Clinical Trials /

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

NCT01532089

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: RC1126
  • SECONDARY ID: NCI-2012-00053
  • SECONDARY ID: 11-006881
  • SECONDARY ID: RC1126
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT01532089

Conditions

  • EGFR Activating Mutation
  • EGFR Exon 19 Deletion Mutation
  • EGFR NP_005219.2:p.L858R
  • Non-Squamous Non-Small Cell Lung Carcinoma
  • Stage IV Non-Small Cell Lung Cancer AJCC v7

Interventions

DrugSynonymsArms
BevacizumabAnti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar FKB238, BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED, 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-VEGFArm B (erlotinib hydrochloride, bevacizumab)
Erlotinib HydrochlorideCp-358,774, OSI-774, TarcevaArm A (erlotinib hydrochloride)

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.

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (erlotinib hydrochloride)Active ComparatorPatients receive erlotinib hydrochloride PO QD on days 1-21.
  • Erlotinib Hydrochloride
Arm B (erlotinib hydrochloride, bevacizumab)ExperimentalPatients receive erlotinib hydrochloride as in Arm A and bevacizumab IV over 30-90 minutes on day 1.
  • Bevacizumab
  • Erlotinib Hydrochloride

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:Time from randomization to disease progression and death of any cause, whichever comes first, assessed up to 6 years
Safety Issue:
Description: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

Measure:Overall survival
Time Frame:Time from randomization to death of any causes, assessed up to 6 years
Safety Issue:
Description: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.
Measure: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 6 years
Safety Issue:
Description: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.
Measure:Progression free survival of patients with different mutation types (exon deletion 19 versus exon 21 L858R)
Time Frame:From the date of randomization to the date of disease progression or death of any cause, whichever comes first, assessed up to 6 years
Safety Issue:
Description: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.
Measure:Incidence of treatment-related adverse events for erlotinib hydrochloride, tabulated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:Up to 42 days after treatment discontinuation
Safety Issue:
Description:Types and the frequency of treatment-related adverse events will be tabulated for erlotinib hydrochloride.
Measure:Incidence of treatment-related adverse events for bevacizumab and erlotinib hydrochloride, tabulated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:Up to 42 days after treatment discontinuation
Safety Issue:
Description:Types and the frequency of treatment-related adverse events will be tabulated for bevacizumab and erlotinib hydrochloride.
Measure:EGFR mutations detected in plasma deoxyribonucleic acid (DNA)
Time Frame:Up to 6 years
Safety Issue:
Description:Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.
Measure:EGFR mutations detected in tumor deoxyribonucleic acid (DNA)
Time Frame:Up to 6 years
Safety Issue:
Description:Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.
Measure:Prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods
Time Frame:Baseline
Safety Issue:
Description: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.
Measure:EGFR T790M mutations
Time Frame:Up to 6 years
Safety Issue:
Description:Detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (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.
Measure: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
Safety Issue:
Description:Evaluated using time-dependent receiver operating characteristic curve and area under curve.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Academic and Community Cancer Research United

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