Clinical trial NCT03296163
Conditions: Non-small Cell Lung Cancer
Sponsor: mAbxience Research S.L.
Start date: 2018-02-06; Completion date: 2020-02-27
Enrollment: 627 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, multinational, double-blind, 1:1 randomized, parallel-group, equivalence Phase 3 study to compare the efficacy and safety of MB02 plus chemotherapy (carboplatin and paclitaxel) versus Avastin® plus chemotherapy (carboplatin and paclitaxel) in subjects with Stage IIIB/IV non-squamous NSCLC

Detailed description:
Efficacy parameters, safety profiles and immunogenicity will be compared between MB02 (Bevacizumab Biosimilar Drug) and European (EU)-approved Avastin®

Arms: arm 1: MB02 (Bevacizumab Biosimilar Drug) + Carboplatin/Paclitaxel arm 2: EU-approved Avastin® + Carboplatin/Paclitaxel
Interventions: intervention 1: MB02 (Bevacizumab Biosimilar Drug) intervention 2: EU-approved Avastin® intervention 3: Carboplatin intervention 4: Paclitaxel
Intervention descriptions: intervention 1: 15 mg/kg IV every 3 weeks on Day 1 intervention 2: 15 mg/kg IV every 3 weeks on Day 1 intervention 3: Carboplatin Area under the curve (AUC) 6 IV every 3 weeks on Day 1 for 6 cycles intervention 4: Paclitaxel 200 mg/m2 IV every 3 weeks on Day 1 for 6 cycles

Protocol documents:
Prot_000.pdf: 
Protocol Title:
STELLA – A Randomized, Multicenter, Multinational, 
Double-Blind Study to Assess the Efficacy and Safety of 
MB02 (Bevacizumab Biosimilar Drug) Versus Avastin® in 
Combination with Carboplatin and Paclitaxel for the 
Treatment of Subjects with Stage IIIB/IV Non-squamous 
Non-Small Cell Lung Cancer (NSCLC)
NCT Number:
NCT03296163
Protocol version 
date:
Version 4.0, 24 May 2019
 


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CLINICAL STUDY PROTOCOL
STELLA – A Randomized, Multicenter, Multinational, Double-Blind Study
to Assess the Efficacy and Safety of MB02 (Bevacizumab Biosimilar Drug)
Versus Avastin® in Combination with Carboplatin and Paclitaxel for the
Treatment of Subjects with Stage IIIB/IV Non-squamous Non-Small Cell
Lung Cancer (NSCLC)
Protocol Number:
MB02-C-02-17
EudraCT Number:
2017-001769-26
InvestigationalProduct:
Bevacizumab biosimilar drug (MB02)
Phase:
Phase 3
Sponsor:
mAbxience
Manuel Pombo Angulo, 28, 3rd Floor
Madrid, Spain
Protocol Date:
04 August 2017
Protocol Version:
Version 1.0
Protocol Amendment 1:
03 December 2018 (Version 3.0)
Protocol Amendment 2:
24 May 2019 (Version 4.0)
CONFIDENTIAL
This protocol may not be reproduced or communicated to a third party without the
written permission of mAbxience




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2 
STUDY PERSONNEL 
 
Sponsor Personnel 
 
Medical Monitor 
 
Name: 
Title: 
Medical Advisor 
Address: 
mAbxience Research SL 
C/ Manuel Pombo Angulo, 28, 3rd floor 
28050 - Madrid 
Spain 
Telephone No.: 
 
Project Manager 
 
Name: 
Title: 
Clinical Project Manager 
Address: 
mAbxience Research SL 
C/ Manuel Pombo Angulo, 28, 3rd 
floor 28050 - Madrid 
Spain 
Telephone No.: 
 
 
Other Personnel 
 
Medical Monitor 
 
Name: 
Title: 
Senior Medical Director, Global Oncology & Hematology 
Address: 
INC Research GmbH – a Syneos Health Company 
Katzbergstr. 1 | D-40764 Langenfield 
Germany 
Telephone No.: 
 
Project Manager 
 
Name: 
Title: 
Senior Project Manager, Oncology 
Address: 
INC Research GmbH – a Syneos Health Company 
1 Pinehurst Road 
Farnborough, Hants 
GU14 7BF 
United Kingdom 
Telephone No.: 


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3 
SYNOPSIS 
 
Protocol Number: 
MB02-C-02-17 
Title: 
STELLA – A Randomized, Multicenter, Multinational, Double-Blind Study to Assess the 
Efficacy and Safety of MB02 (Bevacizumab Biosimilar Drug) Versus Avastin® in 
Combination with Carboplatin and Paclitaxel for the Treatment of Subjects with Stage 
IIIB/IV Non-squamous Non-Small Cell Lung Cancer (NSCLC) 
Investigational Product: 
MB02 
Study Centers: 
Approximately 150 sites and 19 countries 
Phase: 
Phase 3 
Objectives: 
Primary objective: To compare the objective response rates (ORRs) of MB02 and European 
Union (EU) approved Avastin® when administered in combination with carboplatin and 
paclitaxel in subjects with Stage IIIB/IV non-squamous NSCLC as assessed according to 
Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). 
Secondary objective(s): 
x To evaluate the safety profile of MB02 compared with Avastin® in subjects with 
Stage IIIB/IV non-squamous NSCLC as per National Cancer Institute-Common- 
Toxicity Criteria for Adverse Events (NCI-CTCAE; version 4.03). 
x To assess the potential immunogenicity of MB02 compared with that of Avastin® 
assessed through determination of antidrug antibodies (ADA). 
x To assess progression-free survival (PFS) and overall survival (OS) at cutoff points at 
Week 18 and at Week 52 compared with those of Avastin®. 
 
Study Design: 
This is a multicenter, multinational, double-blind, 1:1 randomized, parallel-group, 
equivalence Phase 3 study to compare the efficacy and safety of MB02 plus chemotherapy 
(carboplatin and paclitaxel) versus Avastin® plus chemotherapy (carboplatin and paclitaxel) 
in subjects with Stage IIIB/IV non-squamous NSCLC. MB02/Avastin® plus chemotherapy 
will be repeated every 21 days for 6 cycles unless there is evidence of disease progression or 
intolerance of the study treatment. After 6 cycles (i.e., at the start of Cycle 7), subjects can 
continue to receive MB02/Avastin® monotherapy treatment every 3 weeks until evidence of 
disease progression or until unacceptable toxic effects develop. The study ends at Week 52, 
after Week 52, all subjects (including those randomized to Avastin® during the study) will be 
offered the opportunity to continue receiving biosimilar MB02 monotherapy until disease 
progression, unacceptable toxicity, lost to follow-up, withdrawal of consent, initiation of any 
new treatment or death. For specific information about post Week 52 procedures refer to 
Section 8.6. 


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Subjects eligible for the current study will be randomized centrally in a 1:1 manner and 
stratified by sex (male/female), smoking status (smoker/nonsmoker), disease diagnosis 
(newly diagnosed/recurrent disease) and stage (IIIB/IV). For stratification purposes, former 
smokers will be classified as smokers if they stopped less than 5 years ago and as nonsmokers 
if they have not smoked for the last 5 years or more or have stopped prior to study and cannot 
provide information on when they stopped smoking. 
Tumor assessments will be performed at intervals of 6 weeks, from Cycle 1 Day 1 until the 
end of Cycle 6 (i.e., 18 weeks after first study drug administration); after Cycle 6, tumor 
assessments will be performed at intervals of 9 weeks until evidence of disease progression 
and/or the start of new antitumor treatment, death, or Week 52 (End-of-Study Visit), 
whichever occurs first. 
Subjects who withdraw for any reason other than progression of disease (PD) or withdrawal 
of consent will be followed up every 9 weeks with tumor assessment until PD and/or the start 
of new antitumor treatment, subject decision, death, or Week 52 (End-of-Study Visit), 
whichever occurs first. Subjects who withdraw because of PD and/or initiate new antitumor 
therapy or those who progress during the Follow-up period will then be followed up for 
survival at intervals of 12 weeks until death or Week 52 (End-of-Study Visit), whichever 
occurs first. No further tumor assessment will be required. 
An independent radiology review committee will assess the primary efficacy endpoint 
(observed response rate at Week 18) using computed tomography (CT) and/or magnetic 
resonance imaging (MRI) according to RECIST version 1.1 criteria. A Data Safety 
Monitoring Board (DSMB) will assess the safety data periodically and will recommend to the 
Sponsor whether to continue, modify, or stop the trial. This decision will be based on benefit 
risk evaluation. 
Number of Subjects: 
Based on recommendation of two different agencies, two different analyses will be 
performed: one based on Risk Ratio (United States [US] Food and Drug Administration 
[FDA]) and one based on Risk Difference (RD; European Medicines Agency [EMA]). 
Hence, the sample size calculation should ensure that sufficient power is retained on both 
analyses. No multiplicity correction will be applied. 
The determination of equivalence will be based on the Intent-to-Treat (ITT) population. The 
per protocol population will be used as a supportive population for evaluating sensitivity of 
main analysis. 
 
