A Study Comparing MB02 and Avastin® in Subjects With Stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

1. Males and female subjects aged ≤ 18 years to ≤ 80 years.
2. Signed informed consent must be obtained before initiation of any study-specific procedures or treatment as confirmation of the subject's awareness and willingness to comply with the study requirements.
3. Subjects should have newly diagnosed or recurrent Stage IIIB/IV (defined by seventh edition of the Tumor, Node and Metastasis (TNM) classification for Lung Cancer, 2010) non-squamous NSCLC not amenable to curative intent surgery, and not have received any systemic therapy for advanced disease (exclusion criteria 3 and 4). For subjects with recurrent disease, at least 6 months must have elapsed before randomization from previous adjuvant treatment.
4. Previous radiation therapy if completed >4 weeks before randomization. Palliative radiotherapy to bone lesions is allowed if completed >2 weeks of randomization.
5. Subjects must have at least 1 unidimensional measurable lesion per RECIST version 1.1 (assessed locally).
6. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 at Screening.

7. Subjects must have adequate hepatic, renal and hematologic function defined as:

   • Hepatic function: bilirubin level \<1.5 the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels\<2.5×ULN.
   • Renal function: serum creatinine level \<1.5×ULN, calculated creatinine clearance (CrCl) >50 mL/min (Cockcroft-Gault formula), urine protein to creatinine ratio \<1. Subjects with urine protein-to-creatinine ratio >1 may be enrolled if they have \<1 g of protein in 24-hour urine collection.
   • Hematological function: Absolute neutrophil count >1.5×109 /L; platelets >100×109 /L, hemoglobin (Hb) >9 g/dL.
   • Adequate coagulation parameters such as: INR ≤ 2.0 and aPTT ≤ 1.5 x ULN within 7 days prior to randomization for patients not receiving anticoagulation therapy.
8. Eligible subjects must have a systolic blood pressure of ≤ 140 mm Hg and a diastolic blood pressure of ≤90 mm Hg at screening.
9. Women of childbearing potential, and their partners, must agree to adhere to pregnancy prevention methods throughout the duration of the study (including the Follow-up visits, where applicable). Women of childbearing potential are defined as those who are not surgically sterile (did not underwent bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) and not postmenopausal.

Subjects and their partners must agree to use a highly effective method of contraception, to avoid women becoming pregnant throughout the course of the study. Medically acceptable forms of birth control can include the following, with approval of the treating physician:

• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence.

  10. Non fertile women can be included, that is, those who are physiologically incapable of becoming pregnant, because of:
• Hysterectomy.
• Bilateral oophorectomy (ovariectomy).
• Bilateral tubal ligation or,
• Postmenopausal women defined as:

Subjects not using hormone replacement therapy (HRT) and have experienced total cessation of menses for ≥ 1 year and be greater than 45 years of age, OR, in questionable cases, have a follicle stimulating hormone >40 mIU/mL and an estradiol value \<40 pg/mL (\<140 pmol/L).

Subjects must discontinue HRT before study enrolment because of the potential for inhibition of cytochrome enzymes that metabolize estrogens and progestins. For most forms of HRT, at least 2 to 4 weeks must elapse between the cessation of HRT and determination of menopausal status; the length of this interval depends on the type and dosage of HRT.

If a female subject is determined not to be postmenopausal, that subject must use adequate contraception, as defined immediately above (inclusion 8).

Exclusion Criteria:

1. Inability to comply with protocol procedures.
2. Participation in another clinical trial or treatment with another investigational agent within 4 weeks or 5 half-lives of investigational agent before randomization, whichever is longer.
3. Subjects previously treated with monoclonal antibodies or small molecule inhibitors against Vascular Endothelial Growth Factor (VEGF) or VEGF receptors, including Avastin®.
4. Subjects who have received previous chemotherapy, immunotherapy, targeted therapy, or biological therapy for their lung cancer. Note: Adjuvant and neo- adjuvant therapy are permitted (see: inclusion criterion 3).
5. Subjects who have known central nervous system disease, with the exception of subjects with treated brain metastases who have completed treatment (radiation, surgery or stereotactic surgery) and have not received steroids for at least 4 weeks before randomization. Subjects with central nervous system metastases treated by neurosurgical resection or brain biopsy performed within 8 weeks before randomization will be excluded. Subjects with known or history of brain metastases must undergo brain imaging during screening.
6. Current or recent (within 10 days of the first dose of study treatment) use of aspirin (at least 325 mg/day) or other nonsteroidal anti-inflammatory drugs with antiplatelet activity or treatment with dipyridamole (Persantine®), ticlopidine (Ticlid®), clopidogrel (Plavix®), or cilostazol (Pletal®).
7. Current or recent (within 5 days) use of therapeutic anticoagulation or use of thrombolytic agent. Prophylactic use of low molecular weight heparin is allowed.
8. Subjects with an INR >2, unless receiving active anticoagulation treatment, will be excluded.
9. Subjects who have a diagnosis of small cell carcinoma of the lung or squamous cell carcinoma of the lung. Mixed tumors should be categorized according to the predominant histology. If small cell elements are present, the subject will be excluded.
10. Subjects with known tumors that harbor activating epidermal growth factor receptor and anaplastic lymphoma receptor tyrosine kinase (assessed locally).
11. Subjects who have a history of hypersensitivity to the active substance (bevacizumab, carboplatin, and/or paclitaxel) or any of the excipients (such as trehalose dehydrate, sodium phosphate, or polysorbate 20).
12. Subjects with known active viral infection, including but not limited to: hepatitis B, hepatitis C, or HIV.
13. Subjects who are pregnant or breastfeeding. Women of child-bearing potential must have a negative pregnancy test at Screening.
14. Subjects with previous major surgery, open biopsy, open pleurodesis, or significant traumatic injury within 4 weeks before randomization or those anticipated to require major surgery during the study.
15. Subjects who have had a core biopsy taken or have had another minor surgical procedure, excluding placement of vascular access device, closed pleurodesis, thoracentesis, and mediastinoscopy, within 1 week of randomization.
16. Subjects with a history of abdominal fistula, GI perforation, intra-abdominal abscess within 6 months of randomization.
17. Subjects with a nonhealing wound, active ulcer, or untreated bone fracture.
18. Subjects with previous history of hypertensive crisis or hypertensive encephalopathy.
19. Subjects with New York Heart Association Grade II or greater congestive heart failure, or angina, myocardial infarction within 6 months before randomization; symptomatic arrhythmia or serious cardiac arrhythmia requiring medication; abnormal left ventricular ejection fraction \< 50% assessed by ultrasound or multigated acquisition scan.
20. Subjects with a previous malignancy within 3 years of randomization (other than superficial basal cell and superficial squamous (skin) cell carcinoma, or carcinoma in situ of the uterine cervix, bladder, or prostate).
21. Subjects with history of a significant vascular event within 6 months before randomization (including, but not limited to myocardial infarction and stroke or transient ischemic attack).
22. Subjects with known bleeding diathesis or significant coagulopathy defined as a bleeding event grade ≥ 2 within 3 months before randomization.
23. Subjects with history of grade ≥2 hemoptysis within 6 months before randomization (≥0.5 teaspoons of bright red blood per event).
24. Subjects with a tumor(s) invading or compressing major blood vessels.