randomization

          -  History of bleeding diathesis or coagulopathy

          -  Inadequately controlled hypertension (systolic blood pressure of > 150 mmHg or
             diastolic pressure > 100 mmHg on anti-hypertensive medications); Note: history of
             hypertensive crisis or hypertensive encephalopathy not allowed

          -  Current or recent (=< 10 days prior to randomization) use of aspirin (> 325 mg/day),
             clopidogrel (> 75 mg/day), or prasugrel (> 10 mg/day)

          -  Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical
             procedure, open biopsy, or significant traumatic injury =< 28 days or core biopsy =< 7
             days prior to randomization

          -  History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess
             =< 6 months prior to randomization

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  History of hemoptysis >= grade 2 (defined as bright red blood of at least 2.5 mL) =< 3
             months prior to randomization

          -  Known central nervous system (CNS) disease, except for treated brain metastasis; Note:
             treatment for brain metastases may include whole brain radiotherapy (WBRT),
             radiosurgery (RS); gamma knife, linear accelerator (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 =< 3 months
             prior to randomization will be excluded; Note: craniotomy or intracranial biopsy site
             must be adequately healed, free of drainage or cellulitis, and the underlying
             cranioplasty must appear intact at the time of randomization; study treatment should
             be initiated > 28 days following the last surgical procedure (including biopsy,
             surgical resection, wound revision, or any other major surgery involving entry into a
             body cavity)

          -  Significant vascular disease (e.g. aortic aneurysm surgical repair or recent
             peripheral arterial thrombosis) =< 6 months prior to randomization

          -  Radiotherapy to any site for any reason =< 14 days prior to randomization

          -  Receiving any medications or substances that are strong or moderate inhibitors of
             CYP3A4; use of the following strong or moderate inhibitors are prohibited =< 7 days
             prior to randomization:

               -  Strong inhibitors of CYP3A4: indinavir (Crixivan), nelfinavir (Viracept),
                  atazanavir (Reyataz), ritonavir (Norvir), clarithromycin (Biaxin, Biaxin XL),
                  itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), saquinavir
                  (Fortovase, Invirase), telithromycin (Ketek)

               -  Moderate inhibitors of CYP3A4: aprepitant (Emend), erythromycin (Erythrocin,
                  E.E.S, Ery-Tab, Eryc, EryPed, PCE, fluconazole (Diflucan), grapefruit juice,
                  verapamil (Calan, Calan SR, Covera-HS, Isoptin SR, Verelan, Verelan PM),
                  diltiazem (Cardizem, Cardizem CD, Cardizem LA, Cardizem SR, Cartia XT, Dilacor
                  XR, Diltia XT, Taztia XT, Tiazac)

          -  Receiving any medications or substances that are strong or moderate inducers of
             CYP3A4; use of the following inducers are prohibited =< 7 days prior to randomization:
             efavirenz (Sustiva), nevirapine (Viramune), carbamazepine (Carbatrol, Epitol, Equetro,
             Tegretol, Tegretol-XR), modafinil (Provigil), phenobarbital (Luminal), phenytoin
             (Dilantin, Phenytek), pioglitazone (Actos), rifabutin (Mycobutin), rifampin (Rifadin),
             St. John?s wort