Risk Ratio 
The US FDA requires a primary endpoint of risk ratio (RR) based on ORR, with an 
equivalence margin of [0.73, 1.36]. In order to gain an understanding of the clinical effect of 
the reference treatment, Avastin®, a meta-analysis has been conducted to ascertain the 
expected ORR for the reference arm, including the following references: Sandler et al. (N 
Engl J Med 2006;533:2542-50), Johnson et al. (J Clin Oncol 2004;22:2184-91), Niho et al. 
(Lung Cancer 2012;76:362-7), Reck et al. (Ann Oncol 2010;21:1804-9), and Zhou et al. 
(J Clin Oncol 2015;33:2197-204). The results of this meta-analysis, conducted using 
StatsDirect 3 software, are as follows: 




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x Carboplatin: to achieve an area under the plasma concentration-time curve of 
6 mg/mL × min (AUC6) as an IV infusion on Day 1 of every 3-week treatment cycle 
For up to the first 6 cycles, the study treatment will consist of an initial administration of 
paclitaxel 200 mg/m2 IV over 3 hours, followed by carboplatin AUC6 IV over 15 to 
60 minutes and then, immediately afterward either MB02 or Avastin® 15 mg/kg. MB02 and 
Avastin® will be administered IV. From Cycle 7 onwards, the study treatment will consist of 
either MB02 or Avastin® 15 mg/kg. MB02 and Avastin® monotherapy will be administered 
IV. A window of 30 minutes is allowed between the administration of the 2 chemotherapy 
drugs and/or between the administration of either chemotherapy drug and either study drug 
(MB02 or Avastin®). 
The first MB02 or Avastin® treatment will be administered as a 90-minute infusion. If the 
study drug is well tolerated, the next infusion will be given over a 60-minute period. 
Thereafter, the drug will be given as a 30-minute IV infusion. If the study drug is not well 
tolerated, the instructions from Avastin® Summary of Product Characteristics (SmPC) should 
be followed. 
Retreatment Criteria: 
Further treatment cycles (i.e., Cycle 2 or subsequent) will be administered if the subject 
fulfils all the following retreatment criteria: Absolute neutrophil count > 1.5 × 109/L; 
platelets counts >100,000/PL, hemoglobin level > 9 g/dL, controlled hypertension and 
proteinuria 
< 2+ and all other non-hematological related toxicities have resolved to ≤ grade 1 (except 
alopecia, anorexia, constipation, not optimally treated nausea and/or vomiting and non- 
clinically relevant isolated biochemical abnormalities) or to the subject’s baseline condition. 
Dose Adjustment of MB02/Avastin®: 
Until the Week 18 assessment, any reduction in MB02/Avastin® dose will not be permitted. 
Treatment (both MB02/Avastin® and chemotherapy) should be put on hold in the event of 
toxicities ≥ grade 3, that the investigator considers to be clinically significant and related to 
study treatment. The maximum permitted length of treatment hold is 14 days, equivalent to 
5 weeks from the last treatment dose. Treatment can be restarted when retreatment criteria are 
met. An MB02/Avastin® dose adjustment to weight change may or may not be implemented 
(under investigator’s discretion) if the subject’s body weight changes less than 10% from 
Baseline or from the weight at the last dose adjustment, and must be compulsorily done if the 
subject’s body weight changes by 10% or more from Baseline or from the weight at the last 
dose adjustment. After Week 18, intended dose reduction of MB02/Avastin® is allowed if 
clinically necessary to a dose level of 7.5 mg/kg. No further dose reduction of 
MB02/Avastin® is allowed. 
If a subject discontinues MB02/Avastin® treatment before completing 6 cycles of therapy and 
before the primary endpoint at Week 18, the subject must discontinue study treatment and 
proceed to the End-of-Treatment Visit. 
 
Toxicities should be managed according to the relevant Avastin® SmPCs. If grade 3 toxicity 
recurs upon reintroduction of MB02/Avastin®, the investigator should consider the individual 
benefit versus the risk of continuing therapy. If the event occurs again upon a second 
reintroduction of MB02/Avastin®, treatment should be permanently discontinued. 
The main toxicities anticipated for MB02/Avastin® (on the basis of the product label for EU- 
approved Avastin®) in this study are as follows: 


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x Gastrointestinal (GI) perforations (GI perforations, fistula formation in the GI tract, 
intra-abdominal abscess), fistula formation involving an internal organ. 
x Wound dehiscence and wound healing complications requiring medical intervention. 
x Serious hemorrhage (i.e., requiring medical intervention). 
x Severe arterial thromboembolic events. 
x Life-threatening (grade 4) venous thromboembolic events, including pulmonary 
embolism. 
x Hypertensive crisis or hypertensive encephalopathy. 
x Posterior reversible encephalopathy syndrome. 
x Nephrotic syndrome. 
x Severe hypertension not controlled with medical management. 
x Moderate to severe proteinuria. 
x Severe infusion reactions. 
 
As osteonecrosis of the jaw has been reported for subjects on bevacizumab and invasive 
dental procedures are an identified risk factor, a dental examination and appropriate 
preventive dentistry should be considered before the start of treatment, if clinically indicated. 
Procedures that involve direct osseous injury and placement of dental implants should be 
avoided if not strictly necessary. Caution should be exercised for subjects receiving 
intravenous bisphosphonates. 
Dose modification of chemotherapy 
For the chemotherapy agents paclitaxel/carboplatin, dose adjustments and toxicities will be 
managed according to specific SmPC. 
 
If a subject discontinues paclitaxel and carboplatin before completing 6 cycles of therapy and 
before the primary endpoint at Week 18, the continuation of bevacizumab (MB02 or 
Avastin®, as allocated) as monotherapy should be justified and discussed with the Sponsor 
prior to such a change in schedule. 
 
For additional information please refer to SmPCs for Avastin®, carboplatin, and paclitaxel. 
 
Study Population: 
Inclusion Criteria 
To be eligible for study entry, subjects must satisfy all of the following criteria: 
 
1. Males and female subjects aged t18 years to d80 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 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. For Stage IV disease, malignant pleural or pericardial effusion must be 


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confirmed by cytological examination if the effusion is the only lesion that confirms 
Stage IV of the disease. In all other cases, the cytological confirmation of effusion is 
not mandatory. 
 
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 ECOG performance status ≤1 at Screening. 
 
7. Subjects must have adequate hepatic, renal and hematologic function defined as: 
 
x Hepatic function: bilirubin level <1.5 × ULN, ALT and AST levels<2.5×ULN. 
x Renal function: serum creatinine level <1.5 × ULN, calculated creatinine 
clearance (CrCl) >50 mL/min (Cockroft-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. 
x Hematological function: Absolute neutrophil count >1.5 × 109 /L; platelets >100 
× 109 /L, hemoglobin (Hb) >9 g/dL. 
x Adequate coagulation parameters such as: INR ≤ 2.0 and aPTT ≤ 1.5 × 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: 
 
x 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: 
 
x Hysterectomy. 
x Bilateral oophorectomy (ovariectomy). 
x Bilateral tubal ligation or, 


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x Postmenopausal women defined as: 
 
Subjects not using HRT and who have experienced total cessation of menses for t1 
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 
Subjects will be excluded from the study if 1 or more of the following criteria are applicable: 
 
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 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 malignant 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. 


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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). 


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24. Subjects with a tumor(s) invading or compressing major blood vessels. 
 
Discontinuation from Treatment: 
A subject should be withdrawn from study treatment if, in the opinion of the investigator, it is 
medically necessary, or if it is the wish of the subject. Subjects will be withdrawn from 
treatment for any of the following reasons: 
 
x Progression of disease. 
x Unacceptable toxicity. 
x Withdrawal of consent. 
x Subject decision (may continue in the study for the follow-up visits). 
x Lost to Follow-up. 
x Protocol violation. 
x Death. 
x Investigator decision. 
x Subject becomes pregnant. 
 
