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

PhaseTypeAgeTrial IDs
Phase IIBiomarker/Laboratory analysis, Treatment18 and overRC1126
NCI-2012-00053, 11-006881, Mod11-006881-13, NCT01532089

Trial Description

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.

Further Study Information

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

TERTIARY OBJECTIVES:

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:

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

Measurable disease

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

Exclusion Criteria:

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:

Pregnant women

Nursing women

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
Thomas E. Stinchcombe, Principal Investigator

Trial Sites

U.S.A.

California
La Jolla

UC San Diego Moores Cancer Center

Lyudmila Alexandrovna Bazhenova
Ph: 858-822-5354
Email: cancercto@ucsd.edu

Lyudmila Alexandrovna Bazhenova
Principal Investigator

Minnesota
Rochester

Mayo Clinic

Julian R. Molina
Ph: 507-538-7623
Email: molina.julian@mayo.edu

Julian R. Molina
Principal Investigator

North Carolina
Chapel Hill

University of North Carolina at Chapel Hill

Thomas E. Stinchcombe
Ph: 507-284-4565
Email: thomas_stinchcombe@med.unc.edu

Thomas E. Stinchcombe
Principal Investigator

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.