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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

Phase 2
18 Years
Open (Enrolling)
Stage IV Non-small Cell Lung Cancer

Thank you

Trial Information

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

PRIMARY OBJECTIVES: I. To determine the progression-free survival of erlotinib (erlotinib)
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 orally (PO) once daily (QD) on days 1-21. ARM B: Patients receive
erlotinib 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
periodically for up to 5 years.

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 -Measureable 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 glutamic pyruvic 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

- Prothrombin time (PT) =< 1.5 x ULN

- Partial thromboplastin time (PTT) =< ULN

- Urine dipstick proteinuria < 2+ * 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 Alberta Cooperative Conservation Research Unit (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 because this study involves an investigational agent whose genotoxic,
mutagenic and teratogenic effects on the developing fetus and newborn are unknown *
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 MD

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations 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) * 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

- Ongoing or active infection, symptomatic congestive heart failure (New York Heart
Association >= grade 2), cardiac arrhythmia, psychiatric illness/social situations,
or any other medical condition that would limit compliance with study requirements

- 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 current or recent (=< 10 days prior to randomization
use of full- dose (i.e. therapeutic dose) oral or parenteral anticoagulants or
thrombolytic agent for therapeutic purposes * Note: Prophylactic use of
anticoagulants is allowed

- 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 intrabdominal 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: Treated brain metastases are defined as having no evidence of progression or
hemorrhage after treatment and no ongoing requirement for dexamethasone, for at least
7 days as ascertained by clinical examination and brain imaging (magnetic resonance
imaging [MRI] or computed tomography [CT]) during the screening period;
anticonvulsants (stable dose) are allowed; 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

- 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 =< 28 days prior to randomization *Note: Palliative
radiotherapy to bone lesions and WBRT > 14 days prior to randomization is allowed

- Receiving any medications or substances that are strong or moderate inhibitors of
cytochrome P450 3A4 (CYP3A4) are prohibited =< 7 days prior to registration

- Receiving any medications or substances that are inducers of CYP3A4 use of inducers
are prohibited =< 7 days prior to registration

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome 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.

Outcome Time Frame:

From the date of randomization to the date of disease progression or death of any cause, assessed up to 5 years

Safety Issue:


Principal Investigator

Thomas Stinchcombe, M.D.

Investigator Role:

Study Chair

Investigator Affiliation:

Academic and Community Cancer Research United


United States: Food and Drug Administration

Study ID:




Start Date:

March 2012

Completion Date:

Related Keywords:

  • Stage IV Non-Small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



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