Overview

This trial is active, not recruiting.

Conditions egfr activating mutation, stage iv non-small cell lung cancer
Treatments bevacizumab, erlotinib hydrochloride, laboratory biomarker analysis
Phase phase 2
Targets VEGF, EGFR
Sponsor Academic and Community Cancer Research United
Collaborator National Cancer Institute (NCI)
Start date March 2012
End date March 2018
Trial size 86 participants
Trial identifier NCT01532089, 11-006881, NCI-2012-00053, P30CA015083, RC1126

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.

United States California, Illinois, Michigan, Missouri, ND, New Hampshire, New York, North Dakota, Ohio, South Carolina, South Dakota, and Wisconsin
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking single blind (outcomes assessor)
Primary purpose treatment
Arm
(Active Comparator)
Patients receive erlotinib hydrochloride PO QD on days 1-21.
erlotinib hydrochloride Cp-358,774
Given PO
laboratory biomarker analysis
Correlative studies
(Experimental)
Patients receive erlotinib hydrochloride as in Arm A and bevacizumab IV over 30-90 minutes on day 1.
bevacizumab Anti-VEGF
Given IV
erlotinib hydrochloride Cp-358,774
Given PO
laboratory biomarker analysis
Correlative studies

Primary Outcomes

Measure
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

Secondary Outcomes

Measure
EGFR mutations detected in plasma DNA
time frame: Up to 5 years
EGFR mutations detected in tumor DNA
time frame: Up to 5 years
EGFR T790M mutations
time frame: Up to 5 years
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
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
Overall survival
time frame: Time from randomization to death of any causes, assessed up to 5 years
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
Prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods
time frame: Baseline
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
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

Eligibility Criteria

Male or female participants at least 18 years old.

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

Additional Information

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
Principal investigator Thomas Stinchcombe
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.
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by Academic and Community Cancer Research United.