The SmPC for Avastin® specifies the following reasons for discontinuation: 
 
x Necrotizing fasciitis. 
x Medically significant hypertension that cannot be adequately controlled with 
antihypertensive therapy. 
x Nephrotic syndrome, grade 4 proteinuria. 
x Arterial thromboembolic reactions. 
x Grade 3 or 4 bleeding. 
x Intracranial bleeding. 
 
If a subject discontinues MB02/Avastin® treatment before completing 6 cycles of therapy and 
before the primary endpoint at Week 18, the subject must discontinue study treatment and 
proceed to the End-of-Treatment Visit. 
 
If a subject discontinues paclitaxel and carboplatin before completing 6 cycles of therapy and 
before the primary endpoint at Week 18, the continuation of bevacizumab (MB02 or 
Avastin®, as allocated) as monotherapy should be justified and discussed with the Sponsor 
prior to such a change in schedule. 
 
Every attempt will be made to conduct follow-up visits until the End-of-Study at Week 52 for 
any subject who discontinues treatment before Week 52. 
 
Discontinuation from Study: 
Subjects can be discontinued from the study for any of the following reasons: 
 
x Withdrawal of consent. 
x Death. 
x Lost to Follow-up. 
x Protocol violation. 
x Termination of the study by the Sponsor. 
x Subject becomes pregnant. 


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Re-screening is not allowed. 
Subjects who discontinue from the study prematurely after randomization will not be 
replaced. Subjects are free to withdraw from the study at any time without providing 
reason(s) for withdrawal and without prejudice to further treatment. The reason(s) for 
withdrawal will be documented in the electronic case report form (eCRF). 
 
Every attempt will be made to conduct the assessments scheduled for the End-of-Study Visit 
in any subject who discontinues from the study. The aim is to record data in the same way for 
discontinued subjects as for subjects who completed the study. 
 
Concomitant medications allowed: 
x Antihypertensive: No limitations in type of medication according to the investigators 
discretion. 
x Antiemetic premedication may be used for nausea; paclitaxel premedication by anti- 
histamine receptor (H1 and H2) steroids is allowed. 
x Low molecular weight heparins may be used for the treatment of deep vein 
thrombosis or pulmonary embolism, if they occur. 
x Antidiarrheals: Used as needed per investigator’s discretion. 
x Analgesics: Used as needed per investigator’s discretion. 
x Corticosteroids and/or bisphosphonates for the treatment of bone metastases. 
x Megestrol acetate, when prescribed for appetite stimulation. 
x Primary and secondary prophylaxis with granulocyte colony-stimulating factor, 
according to the investigator’s judgement. 
x Erythropoietin. 
 
Additional details are provided in protocol Section 7.4.8. 
 
Primary Endpoint: 
Objective Response Rate: Objective response (OR) will be assigned for a subject if the 
subject displays either complete response (CR) or partial response (PR) per RECIST version 
1.1 at Week 18 as assessed by independent review. 
Secondary Efficacy Endpoints: 
Progression Free Survival: PFS will be defined as the time from randomization to subsequent 
confirmed progression per RECIST version 1.1, measured in weeks and will be analyzed for 
all subject data at cutoff points at Week 18 and at Week 52. 
Overall Survival: OS will be defined as the time from randomization to subsequent death, 
measured in weeks and will be analyzed for all subject data at cutoff points at Week 18 and at 
Week 52. 
Efficacy: 
Tumor assessments will be performed at intervals of 6 weeks, from Cycle 1 Day 1 until the 
end of Cycle 6 (i.e., 18 weeks after first study drug administration); after Cycle 6, tumor 
assessments will be performed at intervals of 9 weeks until evidence of disease progression 
and/or the start of new antitumor treatment, death, or Week 52 (End-of-Study Visit), 
whichever occurs first. Tumor assessment schedule is not linked to the treatment schedule: in 
case of treatment delays, tumor assessment should be continued according to the initial 
schedule. 


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Subjects who withdraw for any reason other than PD or withdrawal of consent will be 
followed up every 9 weeks with tumor assessment until PD and/or the start of new antitumor 
treatment, subject decision, death, or Week 52 (End-of-Study Visit) whichever occurs first. 
Subjects who withdraw because of PD and/or initiate new antitumor therapy or those who 
progress during the Follow-up period will then be followed up for survival at intervals of 12 
weeks until death or Week 52 (End-of-Study Visit) whichever occurs first. No further tumor 
assessment will be required. 
Immunogenicity: 
Blood samples will be taken to determine serum biomarkers (antidrug antibodies) through 52 
weeks after first study drug administration. Analysis of immunogenicity endpoints will be 
conducted by an external provider. 
Safety: 
Safety will be monitored by: incidence, nature, and severity of adverse events (AEs), 
including adverse drug reactions graded according to NCI-CTCAE (version 4.03); incidence 
of clinical laboratory value abnormalities (hematology, clinical chemistry, and urinalysis); 
physical examination; ECOG performance status; 12-lead electrocardiogram (ECG), vital 
sign assessment and brain CT (in subjects with history of brain metastases only). 
Statistical Analysis: 
The statistical analysis will aim to demonstrate equivalence in terms of ORR between MB02 
and Avastin®. 
The ITT analysis set will consist of all randomized subjects (subjects will be analyzed under 
randomized treatment); the per protocol set (PPS) with regards to the primary endpoint will 
consist of all subjects in the ITT population who complete at least the first 6 cycles of 
treatment and for whom no major protocol deviations affecting efficacy occur until Week 18 
(subjects will be analyzed under randomized treatment); the safety analysis set (SAF) will 
consist of all randomized subjects who received at least 1 administration of study drug. On 
the SAF, all subjects will be analyzed under the actual treatment received. 
For RR (FDA recommendations) equivalence on the primary endpoint will be declared if the 
2-sided 90% CI of the strata adjusted using the Cochran- Mantel-Haenszel estimate of the RR 
lies entirely within the range 0.73 (excluded) to 1.36 (excluded). This primary analysis will 
be conducted in the ITT population. 
For RD (EMA recommendation), equivalence on the primary endpoint will be declared if the 
2-sided 90% CI of the strata adjusted Cochran- Mantel-Haenszel estimate of the RD lies 
within the range -12% (excluded) to +12% (excluded). This primary analysis will be 
conducted in the ITT population. 
For additional equivalence criteria on the primary endpoint required by regulatory bodies 
(i.e., Pharmaceuticals and Medical Devices Agency, [PMDA]), 90% and 95% for RR and 
RD will also be provided in the ITT population. 
Progression-free survival will be presented using Kaplan-Meier figures and estimates and 
estimated median (95% CI) (if available), along with the log-rank test to compare the survival 
distributions; a Cox proportional hazards model will be used to estimate the hazard ratio (90% 
CI) of MB02 compared with Avastin® at cutoff points at Week 18 and Week 52. 
Overall survival will be analyzed in the same way. For both assessments, all subject data will 
be included as accrued up to the cutoff time point. For example, if a subject has survival data 
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Descriptive analysis of safety variables will be performed on the SAF. Further information 
will be provided in the Statistical Analysis Plan (SAP). 


