Erlotinib Hydrochloride with or without Bevacizumab in Treating Patients with Stage IV Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations
Basic Trial Information
|Phase II||Biomarker/Laboratory analysis, Treatment||18 and over||RC1126|
NCI-2012-00053, 11-006881, Mod11-006881-13, NCT01532089
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.
Further Study Information
I. To determine the progression-free survival of erlotinib (erlotinib hydrochloride) and bevacizumab versus that of erlotinib alone for the purpose of deciding if the combination arm is worth pursuing in a phase III trial.
I. To investigate the overall survival of erlotinib and bevacizumab versus erlotinib alone.
II. To investigate the response rate of erlotinib and bevacizumab versus erlotinib alone.
III. To investigate the progression-free survival in patients with exon deletion 19 or exon 21 L858R EGFR point mutations.
IV. To investigate the toxicity of erlotinib and bevacizumab versus erlotinib alone using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
I. To correlate EGFR mutations detected in plasma deoxyribonucleic acid (DNA) with those detected in tumor DNA.
II. To estimate the prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods.
III. To investigate progression free survival of EGFR mutant NSCLC patients with and without concurrent EGFR T790M detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR).
IV. To prospectively evaluate the predictive value of plasma vascular endothelial growth factor A (VEGF-A) levels on progression free survival in patients treated with erlotinib alone or in combination with bevacizumab.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM A: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21.
ARM B: Patients receive erlotinib hydrochloride as in Arm A and bevacizumab intravenously (IV) over 30-90 minutes on day 1.
In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3-6 months for 6 years.
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
Provide informed written consent
Negative pregnancy test done =< 7 days prior to randomization, for women of childbearing potential only
Urine dipstick proteinuria < 2+ or urine protein/creatinine (UPC) ratio =< 1.0
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
Cockcroft-Gault calculated creatinine clearance of >= 45 ml/min or creatinine =< 1.5 x ULN
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
Total bilirubin =< 1.5 x upper limit of normal (ULN)
Hemoglobin >= 9.0 g/dL
Platelet count >= 100,000/mm^3
Absolute neutrophil count (ANC) >= 1,500/mm^3
Stage IV disease according to the 7th Edition of the American Joint Committee on Cancer staging system
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
Life expectancy of >= 12 months
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
Prior chemotherapy or treatment for metastatic non-small cell lung cancer
Receiving any medications or substances that are 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
Receiving any medications or substances that are strong or moderate inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (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®)
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)
Current or recent (=< 10 days prior to randomization use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or prasugrel (> 10 mg/day)
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
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
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
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
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
Radiotherapy to any site for any reason =< 14 days prior to randomization
Significant vascular disease (e.g. aortic aneurysm surgical repair or recent peripheral arterial thrombosis) =< 6 months prior to randomization
History of hemoptysis >= grade 2 (defined as bright red blood of at least 2.5 mL) =< 3 months prior to randomization
Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess =< 6 months prior to randomization
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 cerebral vascular accident (CVA) or transient ischemic attack (TIA) =< 6 months prior to randomization
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
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
Any of the following:
Men or women of childbearing potential who are unwilling to employ adequate contraception
Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component
History of bleeding diathesis or coagulopathy
Trial Contact Information
Trial Lead Organizations / Sponsors / Collaborators
Academic and Community Cancer Research United
- National Cancer Institute
UC San Diego Moores Cancer Center
Lyudmila Alexandrovna Bazhenova
Lyudmila Alexandrovna Bazhenova
Julian R. Molina
Julian R. Molina
University of North Carolina at Chapel Hill
Thomas E. Stinchcombe
Thomas E. Stinchcombe
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01532089
Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.