Study Comparing Bevacizumab + Erlotinib vs Erlotinib Alone as First Line Treatment of Patients With EGFR Mutated Advanced Non Squamous Non Small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to test whether the combination of bevacizumab and erlotinib can prolong progression free survival as compared with erlotinib alone as first-line treatment in patients with non small cell lung cancer (NSCLC) with activating mutation of EGFR.

Detailed Description
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The co-primary objectives are to assess investigator-assess, and blinded independent centrally-reviewed progression-free survival .

Official Title
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A Randomized Open-label Phase 3 Trial Comparing Bevacizumab + Erlotinib vs Erlotinib Alone as First Line Treatment of Patients With EGFR Mutated Advanced Non Squamous Non Small Cell Lung Cancer

Conditions
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Non-squamous Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Erlotinib
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Histological documentation of primary non squamous lung carcinoma Stage IV or IIIB disease with supraclavicular metastatic nodes (according to TNM 7th edition) Activating epidermal growth factor receptor mutation (exon19 deletion or exon 21 L858R mutation or other activating/sensitizing mutations, such as exon 21 L861Q, exon 18 G719S, G719A and G719C, exon 20 S768I and V769L). EGFR mutation testing must be performed at participating centres in a certified lab (AIOM-SIAPEC program or other European Quality Assurance [EQA] schemes) Clinical or radiologic evidence of disease (at least one target or non target lesion according to RECIST 1.1) ECOG performance status 0 to 2 Life expectancy > 3 months Use of an acceptable mean of contraception for men and women of childbearing potential Written informed consent. Exclusion Criteria: EGFR T790M mutation alone or exon 20 insertions as unique mutation Tumors with a squamous component Prior chemotherapy or any other medical treatment for advanced NSCLC (previous neoadjuvant or adjuvant chemotherapy is allowed if > 6 months before randomisation) Radiotherapy to any site for any reason within 28 days prior to randomization (palliative radiotherapy to bone lesions is allowed if ≥ 14 days before randomization) Full-dose anticoagulation with warfarin Current or recent (within 10 days of enrolment) use of aspirin (>325 mg/day) or chronic use of other full-dose nonsteroidal anti-inflammatory drugs (NSAIDs) with anti-platelet activity 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 Inadequate coagulation parameters: activated partial thromboplastin time (APTT) >1.5 x the upper limit of normal (ULN) or INR >1.5 Inadequate liver function, defined as: serum (total) bilirubin >1.5 x ULN AST/SGOT or ALT/SGPT >2.5 x ULN Inadequate renal function, defined as: serum creatinine >2.0 mg/dl or >177 micromol/l urine dipstick for proteinuria >2+. Patients with > o = 1+ proteinuria at baseline dipstick analysis must undergo a 24-hour urine collection and must demonstrate ≤1g of protein in their 24-hour urine collection. Pregnancy or breast-feeding Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure >100 mmHg on antihypertensive medications) History of gross hemoptysis within 3 months prior to randomization unless definitively treated with surgery or radiation History of any of the following within 6 months prior to randomisation: serious systemic disease, unstable angina, New York Heart Association (NYHA) Grade 2 or greater Congestive Heart Failure (CHF), unstable symptomatic arrhythmia requiring medication, clinically significant peripheral vascular disease, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess Serious, non-healing wound, ulcer, or bone fracture Evidence of bleeding diathesis or coagulopathy or other serious or acute internal bleeding within 6 months prior to randomization Central Nervous System (CNS) bleeding; history or clinical evidence of CNS stroke (hemorrhagic or thrombotic) within the last 6 months In-patient surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization Minor surgical procedure, fine needle aspirations or core biopsy within 7 days prior to randomization Anticipation of need for a major surgical procedure during the course of the study Inability to take oral medication or requirement for intravenous (IV) alimentation or total parenteral nutrition with lipids, or prior surgical procedures affecting absorption Evidence of confusion or disorientation, or history of major psychiatric illness that may impair the patient's understanding of the Informed Consent Form or his/her ability to comply with study requirements Any other invasive malignancies within 5 years (except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer or surgically resected prostate cancer with normal PSA) Brain metastasis Patients who have had radiotherapy ≥ 4 weeks prior to the first dose of study treatment, but who are still experiencing acute toxic effects of radiotherapy Known HIV positive patients (patients with both acute or chronic infection are excluded) Active HBV or HCV infection (patients with chronic non-active infection are eligible) Any already known inflammatory changes of the surface of the eye at baseline Any other concomitant pathologies or laboratory alterations that prevent or contraindicate the use of erlotinib or bevacizumab.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: erlotinib and bevacizumab<br> | Drug: Erlotinib<br>* given orally 150 mg daily<br>Drug: Bevacizumab<br>* 15 mg/kg intravenously every 21 days.<br>|
| Active Comparator: erlotinib<br> | Drug: Erlotinib<br>* given orally 150 mg daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression free survival | as determined by investigator | up to 2 years | 
| progression free survival | as determined by an independent central review board blinded to study treatment | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival |  | 1 year | 
| changes in quality of life scores from baseline |  | up to 2 years | 
| number of patients with complete and partial responses , investigator assessed |  | 6 months | 
| number of patients with complete and partial responses , centrally reviewed |  | 6 months | 
| worst grade toxicity per patient |  | up to one year | 
| progression free survival according to type of EGFR mutation (exon 19del, exon 21L858R, other) |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV, stage IIIB, EGFR mutation, non-squamous, liquid biopsy, erlotinib, bevacizumab