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4 
TABLE OF CONTENTS 
1 
Protocol Approval Signatures ....................................................................................... 2 
2 
Study Personnel .............................................................................................................. 3 
3 
Synopsis ........................................................................................................................... 4 
4 
Table of Contents ......................................................................................................... 16 
List of Abbreviations and Definition of Terms ......................................................................... 21 
 
5  
 
5.1 
Introduction .................................................................................................................. 23 
Background: Non-Small Cell Lung Cancer .............................................................. 23 
5.2 
Reference Therapy (Bevacizumab; Avastin®) .......................................................... 23 
5.3 
Investigational Product (MB02; Bevacizumab biosimilar) ..................................... 24 
5.3.1 
Nonclinical Data ......................................................................................... 24 
5.3.2 
Clinical Data ............................................................................................... 25 
5.4 
Rationale for Current Study ....................................................................................... 25 
5.5 
Additional Information on Non-Investigational Medicinal Products ................... 26 
6  
Study Objectives ........................................................................................................ 27 
6.1 
Primary Objective ........................................................................................................ 27 
6.2 
Secondary Objectives ................................................................................................... 27 
7  
Investigational Plan ................................................................................................... 28 
7.1 
Overall Study Design and Plan: Description ............................................................ 28 
7.1.1 
Schedule of Assessments .............................................................................. 30 
7.2 
Discussion of Study Design ....................................................................................... 33 
7.3 
Selection of Study Population ................................................................................... 33 
7.3.1 
Number of Planned Subjects ..................................................................... 33 
7.3.2 
Inclusion Criteria ........................................................................................ 33 
7.3.3 
Exclusion Criteria ......................................................................................... 35 
7.3.4 
Removal of Subjects From Therapy or Assessments ................................. 37 
7.3.4.1 
Removal of Subjects From Treatment ......................................................... 37 
7.3.4.2 
Removal of Subjects From Study .............................................................. 38 
7.4 
Investigational Products .............................................................................................. 39 
7.4.1 
Investigational Products Administered ...................................................... 39 
7.4.2 
Identity of Investigational Products ............................................................. 40 
7.4.3 
Packaging and Labeling ............................................................................... 41 
7.4.4 
Method of Assigning Subjects to Treatment Groups ................................ 41 
7.4.5 
Selection of Doses in the Study................................................................. 42 
7.4.6 
Selection and Timing of Dose for Each Subject ......................................... 42 
7.4.7 
Blinding ......................................................................................................... 43 


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7.4.8 
Previous and Concomitant Therapy .......................................................... 43 
7.4.8.1 
Prohibited Medication/Therapy .................................................................... 43 
7.4.8.2 
Permitted Medication ................................................................................... 43 
7.4.9 
Treatment Compliance ................................................................................. 44 
8 
TIMING OF STUDY PROCEDURES ...................................................................... 44 
8.1 
Pretreatment ................................................................................................................. 44 
8.1.1 
Screening Visit (Days -28 to -1; Visit 1) ................................................... 44 
8.2 
Treatment Period ....................................................................................................... 45 
8.2.1 
Cycle 1 (-1/+3 Days) .................................................................................... 45 
8.2.2 
Cycle 2 (-1/+3 Days) .................................................................................... 46 
8.2.3 
Cycle 3 (-1/+3 Days) .................................................................................... 47 
8.2.4 
Cycle 4 (-1/+3 Days) .................................................................................... 47 
8.2.5 
Cycle 5 (-1/+3 Days) .................................................................................... 48 
8.2.6 
Cycle 6 (-1/+3 Days) .................................................................................... 49 
8.2.7 
Additional Cycles until Treatment Withdrawal (From Week 19 
(Cycle 7) onwards, Then Every 3 Weeks; -1/+3 Days) .............................. 50 
8.3 
End of Treatment Visit (Within 3 Weeks of Completion of Last Cycle; 
±5 Days) ......................................................................................................................... 51 
8.4 
Additional Follow-up Visits ...................................................................................... 52 
8.4.1 
Subjects Who Discontinue Treatment Without Radiological 
Disease Progression Before Week 52 (9 Week Intervals; ±7 
Days) ............................................................................................................. 52 
8.4.2 
Subjects with Radiological Progression or New Antitumor 
Therapy Initiated (3 Months Intervals; ±14 Days) ...................................... 53 
 
8.5 
Week 52 End-of-Study Visit (±7 Days) .................................................................... 53 
8.6 
Post Week 52 Period Procedures for Subjects Responding to Treatment .......... 54 
8.7 
Duration of Treatment ................................................................................................. 55 
9 
Efficacy, Immunogenicity, and Safety Variables ..................................................... 55 
9.1 
Efficacy, Immunogenicity, and Safety Measurements Assessed ........................... 55 
9.1.1 
Efficacy Variables ........................................................................................ 55 
9.1.1.1 
Tumor Assessments ...................................................................................... 55 
9.1.2 
Immunogenicity Variables ........................................................................... 56 
9.1.3 
Safety Assessments .................................................................................... 56 
9.1.3.1 
Adverse Events ......................................................................................... 56 
9.1.3.2 
Serious Adverse Events ............................................................................. 59 
9.1.3.3 
Unexpected Adverse Reactions .................................................................. 62 
9.1.3.4 
Clinical Laboratory Evaluation .................................................................... 63 
9.1.3.5 
Other Laboratory Variables ......................................................................... 64 
9.1.3.6 
Vital Signs ..................................................................................................... 64 
9.1.3.7 
Physical Examination ................................................................................... 64 
9.1.3.8 
Eastern Cooperative Oncology Group Performance Status ....................... 64 
9.1.3.9 
12-Lead Electrocardiogram .......................................................................... 65 


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9.1.3.10 Cardiac Ultrasound or Multigated Acquisition Scan .................................. 66 
9.1.3.11 Brain CT Scan ............................................................................................ 66 
9.1.3.12 Survival Status ............................................................................................ 66 
9.2 
Data Safety Monitoring Board ................................................................................... 66 
9.2.1 
Appropriateness of Measurements ............................................................. 66 
10 
Statistical Methods ....................................................................................................... 66 
10.1 Statistical and Analytical Plans .................................................................................. 66 
10.1.1 
Datasets or Populations Analyzed ................................................................ 67 
10.1.2 
Demographic and Other Baseline Characteristics ....................................... 67 
10.1.3 
Efficacy Variables ........................................................................................ 67 
10.1.3.1 Definition of Primary Efficacy Endpoint .................................................... 67 
10.1.3.2 Definition and Analysis of Secondary Efficacy Endpoints ....................... 69 
10.1.4 
Immunogenicity Variables ........................................................................... 70 
10.1.5 
Safety Variables ............................................................................................ 70 
10.1.6 
Schedule of Analyses .................................................................................... 71 
10.1.7 
Handling of Missing Data .......................................................................... 71 
10.2 Determination of Sample Size ..................................................................................... 71 
10.3 Protocol Deviations ....................................................................................................... 73 
11 
Quality Assurance and Quality Control.................................................................... 73 
11.1 Audit and Inspection .................................................................................................... 73 
11.2 Monitoring ..................................................................................................................... 73 
11.3 Data Management and Coding ................................................................................... 73 
12 
Records and Supplies ................................................................................................... 75 
12.1 Drug Accountability ..................................................................................................... 75 
12.2 Financing and Insurance .......................................................................................... 75 
13 
Ethics .............................................................................................................................. 76 
13.1 Independent Ethics Committee or Institutional Review Board ............................ 76 
13.2 Regulatory Authorities ................................................................................................ 76 
13.3 Ethical Conduct of the Study ...................................................................................... 76 
13.4 Informed Consent ......................................................................................................... 76 
13.5 Subject Confidentiality ................................................................................................ 77 
14 
Reporting and Publication, Including Archiving ................................................... 78 
15 
References ...................................................................................................................... 79 
16 
Appendices .................................................................................................................... 81 


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16.1 Investigator Signature Page ........................................................................................ 82 
16.2 Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1  
Guidelines (January 2009) ....................................................................................... 83 
16.3 American Joint Committee on Cancer; Lung Cancer Staging, 7th 
edition 
89 
16.4 Protocol Amendment 2 Summary of Changes ......................................................... 91 


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List of Tables: 
Table 1 Summary of Eastern Cooperative Oncology Group (ECOG) Performance Status ...... 65 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine transaminase 
aPTT 
activated partial prothrombin time 
AST 
aspartate transaminase 
AUC6 
area under the plasma concentration time curve of 6 mg/mL × min 
CI 
confidence interval 
CR 
complete response 
CT 
computed tomography 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
Identifier 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IRC 
independent radiology review committee 
ITT 
Intention-to-treat 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NSCLC 
non-small cell lung cancer 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PD 
progression of disease 
PET 
positron emission tomography 
PFS 
progression free survival 
PK 
Pharmacokinetic 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
per protocol set 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RD 
risk difference 
RR 
risk ratio 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD 
stable disease 
SmPC 
summary of product characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 


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US 
 
United States 
VEGF 
vascular endothelial growth factor 
WHO 
World Health Organization 
 


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5 
INTRODUCTION 
 
5.1 
Background: Non-Small Cell Lung Cancer 
 
Global cancer statistics show that deaths from lung cancer exceed those from any other 
malignancy; primary lung cancer is the second-most common malignancy.1 Non-small cell 
lung cancers (NSCLCs) account for 85%–90% of lung cancers1 and there are 3 main 
subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. The 
distribution of histological types of NSCLC has changed over the last 25 years. In the United 
States, the incidence of squamous cell carcinoma has decreased, although adenocarcinoma 
has increased for both men and women. In Europe, similar trends have occurred in men; 
however, in women, incidence of both squamous cell carcinoma and adenocarcinoma have 
increased.2 
 
Platinum-based chemotherapy regimens can improve survival time and the quality of life for 
subjects with newly diagnosed, advanced NSCLC; however, most subjects still develop 
progressive disease in the first 6 months of treatment. Therefore, newer therapies that disrupt 
critical growth factor/receptor signaling pathways involved in tumor angiogenesis and 
lymphangiogenesis are required. One potential treatment target is vascular endothelial growth 
factor (VEGF), which induces the proliferation, migration, and survival of vascular 
endothelial cells and stimulates the recruitment of bone marrow-derived endothelial 
progenitor cells to new blood vessels serving the tumor. High expression levels of VEGF in 
the tumor microenvironment have been correlated with increased tumor vascular density, 
invasive behavior, and metastasis in NSCLC and other tumor types. 
 
