Erlotinib Hydrochloride with or without Bevacizumab in Treating Patients with Stage IV Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations

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Basic Trial Information

PhaseTypeStatusAgeTrial IDs
Phase IIBiomarker/Laboratory analysis, TreatmentActive18 and overRC1126
NCI-2012-00053, 11-006881, Mod11-006881-13, NCT01532089

Trial Description


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.

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

Platelet count >= 100,000/mm^3

Hemoglobin >= 9.0 g/dL

Total bilirubin =< 1.5 x upper limit of normal (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

Cockcroft-Gault calculated creatinine clearance of >= 45 ml/min or creatinine =< 1.5 x ULN

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

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 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)

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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Academic and Community Cancer Research United

  • National Cancer Institute
Thomas E. Stinchcombe, Principal Investigator

Trial Sites


La Jolla

UC San Diego Moores Cancer Center

Lyudmila Alexandrovna Bazhenova
Ph: 858-822-5352

Lyudmila Alexandrovna Bazhenova
Principal Investigator


Heartland Cancer Research NCORP

Bryan A. Faller
Ph: 314-996-6955

Bryan A. Faller
Principal Investigator


Illinois CancerCare-Peoria

Gregory J. Gerstner
Ph: 309-243-3614

Gregory J. Gerstner
Principal Investigator


Carle Cancer Center NCI Community Oncology Research Program

James R. Egner
Ph: 217-383-3394

James R. Egner
Principal Investigator

Ann Arbor

Michigan Cancer Research Consortium NCORP

Philip J. Stella
Ph: 734-712-4931

Philip J. Stella
Principal Investigator

Grand Rapids

Cancer Research Consortium of West Michigan NCORP

Kathleen J. Yost
Ph: 616-954-9800

Kathleen J. Yost
Principal Investigator

Saint Louis

Washington University School of Medicine

Maria Quintos Baggstrom
Ph: 314-362-5737

Maria Quintos Baggstrom
Principal Investigator

New Hampshire

New Hampshire Oncology Hematology PA-Hooksett

Douglas J. Weckstein
Ph: 603-622-6484

Douglas J. Weckstein
Principal Investigator

New York

State University of New York Upstate Medical University

Stephen L. Graziano
Ph: 315-464-8237

Stephen L. Graziano
Principal Investigator

North Carolina
Chapel Hill

University of North Carolina-Chapel Hill

Thomas E. Stinchcombe
Ph: 919-966-9268

Thomas E. Stinchcombe
Principal Investigator


Duke University Medical Center

Jeffrey Crawford
Ph: 919-668-6730

Jeffrey Crawford
Principal Investigator

North Dakota

Sanford Medical Center-Fargo

Preston D. Steen
Ph: 701-234-5899

Preston D. Steen
Principal Investigator


Ohio State University Comprehensive Cancer Center

Gregory A. Otterson
Ph: 614-293-8574

Gregory A. Otterson
Principal Investigator

South Carolina

Upstate Carolina CCOP

James Dewitt Bearden
Ph: 864-560-6812

James Dewitt Bearden
Principal Investigator

South Dakota
Rapid City

Rapid City Regional Hospital

Joshua Cole Lukenbill
Ph: 605-755-2301

Joshua Cole Lukenbill
Principal Investigator

Green Bay

Saint Vincent Hospital

Anthony John Jaslowski
Ph: 920-433-8272

Anthony John Jaslowski
Principal Investigator

Link to the current record.
NLM Identifier NCT01532089

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