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EGFR Exon 19 Deletion MutationPhase 2NCT01532089

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

A Phase 2 study testing Bevacizumab, Erlotinib and Erlotinib Hydrochloride in people with EGFR Exon 19 Deletion Mutation and EGFR NP_005219.2:p.L858R, run by Academic and Community Cancer Research United at 19 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Bevacizumab, Erlotinib and Erlotinib Hydrochloride
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
88 participants
Where
19 sitesUnited States
Study dates
16 Mar 2012to 18 Aug 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 17Show fewer
  • 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

Who cannot join

  • 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
Show all 27Show fewer
  • 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

Trial locations and contacts

19 sites in 1 country.

19 sites in 1 country

United States19 sites

  • Michigan Cancer Research Consortium NCORP

    Ann Arbor, Michigan, 48106

  • UNC Lineberger Comprehensive Cancer Center

    Chapel Hill, North Carolina, 27599

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • Heartland Cancer Research NCORP

    Decatur, Illinois, 62526

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • Hematology Oncology Associates of Central New York-East Syracuse

    East Syracuse, New York, 13057

  • Sanford Broadway Medical Center

    Fargo, North Dakota, 58122

  • Cancer Research Consortium of West Michigan NCORP

    Grand Rapids, Michigan, 49503

  • Saint Vincent Hospital Cancer Center Green Bay

    Green Bay, Wisconsin, 54301

  • New Hampshire Oncology Hematology PA-Hooksett

    Hooksett, New Hampshire, 03106

  • UC San Diego Moores Cancer Center

    La Jolla, California, 92093

  • Illinois CancerCare-Peoria

    Peoria, Illinois, 61615

  • Rapid City Regional Hospital

    Rapid City, South Dakota, 57701

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • Coborn Cancer Center at Saint Cloud Hospital

    Saint Cloud, Minnesota, 56303

  • Upstate Carolina CCOP

    Spartanburg, South Carolina, 29303

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • State University of New York Upstate Medical University

    Syracuse, New York, 13210

  • Carle Cancer Center NCI Community Oncology Research Program

    Urbana, Illinois, 61801

Other trials in United States

About this study

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

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. 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:

  1. 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:

  1. 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.

Being tested
Bevacizumab, Erlotinib, Erlotinib Hydrochloride, Laboratory Biomarker Analysis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BevacizumabBiological

    Also called Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin

    Given IV

  • ErlotinibDrug

    Given PO

  • Erlotinib HydrochlorideDrug

    Also called Cp-358,774, OSI-774, Tarceva

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

Study groups in NCT01532089
Study groupRoleWhat they receive
Arm A (erlotinib hydrochloride)Active comparatorPatients 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)
Receives: Drug: Erlotinib; Drug: Erlotinib Hydrochloride; Other: Laboratory Biomarker Analysis
Arm B (erlotinib hydrochloride, bevacizumab)ExperimentalPatients 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)
Receives: Biological: Bevacizumab; Drug: Erlotinib; Drug: Erlotinib Hydrochloride; Other: Laboratory Biomarker Analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression Free Survival (PFS)

    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.

    Measured: Time from randomization to disease progression and death of any cause, whichever comes first, assessed up to 6 years

Secondary outcomes (4)

  1. Overall Survival

    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.

    Measured: Time from randomization to death of any causes, assessed up to 6 years

  2. 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)

    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).

    Measured: Up to 6 years

  3. Progression Free Survival of Patients With Different Mutation Types (Exon Deletion 19 Versus Exon 21 L858R)

    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.

    Measured: From the date of randomization to the date of disease progression or death of any cause, whichever comes first, assessed up to 6 years

  4. Number of Patients Experiencing Toxicity

    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.

    Measured: Up to 42 days after treatment discontinuation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Feb 2012 (estimated)
  2. Study start16 Mar 2012
  3. Primary completion13 Feb 2018
  4. Study completion18 Aug 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
88 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01532089
Sponsor's protocol ID
RC1126
Other IDs
NCI-2012-00053, 11-006881, RC1126, P30CA015083
Status last verified
Jul 2020
First submitted
7 Feb 2012
Last updated
6 Oct 2020
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

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.

    PubMed 31393548

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Bevacizumab, Erlotinib and Erlotinib Hydrochloride in people with EGFR Exon 19 Deletion Mutation and EGFR NP_005219.2:p.L858R, run by Academic and Community Cancer Research United at 19 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 19 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Dec 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01532089, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Oct 2020.

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