5.2 
Reference Therapy (Bevacizumab; Avastin®) 
Bevacizumab, the active component of Avastin®, is a recombinant humanized monoclonal 
immunoglobulin G1 antibody (93% human, 7% murine sequences, molecular weight 
149 kDa) that selectively binds with high affinity to all isoforms of human VEGF and 
neutralizes VEGF’s biologic activity through steric blocking of the binding of VEGF to its 
receptors on the surface of endothelial cells. Because there is very low or undetectable 
expression of VEGF receptors in most normal tissues but significant up-regulation in the 
vasculature of many tumors, neutralization of VEGF by bevacizumab is thought to inhibit 
tumor growth and block metastasis.3,4 
 
Avastin® has been approved by the US Food and Drug Administration (FDA) and by the 
European Medicines Agency (EMA) as first-line treatment for a range of solid tumors in 
combination with other chemotherapeutic agents including: non-squamous NSCLC; 
metastatic renal cell cancer; metastatic carcinoma of the colon or rectum; metastatic breast 
cancer; epithelial ovarian, fallopian tube and primary peritoneal cancer; and cervical cancer.5 
 
According to the Avastin® Summary of Product Characteristics (SmPC), the elimination half- 
life is 18 days for a typical female subject and 20 days for a typical male subject. 5 
 
The main toxicities anticipated (on the basis of the product label for European Union [EU-] 
approved Avastin®) in this study are as follows: 
x Gastrointestinal perforations (GI perforations, fistula formation in the GI tract, intra- 
abdominal abscess), fistula formation involving an internal organ. 
x Wound dehiscence and wound healing complications requiring medical intervention. 


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x Serious hemorrhage (i.e., requiring medical intervention). 
x Severe arterial thromboembolic events. 
x Life-threatening (grade 4) venous thromboembolic events, including pulmonary 
embolism. 
x Hypertensive crisis or hypertensive encephalopathy. 
x Posterior reversible encephalopathy syndrome. 
x Nephrotic syndrome. 
x Severe hypertension not controlled with medical management. 
x Moderate to severe proteinuria. 
x Severe infusion reactions. 
 
5.3 
Investigational Product (MB02; Bevacizumab biosimilar) 
 
5.3.1 
Nonclinical Data 
 
MB02 was shown to have the same characteristics as the reference product Avastin® in a 
series of in vitro assays, selected according to the current EMA guideline on biosimilars 
(EMA/CHMP/BMWP/403543/2010). 
 
The results of these assays are presented in detail in the MB02 Investigator’s Brochure 
(version 5.0, dated May 2017).6 In summary: 
x MB02 and Avastin® have a similar molecular mass. 
x MB02 and Avastin® have the same amino acid sequence (100% sequence match); no 
chemical modification was observed on any of the amino acids. 
x MB02 and Avastin® have the same glycan attachment site. 
x MB02 and Avastin® have a similar protein conformation. 
x The distribution of glycans is similar in MB02 and Avastin®. 
x MB02 and Avastin® have a similar charge variants profile as confirmed by the 
capillary isoelectric focusing and ion-exchange analysis. 
x MB02 and Avastin® have similar purity in sodium dodecyl sulfate polyacrylamide gel 
electrophoresis, size-exclusion high performance liquid chromatography and area 
under the curve analysis. 
x The values found in the aggregation kinetics study for the conformational and 
colloidal stability (unfolding transition temperature, aggregation onset temperatures 
[Tagg; 266 nm and Tagg; 473 nm]) show extreme similarity in both colloidal and 
conformational stability between MB02 and Avastin®. This indicates that both 
products behave similarly in stress conditions, an observation indicative of a similar 
stability profile. 
x MB02 and Avastin® have similar affinity for VEGF as determined by 2 independent 
techniques. 
x MB02 and Avastin® have similar potency as evidenced by human umbilical vein 
endothelial cell assay activity. 
x MB02 and Avastin® have similar neonatal Fc receptor binding, which is predictive of 
similar pharmacokinetic (PK) profiles for the 2 products. 
 
In addition, a repeat-dose (twice weekly for 28 days) toxicokinetic study in monkeys showed 
that: 


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x Maximum serum concentrations were attained generally at or near to the end of 
infusion. The degree of accumulation observed on Day 25 of repeat dosing was 
similar for MB02 and Avastin®, with mean accumulation ratios ranging from 3.7 to 
4.2 and 3.0 to 3.1, respectively. 
x According to the area under the plasma concentration-time curve from time zero to 
72 hours and maximum plasma concentration after single and repeat dosing, there 
were no appreciable (>2-fold) sex-related differences in exposure to MB02 and 
Avastin®. 
x Systemic exposure to MB02 was similar to that of Avastin® on Days 1 and 25 
(relative bioavailability estimates ranged from 88% to 107% in male monkeys and 
89% to 128% in female monkeys). 
 
 
Moreover, MB02 and Avastin® were well tolerated with no clear differences between them. 
Microscopic findings of physeal thickening in the femur, adrenal cortical eosinophilia, and 
reduced glands in the uterus were similar for both products. 
 
5.3.2 
Clinical Data 
 
A multicenter, open label, randomized, parallel group bioequivalence study of MB02 
(bevacizumab biosimilar) and Avastin® was conducted to compare the PK efficacy and safety 
of MB02 and Avastin® in combination with FOLFOX or FOLFIRI chemotherapy as first-line 
treatment in subjects with metastatic colorectal cancer (Protocol number: BEVZ92-A-01-13; 
ClinicalTrials.gov identifier: NCT02069704). 
 
There were no new findings related to the safety of MB02/Avastin®. Overall, the safety 
comparability exercise showed no signals of concern regarding previous experience with 
bevacizumab, and no obvious differential effects between the biosimilar and the reference 
medicinal product. This pivotal study indicated no new safety signals, raised no concerns 
about immunogenicity and did not suggest an increase in risk of bleeding. The analysis of the 
number of subjects with treatment-emergent AEs in the 2 treatment arms suggested that the 
safety profile in terms of nature, frequency and severity of AEs was similar to that of the 
reference medicinal product and according to what is expected given the underlying disease 
and concurrent use of chemotherapy. Moreover, no new events were reported in any 
treatment arm in relation to the current SmPC for Avastin.5 
 
The pattern of AEs and serious AEs (SAEs) in subjects treated with MB02 was consistent 
with the profile of subjects undergoing Avastin® therapy for the treatment of metastatic 
colorectal cancer. 
 
Data from the BEVZ92-A-01-13 study showed MB02 and Avastin® to have equivalent PK in 
terms of AUC and similar efficacy in terms of tumor response in the sensitive population of 
metastatic colorectal subjects. It was concluded that MB02 was biosimilar to Avastin®. When 
MB02 is used in the same way as Avastin®, following the same warnings and precautions, it 
is anticipated that MB02 will provide the same benefit with no difference in risk. 
 
5.4 
Rationale for Current Study 
 
Non-small cell lung cancer is the most common type of lung cancer, is among the leading 
causes of death worldwide and contributes significantly to growing health care costs. 


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Avastin® has been approved for use in many cancer indications and settings, including first- 
line treatment of NSCLC in combination with other chemotherapeutic agents. 
 
MB02 is currently being developed as a treatment biosimilar to Avastin®. In order to support 
the similarity of MB02 already demonstrated in preclinical development, according to 
guidelines issued by the US FDA, EMA and World Health Organization (WHO) a properly 
conducted comparative clinical trial demonstrating comparable efficacy is necessary.7,8,9 The 
current study is part of the stepwise development of MB02 and has been requested and 
validated by the EMA as an equivalence trial. 
 
