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

• ClinicalTrials.gov Identifier: NCT01532089
• Recruitment Status: Completed
• First Posted: February 14, 2012
• Results First Posted: December 26, 2019
• Last Update Posted: October 6, 2020
• Sponsor: Academic and Community Cancer Research United
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Academic and Community Cancer Research United

Tracking Information

• First Submitted Date: February 7, 2012
• First Posted Date: February 14, 2012
• Results First Submitted Date: December 9, 2019
• Results First Posted Date: December 26, 2019
• Last Update Posted Date: October 6, 2020
• Actual Study Start Date: March 16, 2012
• Actual Primary Completion Date: February 13, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 30, 2019)

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 ]

Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Original Primary Outcome Measures (submitted: February 9, 2012)

Progression free survival (PFS) of erlotinib and bevacizumab versus that of erlotinib alone in untreated advanced non-small cell lung cancer patients who have activating EGFR mutations [ Time Frame: From the date of randomization to the date of disease progression or death of any cause, assessed up to 5 years ]

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.

Current Secondary Outcome Measures (submitted: December 30, 2019)

• Overall Survival [ Time Frame: Time from randomization to death of any causes, assessed up to 6 years ]
  Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
• 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 ]
  The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).
• 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 ]
  Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator by mutation type.
• Number of Patients Experiencing Toxicity [ Time Frame: Up to 42 days after treatment discontinuation ]
  The number of patients experiencing toxicity defined as grade 3 or higher adverse events (using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) considered at least possibly related to treatment is reported below.

Original Secondary Outcome Measures (submitted: February 9, 2012)

• Overall survival of erlotinib and bevacizumab versus erlotinib alone [ Time Frame: Time from randomization to death of any causes assessed up to 5 years ]
• Response rate (complete or partial) to each treatment [ Time Frame: Baseline, every 6 weeks for 18 months, then every 3 months ]
• 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 ]
• Types and the frequency of treatment-related adverse events for erlotinib and bevacizumab and erlotinib alone [ Time Frame: Prior to each course and 21-42 days after treatment discontinuation ]
• Correlation of EGFR mutations detected in plasma DNA with those detected in tumor DNA [ Time Frame: Baseline, during each radiographic assessment and at the time of progression ]
• Prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods [ Time Frame: Baseline ]
• Effect of EGFR T790M on progression free survival [ Time Frame: Baseline, up to 5 years ]
• Predictive value of plasma VEGF-A levels on progression free survival in patients treated with erlotinib alone or in combination with bevacizumab [ Time Frame: Baseline ]

Current Other Pre-specified Outcome Measures (submitted: December 11, 2019)

• EGFR Mutations Detected in Plasma Deoxyribonucleic Acid (DNA) [ Time Frame: Up to 6 years ]
  Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.
• EGFR Mutations Detected in Tumor Deoxyribonucleic Acid (DNA) [ Time Frame: Up to 6 years ]
  Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.
• Prevalence of EGFR T790M Resistance Mutations From Pretreatment > Tumor Biopsies Using More Sensitive Mutation Detection Methods [ Time Frame: Baseline ]
  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.
• EGFR T790M Mutations [ Time Frame: Up to 6 years ]
  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.
• 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 ]
  Evaluated using time-dependent receiver operating characteristic curve and area under curve.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief 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.

Detailed Description

PRIMARY OBJECTIVE:

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.

CORRELATIVE RESEARCH 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. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)

ARM B: Patients receive erlotinib hydrochloride as in Arm A and bevacizumab intravenously (IV) over 30-90 minutes on day 1. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment

Condition

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

Intervention

• Biological: Bevacizumab
  Given IV
  Other Names:

  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab awwb
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar CT-P16
  • Bevacizumab Biosimilar FKB238
  • Bevacizumab Biosimilar HD204
  • Bevacizumab Biosimilar HLX04
  • Bevacizumab Biosimilar IBI305
  • Bevacizumab Biosimilar LY01008
  • Bevacizumab Biosimilar MIL60
  • Bevacizumab Biosimilar QL 1101
  • Bevacizumab Biosimilar RPH-001
  • Bevacizumab Biosimilar SCT501
  • BP102
  • BP102 Biosimilar
  • HD204
  • 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
  • SCT501
• Drug: Erlotinib
  Given PO
• Drug: Erlotinib Hydrochloride
  Given PO
  Other Names:

  • Cp-358,774
  • OSI-774
  • Tarceva
• Other: Laboratory Biomarker Analysis
  Correlative studies

Study Arms

• Active Comparator: Arm A (erlotinib hydrochloride)
  Patients receive erlotinib hydrochloride PO QD on days 1-21. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)
  Interventions:

  • Drug: Erlotinib
  • Drug: Erlotinib Hydrochloride
  • Other: Laboratory Biomarker Analysis
• Experimental: Arm B (erlotinib hydrochloride, bevacizumab)
  Patients receive erlotinib hydrochloride as in Arm A and bevacizumab IV over 30-90 minutes on day 1. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)
  Interventions:

  • Biological: Bevacizumab
  • Drug: Erlotinib
  • Drug: Erlotinib Hydrochloride
  • Other: Laboratory Biomarker Analysis

• Publications *: Stinchcombe TE, Janne PA, Wang X, Bertino EM, Weiss J, Bazhenova L, Gu L, Lau C, Paweletz C, Jaslowski A, Gerstner GJ, Baggstrom MQ, Graziano S, Bearden J 3rd, Vokes EE. Effect of Erlotinib Plus Bevacizumab vs Erlotinib Alone on Progression-Free Survival in Patients With Advanced EGFR-Mutant Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019 Oct 1;5(10):1448-1455. doi: 10.1001/jamaoncol.2019.1847.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 11, 2019): 88
• Original Estimated Enrollment (submitted: February 9, 2012): 118
• Actual Study Completion Date: August 18, 2020
• Actual Primary Completion Date: February 13, 2018 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01532089
• Other Study ID Numbers: RC1126; NCI-2012-00053 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 11-006881; RC1126 ( Other Identifier: Academic and Community Cancer Research United ); P30CA015083 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Academic and Community Cancer Research United
• Original Responsible Party: Thomas E. Stinchcombe, M.D., (ACCRU), Academic and Community Cancer Research United, Study Chair
• Current Study Sponsor: Academic and Community Cancer Research United
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Thomas E Stinchcombe; Academic and Community Cancer Research United

• PRS Account: Academic and Community Cancer Research United
• Verification Date: July 2020