Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United
ClinicalTrials.gov Identifier:
NCT01532089
First received: February 7, 2012
Last updated: October 13, 2016
Last verified: October 2016
  Purpose
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.

Condition Intervention Phase
EGFR Activating Mutation
Stage IV Non-Small Cell Lung Cancer
Biological: Bevacizumab
Drug: Erlotinib Hydrochloride
Other: Laboratory Biomarker Analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Phase II Trial of Erlotinib Alone or in Combination With Bevacizumab in Patients With Non-small Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

Resource links provided by NLM:


Further study details as provided by Academic and Community Cancer Research United:

Primary Outcome Measures:
  • Progression free survival (PFS) [ Time Frame: Time from randomization to disease progression and death of any cause, whichever comes first, assessed up to 5 years ] [ Designated as safety issue: No ]
    Described graphically using the Kaplan and Meier product limit estimator. Comparisons of PFS between arms will be conducted using a stratified log rank test. Cox proportional hazards model will be used to estimate the adjusted hazard ratios and their 95% confidence intervals. Hazard ratio for treatment effect will be estimated for each subgroup of patients that has significant interaction with treatment. The robustness of treatment effects in different patient subgroups will examined in Forest plots.


Secondary Outcome Measures:
  • EGFR mutations detected in plasma DNA [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

  • EGFR mutations detected in tumor DNA [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

  • EGFR T790M mutations [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Detected from pre-treatment tumor specimen using allele specific quantitative PCR. The PFS of patients with EGFR T790M mutations will be estimated and the survival difference will be tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

  • Incidence of treatment-related adverse events for bevacizumab and erlotinib hydrochloride, tabulated using the CTCAE version 4.0 [ Time Frame: Up to 42 days after treatment discontinuation ] [ Designated as safety issue: Yes ]
    Types and the frequency of treatment-related adverse events will be tabulated for bevacizumab and erlotinib hydrochloride.

  • Incidence of treatment-related adverse events for erlotinib hydrochloride, tabulated using the CTCAE version 4.0 [ Time Frame: Up to 42 days after treatment discontinuation ] [ Designated as safety issue: Yes ]
    Types and the frequency of treatment-related adverse events will be tabulated for erlotinib hydrochloride.

  • Overall survival [ Time Frame: Time from randomization to death of any causes, assessed up to 5 years ] [ Designated as safety issue: No ]
    Described graphically using the Kaplan and Meier product limit estimator. Comparisons between arms will be conducted using a stratified log rank test. Cox proportional hazards model will be used to estimate the adjusted hazard ratios and their 95% confidence intervals. Hazard ratio for treatment effect will be estimated for each subgroup of patients that has significant interaction with treatment. The robustness of treatment effects in different patient subgroups will examined in Forest plots.

  • Predictive value of plasma VEGF-A levels on progression free survival in patients treated with erlotinib hydrochloride alone or in combination with bevacizumab [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Evaluated using time-dependent receiver operating characteristic curve and area under curve.

  • Prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

  • Progression free survival of patients with different mutation types (exon deletion 19 vs. exon 21 L858R) [ Time Frame: From the date of randomization to the date of disease progression or death of any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    Tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

  • Response rate (complete or partial) to each treatment, evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors guidelines (version 1.1) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    95% confidence intervals will be estimated. Tested using Fisher's exact test and multivariately using a logistic regression model with performance status, gender and genetic mutation type and other significant prognostic factors.


Estimated Enrollment: 86
Study Start Date: March 2012
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A (erlotinib hydrochloride)
Patients receive erlotinib hydrochloride PO QD on days 1-21.
Drug: Erlotinib Hydrochloride
Given PO
Other Names:
  • Cp-358,774
  • OSI-774
  • Tarceva
Other: Laboratory Biomarker Analysis
Correlative studies
Experimental: Arm B (erlotinib hydrochloride, bevacizumab)
Patients receive erlotinib hydrochloride as in Arm A and bevacizumab IV over 30-90 minutes on day 1.
Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF
Drug: Erlotinib Hydrochloride
Given PO
Other Names:
  • Cp-358,774
  • OSI-774
  • Tarceva
Other: Laboratory Biomarker Analysis
Correlative studies

Detailed Description:

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 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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01532089

Locations
United States, California
UC San Diego Moores Cancer Center
La Jolla, California, United States, 92093
United States, Illinois
Illinois CancerCare-Peoria
Peoria, Illinois, United States, 61615
Carle Cancer Center NCI Community Oncology Research Program
Urbana, Illinois, United States, 61801
United States, Michigan
Michigan Cancer Research Consortium NCORP
Ann Arbor, Michigan, United States, 48106
Cancer Research Consortium of West Michigan NCORP
Grand Rapids, Michigan, United States, 49503
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Coborn Cancer Center at Saint Cloud Hospital
Saint Cloud, Minnesota, United States, 56303
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Heartland Cancer Research NCORP
St. Louis, Missouri, United States, 63131
United States, New Hampshire
New Hampshire Oncology Hematology PA-Hooksett
Hooksett, New Hampshire, United States, 03106
United States, New York
Hematology Oncology Associates of Central New York-East Syracuse
East Syracuse, New York, United States, 13057
State University of New York Upstate Medical University
Syracuse, New York, United States, 13210
United States, North Carolina
University of North Carolina-Chapel Hill
Chapel Hill, North Carolina, United States, 27514
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, North Dakota
Sanford Medical Center-Fargo
Fargo, North Dakota, United States, 58122
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, South Carolina
Upstate Carolina CCOP
Spartanburg, South Carolina, United States, 29303
United States, South Dakota
Rapid City Regional Hospital
Rapid City, South Dakota, United States, 57701
United States, Wisconsin
Saint Vincent Hospital
Green Bay, Wisconsin, United States, 54301
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
Principal Investigator: Thomas Stinchcombe Academic and Community Cancer Research United
  More Information

Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT01532089     History of Changes
Other Study ID Numbers: RC1126  NCI-2012-00053  11-006881  RC1126  P30CA015083 
Study First Received: February 7, 2012
Last Updated: October 13, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Bevacizumab
Erlotinib Hydrochloride
Endothelial Growth Factors
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Mitogens
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunologic Factors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Mitosis Modulators

ClinicalTrials.gov processed this record on December 08, 2016