5.5 
Additional Information on Non-Investigational Medicinal Products 
 
For additional information on the non-investigational medicinal products in this study, please 
refer to SmPCs for Avastin®5, carboplatin10,11,12, and paclitaxel13,14,15. 


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6 
STUDY OBJECTIVES 
 
6.1 
Primary Objective 
 
The primary objective of the study is to compare the ORR of MB02 and EU-approved 
Avastin® when they are administered in combination with carboplatin and paclitaxel in 
subjects with Stage IIIB/IV non-squamous NSCLC as assessed according to RECIST 
(version 1.1).16 
 
6.2 
Secondary Objectives 
 
The secondary objectives of the study are as follows: 
 
x To evaluate the safety profile of MB02 compared with Avastin® in subjects with 
Stage IIIB/IV non-squamous NSCLC as per NCI-CTCAE (v4.03). 
x To assess the potential immunogenicity of MB02 compared with Avastin® assessed 
through determination of antidrug antibodies (ADA). 
x To assess PFS and OS at cutoff points at Week 18 and at Week 52 compared with 
those of Avastin®. 


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7 
INVESTIGATIONAL PLAN 
 
7.1 
Overall Study Design and Plan: Description 
 
This is a multicenter, multinational, double-blind, 1:1 randomized, parallel-group, 
equivalence Phase III study to compare the efficacy and safety of MB02 plus chemotherapy 
(carboplatin and paclitaxel) versus Avastin® plus chemotherapy (carboplatin and paclitaxel) 
in 600 subjects with Stage IIIB/IV non-squamous NSCLC. MB02/Avastin® plus 
chemotherapy will be repeated every 21 days for 6 cycles unless there is evidence of disease 
progression or intolerance of the study treatment. After 6 cycles, (i.e., at the start of Cycle 
7), subjects can continue to receive MB02/Avastin® monotherapy treatment every 3 weeks 
until evidence of disease progression or until unacceptable toxic effects develop. 
 
The study ends at Week 52, after Week 52, all subjects (including those randomized to 
Avastin® during the study) will be offered the opportunity to continue receiving biosimilar 
MB02 monotherapy until disease progression, unacceptable toxicity, lost to follow-up, 
withdrawal of consent, initiation of any new treatment or death. For specific information 
about post Week 52 procedures refer to Section 8.6. 
 
Subjects eligible for the current study will be randomized centrally in a 1:1 manner and 
stratified by sex (male/female), smoking status (smoker/nonsmoker), disease diagnosis 
(newly diagnosed/recurrent disease) and stage (IIIB/IV). A rationale for the study design is 
presented in Section 7.2. 
 
Tumor assessments will be performed at intervals of 6 weeks, from Cycle 1 Day 1 until the 
end of Cycle 6 (i.e., 18 weeks after first study drug administration); after Cycle 6, tumor 
assessments will be performed at intervals of 9 weeks until evidence of disease progression 
and/or the start of new antitumor treatment, death, or Week 52 (End-of-Study Visit), 
whichever occurs first. 
Subjects who withdraw for any reason other than progression of disease (PD) or withdrawal 
of consent will be followed up every 9 weeks with tumor assessment until PD and/or the start 
of new antitumor treatment, subject decision, death, or Week 52 (End-of-Study Visit) 
whichever occurs first. Subjects who withdraw because of PD and/or initiate new antitumor 
therapy or those who progress during the Follow-up Period will then be followed up for 
survival at intervals of 12 weeks until death or Week 52 (End-of-Study Visit), whichever 
occurs first. No further tumor assessment will be required. 
The primary endpoint is ORR (i.e., complete response [CR] or partial response [PR] per 
RECIST version 1.1) at Week 18; an independent radiology review committee (IRC) will 
assess the primary efficacy endpoint using computed tomography (CT) and/or magnetic 
resonance imaging (MRI) according to RECIST version 1.1 criteria. 
 
A Data Safety Monitoring Board (DSMB) will assess the safety data periodically and will 
recommend to the Sponsor whether to continue, modify or stop the trial. This decision will be 
based on benefit risk evaluation. Further details of the DSMB are provided in Section 9.2. 
 
If a subject discontinues treatment before Week 52 from first study drug administration, 
he/she will be requested to attend follow-up visits. The following assessments will be made: 
 
x Subjects with no radiological disease progression will be assessed for: tumor 
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Oncology Group (ECOG) performance status, supine vital signs, concomitant 
medications, surgeries, procedures, AEs/SAEs , concomitant diseases and 
immunogenicity will be recorded in the electronic case report form (eCRF) at follow- 
up visits at intervals of 9 weeks up to disease progression and/or the start of new 
antitumor treatment, death, or Week 52 (End-of-Study Visit). 
x Subjects that discontinue treatment with radiological progression and/ or initiate new 
antitumor therapy will be assessed for: initiation of other treatments, concomitant 
medications, surgeries, procedures, AEs/SAEs (ongoing and/or related to drug study) 
and concomitant diseases, all of which will be recorded in the eCRF. Subjects will be 
followed up for survival at intervals of 3 months (±14 days) until death or Week 52 
End-of-Study Visit (documented phone call is acceptable), but no further tumor 
assessment will be required. 
 
After Week 52, all subjects (including those randomized to Avastin® during the study) will be 
offered to continue receiving biosimilar MB02 monotherapy until disease progression, 
unacceptable toxicity, lost to follow-up, withdrawal of consent, initiation of any new 
treatment or death. For specific information about post Week 52 procedures refer to Section 
8.6. 
 
If a subject discontinues MB02/Avastin® treatment before completing 6 cycles of therapy and 
before the primary endpoint at Week 18, the subject must discontinue study treatment and 
proceed to the End-of-Treatment Visit. 
 
If a subject discontinues paclitaxel and carboplatin before completing 6 cycles of therapy and 
before the primary endpoint at Week 18, the continuation of bevacizumab (MB02 or 
Avastin®, as allocated) as monotherapy should be justified and discussed with the Sponsor 
prior to such a change in schedule. 


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7.1.1 
Schedule of Assessments 
 
 
 
 
Tests & Procedures 
 
 
Screening period 
 
Cycle 1 
 
Cycle 2 
 
Cycle 3 
 
Cycle 4 
 
Cycle 5 
 
Cycle 6 
 
 
Additional 
Cyclesb 
 
End of 
Treatment 
Additional 
Follow -up Visits 
(no disease 
progression) 
Additional 
Follow-up 
(disease 
progression) 
Week 52 
End-of-Study 
Visit 
 
 
 
Post Week 
52Periodq 
 
Week (Day)a 
Days -28 to 
-1 
1 
(1) 
4 
(22) 
7 
(43) 
10 
(64) 
13 
(85) 
16 
(106) 
19 (127) then 
every 3 
weeks 
Within 3 
weeks of 
last cycle 
Every 9 
weeks 
Every 3 
months 
52 
Window (Days) 
 
-1/+3 
-1/+3 
-1/+3 
-1/+3 
-1/+3 
-1/+3 
-1/+3 
± 5 
± 7 
± 14 
± 7 
 
Written Informed Consentc 
Before any 
study 
procedure: - 
28 to -1 
 
 
 
 
 
Informed Consent 
accepting the risk of 
potential treatment switchq 
 
 
 
 
 
 
X 
Eligibility 
(inclusion/exclusion 
criteria) 
 
-7 to -1 
 
 
 
 
 
Demography data 
-28 to -1 
 
 
 
 
 
Medical history / baseline 
conditions 
-28 to -1 
 
 
 
 
 
NSCLC History 
-28 to -1 
 
 
 
 
 
Randomizationd 
-1 to 1 
 
 
 
 
 
Physical examination 
-14 to -1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG/ performance status 
-14 to -1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, weight and 
heighte 
-14 to -1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyf 
-7 to -1 
Xf 
X 
X 
X 
X 
X 
X 
X 
Blood chemistryf 
-7 to -1 
Xf 
X 
X 
X 
X 
X 
X 
X 
Coagulationf 
-7 to -1 
Xf 
X 
X 
X 
X 
X 
X 
X 


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Tests & Procedures 
 
 
Screening period 
 
Cycle 1 
 
Cycle 2 
 
Cycle 3 
 
Cycle 4 
 
Cycle 5 
 
Cycle 6 
 
 
Additional 
Cyclesb 
 
End of 
Treatment 
Additional 
Follow -up Visits 
(no disease 
progression) 
Additional 
Follow-up 
(disease 
progression) 
Week 52 
End-of-Study 
Visit 
 
 
 
Post Week 
52Periodq 
 
Week (Day)a 
Days -28 to 
-1 
1 
(1) 
4 
(22) 
7 
(43) 
10 
(64) 
13 
(85) 
16 
(106) 
19 (127) then 
every 3 
weeks 
Within 3 
weeks of 
last cycle 
Every 9 
weeks 
Every 3 
months 
52 
Window (Days) 
 
-1/+3 
-1/+3 
-1/+3 -1/+3 
-1/+3 
-1/+3 
-1/+3 
± 5 
± 7 
± 14 
± 7 
Urinalysisf 
-14 to -1 
Xf 
X 
X 
X 
X 
X 
X 
X 
Virologyg 
-14 to -1 
 
 
 
 
Pregnancy testh 
-14 to -1 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead  electrocardiogrami 
-28 to -1 
 
 
X  
X 
X 
X 
X 
LVEF measurementp 
-28 to -1 
 
 
 
 
X 
Brain CTj 
-28 to -1 
If clinically indicated 
Tumor assessmentk 
-28 to -1 
 
X 
 
X 
X 
Xk 
X 
Xk 
Xk 
Serum biomarkers (ADA)l 
 
X 
X 
 
X 
Xl 
X 
Xl 
X 
Prior and Concomitant 
medicationsm 
-14 to -1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Surgeries and Proceduresm 
 
-14 to -1 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsn 
-28 to -1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug administration 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X (Not to be captured in 
eCRF, source documents 
only) 
Initiation of new antitumor 
therapy recordedo 
 
 
 
 
 
X 
X 
X 
Survival Statuso 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abbreviations: ADA = antidrug antibodies; CT = computed tomography, ECOG = Eastern Cooperative Oncology Group; HIV = human immunodeficiency virus; LVEF=left ventricular ejection fraction; 
NSCLC = non-small cell lung cancer; PD=progression of disease; WOCBP=women of childbearing potential; 
a Calculated using the first day of assigned treatment as Day 1 and unless otherwise specified in other footnotes for a specific activity  
b Treatment in additional cycles should continue until: PD, unacceptable toxicity, withdrawal of consent, subject decision, lost to follow-up, protocol violation, death, investigator decision, or subject 
becomes pregnant  


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c Must have been obtained before any study-related procedures are performed  
d Randomization of subjects will take place on the same day (Day 1) or the day before the planned treatment dose administration (Day -1); should an unintended delay occur, the initial cycle of MB02 must 
start within 4 (-1/+3) days of randomization  
e Supine Vital signs including blood pressure, pulse rate, respiratory rate and body temperature  Height will be measured at Screening only  
f Laboratory assessments will be conducted by a central laboratory and will include hematology (complete blood count including hemoglobin, hematocrit, white blood cell count with 5-part differential, 
red blood cell count and platelet count), blood chemistry (bicarbonate, calcium, phosphorus, magnesium, albumin, glucose, serum creatinine, total protein, and blood urea nitrogen), liver function tests 
(aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, and total and direct bilirubin), coagulation analysis (international normalized ratio, prothrombin time, 
partial thromboplastin time and fibrinogen), and urinalysis (microscopy including protein, protein-to-creatinine ratio (Screening only), specific gravity, glucose, and blood)  If protein-to creatinine ratio is ≥ 1 
at Screening, then 24-hour urine must demonstrate < 1 g of protein in 24 hours  For routine on-study urinalysis assessments, dipstick is sufficient as long as the urine protein result is less than 2+ 
(urinalysis also acceptable)  If dipstick urine protein result is ≥ 2+, 24-hour urine must demonstrate < 1 g of protein in 24 hours  A window timeframe of -5/+3 days will be allowed for laboratory 
assessments. If screening laboratory assessments are done within 7 days of Cycle 1 Day 1 (first dose), they do not need to be repeated on Day 1  For retreatment (Cycle 2 and on) purposes, local 
laboratories may be utilized, in addition to the central laboratory  
g Testing for viral infection is not required at screening only to assess whether the status of viral infection (including but not limited to hepatitis B, hepatitis C, and HIV) is known  
h Urine or serum as per local requirements; WOCBP only 
i Electrocardiogram will be performed at Screening, at Cycle 3 (before dosing), Cycle 5 (before dosing), Cycle 6 (Week 18 [± 1 week]), End of Treatment Visit, at Week 52 (Cycle 18 predose) and any 
time if clinically indicated  
j Brain CT will be performed only in subjects with known or history of brain metastases or if clinically indicated  
k Perform a CT and/or MRI of the chest, upper abdomen, and any other involved regions  Disease status and tumor response will be assessed per RECIST version 1 1 criteria at Screening (within 4 weeks 
before the first scheduled dose of study drug) and then every 6 weeks (±3 days) from Cycle 1 Day 1 until end of Cycle 6 (Week 18) and, thereafter every 9 weeks (±5 days) until Week 52, PD, start of new 
treatment, subject decision, or death, whichever occurs first  Week 18 tumor assessments have a 1 week window (±1 week)  In addition, tumor assessment should be performed at any time if clinically 
indicated  Tumor measurement will also be performed during the End-of-Treatment Visit if it was not done within the previous 4 weeks  Every effort will be made to ensure that the same method of 
assessment used at Screening is used at all subsequent time points  For those subjects who discontinue treatment without radiological disease progression, tumor assessment should be performed every 9 
weeks (±5 days) until Week 52, PD, start of new treatment, subject decision, or death, whichever occurs first  Once radiological disease progression is documented, subjects are no longer required to 
undergo additional tumor assessment  
l Blood sample for Serum Biomarkers (ADA) determination will be collected at Week 1 (Cycle 1 Predose), at Week 4 (Cycle 2 Predose), at Week 10 (Cycle 4 Predose), at Week 19 (Cycle 7 Predose), at 
Week 34 (Cycle 12 Predose) and at Week 52 and, at the End of Treatment Visit if an ADA sample has not been collected within the previous 3 weeks  If study treatment should be delayed, ADA sample 
should also be delayed accordingly  Once subject discontinues treatment, ADA sample will follow specified weeks as scheduled  
m Concomitant medications, surgeries and procedures will be collected/reported from signing of informed consent form until 30 days after last cycle administration  Beyond this date, only concomitant 
medications, surgeries and procedures administered for an AE or SAE considered related to study drugs will be collected/reported 
n All AEs and SAEs will be collected/reported from signing of informed consent form until 30 days after last cycle administration  Beyond this date, only AEs and SAEs considered related to study drugs 
will be collected/reported 
 
o Subjects who discontinue treatment due to disease progression will be followed up every 3 months (±14 days) until start of new antitumor therapy, death, or week 52, whichever occurs first  This 
follow-up may be performed through a documented phone call  No further tumor assessments will be required  
p Left ventricular ejection fraction to be measured by cardiac ultrasound or multigated acquisition scan at Screening Visit and End of Treatment Visit (if not done in previous 6 weeks); left ventricular 
ejection can also be measured during any treatment cycle, if clinically indicated  
q Subjects will be asked to reconsent for the potential risk of switching treatment to MB02 in case they have been randomized to Avastin ® treatment  Subjects will remain blinded  


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7.2 
Discussion of Study Design 
 
This is a double-blind study, i.e., all those involved in study conduct including 
investigators and the subjects are unaware of who will receive each of the 2 treatments. 
The double-blind design reduces the potential for bias, particularly in the assessment of 
AEs. Most of the other assessments in the current study are objective in nature and, 
therefore, less prone to bias. A DSMB will assess safety data periodically and, on 
benefit/risk evaluation, will recommend to the Sponsor any required change in study 
conduct. 
 
This is a comparator-controlled study in which the test product, the bevacizumab 
biosimilar MB02, will be compared with the EU-approved bevacizumab product, 
Avastin®. Use of a placebo in the planned subject population would provide no potential 
for benefit and therefore is not considered appropriate. The primary objective is to 
compare the ORR of MB02 and Avastin®. During their participation in the study, each 
subject will be exposed to 1 of the 2 treatments. A parallel-group study is preferred to a 
crossover design for its shorter duration and for continuity of treatment in this 
population with advanced disease. Should subjects complete 6 cycles, and they wish to 
and are eligible to continue to receive treatment, they can receive MB02 or Avastin® 
monotherapy to be administered every 3 weeks until treatment withdrawal (see 
Sections 7.1.1 and 7.3.4.1). 
 
The study population will comprise subjects with Stage IIIB/IV non-squamous NSCLC 
not amenable to curative intent surgery and, who have not received any systemic 
therapy for advanced disease. There is a potential for this population to benefit from 
either treatment. 
 
7.3 
Selection of Study Population 
 
7.3.1 
Number of Planned Subjects 
 
The sample size calculation found that 600 subjects (300 subjects per group) are 
required to complete the study for determination of equivalence. Sufficient subjects will 
be screened to enable 600 subjects to be randomized. 
 
7.3.2 
Inclusion Criteria 
 
To be eligible for study entry, subjects must satisfy all of the following criteria: 
 
1. Males and female subjects aged t18 years to d80 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. 


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3. Subjects should have newly diagnosed or recurrent Stage IIIB/IV (defined by 
seventh edition of the 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) 
(Section 16.3). For subjects with recurrent disease, at least 6 months must have 
elapsed before randomization from previous adjuvant treatment. For Stage IV 
disease, malignant pleural or pericardial effusion must be confirmed by 
cytological examination if the effusion is the only lesion that confirms Stage IV 
of the disease. In all other cases, the cytological confirmation of effusion is not 
mandatory. 
 
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 ECOG performance status ≤1 at Screening. 
 
7. Subjects must have adequate hepatic, renal and hematologic function defined as: 
 
x Hepatic function: bilirubin level <1.5 ULN, ALT and AST 
levels<2.5×ULN. 
x Renal function: serum creatinine level <1.5×ULN, calculated creatinine 
clearance (CrCl) >50 mL/min (Cockroft-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. 
x Hematological function: Absolute neutrophil count >1.5×109 /L; platelets 
>100×109 /L, hemoglobin (Hb) >9 g/dL. 
x Adequate coagulation parameters such as: INR ≤ 2.0 and aPTT ≤ 
1.5 × 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. 


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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: 
 
x 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: 
 
x Hysterectomy. 
x Bilateral oophorectomy (ovariectomy). 
x Bilateral tubal ligation or, 
x Postmenopausal women defined as: 
 
Subjects not using HRT and who have experienced total cessation of menses for 
t1 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). 
 
7.3.3 
Exclusion Criteria 
 
Subjects will be excluded from the study if 1 or more of the following criteria are 
applicable: 
 
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. 


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3. Subjects previously treated with monoclonal antibodies or small molecule 
inhibitors against 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 malignant 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. 


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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 Association17 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. 
 
7.3.4 
Removal of Subjects from Therapy or Assessments 
 
7.3.4.1 Removal of Subjects From Treatment 
 
A subject should be withdrawn from study treatment if in the opinion of the 
investigator, it is medically necessary or if it is the wish of the subject. Subjects will be 
withdrawn from treatment for any of the following reasons: 


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x Progression of disease. 
x Unacceptable toxicity. 
x Withdrawal of consent. 
x Subject decision (may continue in the study for the follow-up visits). 
x Lost to follow-up. 
x Protocol violation. 
x Death. 
x Investigator decision. 
x Subject becomes pregnant. 
 
The SmPC for Avastin® specifies the following reasons for discontinuation: 
 
x Necrotizing fasciitis. 
x Medically significant hypertension cannot be adequately controlled with 
antihypertensive therapy. 
x Nephrotic syndrome, grade 4 proteinuria. 
x Arterial thromboembolic reactions. 
x Grade 3 or 4 bleeding. 
x Intracranial bleeding. 
 
If a subject discontinues MB02/Avastin® treatment before completing 6 cycles of 
therapy and before the primary endpoint at Week 18, the subject must discontinue study 
treatment and proceed to the End-of-Treatment Visit. 
 
If a subject discontinues paclitaxel and carboplatin before completing 6 cycles of 
therapy and before the primary endpoint at Week 18, the continuation of bevacizumab 
(MB02 or Avastin®, as allocated) as monotherapy should be justified and discussed with 
the Sponsor prior to such a change in schedule. 
 
Every attempt will be made to conduct follow-up visits every 9 weeks until Week 52 as 
well as the End-of-Study Visit in any subject who discontinues treatment before 
Week 52. 
 
7.3.4.2 Removal of Subjects from Study 
 
Subjects can be discontinued from the study for any of the following reasons: 
 
x Withdrawal of consent. 
x Death. 
x Lost to follow-up. 
x Protocol violation. 
x Termination of the study by the Sponsor. 
x Subject becomes pregnant. 


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Rescreening is not allowed. 
Subjects who discontinue the study prematurely after randomization will not be 
replaced. Subjects are free to withdraw from the study at any time without providing 
reason(s) for withdrawal and without prejudice to further treatment. The reason(s) for 
withdrawal will be documented in the eCRF. 
 
Every attempt will be made to conduct the assessments scheduled for the End-of-Study 
Visit in any subject that discontinues from the study. The aim is to record data in the 
same way for discontinued subjects as for subjects who completed the study. 
 
Reasonable efforts will be made to contact subjects who are lost to follow-up. These 
efforts must be documented in the subject’s file. 
 
The Sponsor has the right to terminate the study at any time in case of SAEs or if 
special circumstances concerning MB02 or the company itself occur, making further 
treatment of subjects impossible. In this event, the investigator(s) will be informed of 
the reason for study termination. 
 
Pregnancy and breast feeding 
 
Subjects will be instructed that known or suspected pregnancy occurring during the 
study, in subjects or in female partners of male subjects, should be confirmed and 
reported to the investigator, who will then withdraw the subject from treatment without 
delay. The investigator should also be notified of pregnancy occurring during the study 
but confirmed after completion of the study. In the event that a female subject is 
subsequently found to be pregnant after inclusion in the study, any pregnancy will be 
followed up to term, and the status of mother and child will be reported to the Sponsor 
after delivery. Female partners of male subjects who become pregnant will be followed 
up in the same way. 
 
It is not known whether Avastin® is excreted in human milk. Because maternal 
immunoglobulin G is excreted in milk and Avastin® could harm infant growth and 
development, women must discontinue breastfeeding during therapy and not breastfeed 
for at least 6 months after the last dose of Avastin®. Breastfeeding is listed as an 
exclusion criterion for this study. 
 
Full details will be recorded on the withdrawal page of the eCRF. A pregnancy form 
should be sent within 24 hours of investigator´s knowledge of the pregnancy or 
breastfeeding (see Section 9.1.3.2). 
 
7.4 
Investigational Products 
 
7.4.1 
Investigational Products Administered 
 
The investigational products will be as follows: 


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x MB02 (test; bevacizumab biosimilar drug sourced from mAbxience Spain), to 
be administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of 
every 3 week treatment cycle. 
x Avastin® (reference; sourced from the EU), to be administered as an IV infusion 
at an intended dose of 15 mg/kg on Day 1 of every 3 week treatment cycle. 
 
The investigational product (MB02 or Avastin®) will be given in combination with 
paclitaxel and carboplatin (both to be sourced centrally). 
Combination chemotherapy treatment (from Cycle 1 to Cycle 6) will be as follows: 
x Paclitaxel: to be administered as an IV infusion at an intended dose of 
200 mg/m2 on Day 1 of every 3 week treatment cycle 
x Carboplatin: to achieve an AUC6 as an IV infusion on Day 1 of every 3 week 
treatment cycle 
 
For up to the first 6 cycles, the study treatment will consist of an initial administration 
of paclitaxel 200 mg/m2 IV over 3 hours, followed by carboplatin AUC6 IV over 15 to 
60 minutes and then, immediately afterward either MB02 or Avastin® 15 mg/kg. MB02 
and Avastin® will be administered IV. A window of 30 minutes is allowed between the 
administration of the 2 chemotherapy drugs and/or between the administration of either 
chemotherapy drug and either study drug (MB02 or Avastin®). 
The first MB02 or Avastin® treatment will be administered as a 90-minute infusion. If 
the study drug is well tolerated, the next infusion will be given over a 60-minute period. 
Thereafter, the drug will be given as a 30-minute IV infusion. 
Subjects who complete 6 cycles of the combination treatment (MB02 or Avastin® in 
combination with paclitaxel and carboplatin) can continue to receive monotherapy 
treatment every 3 weeks until PD, unacceptable toxicity, death, or withdrawal. 
 
7.4.2 
Identity of Investigational Products 
 
MB02 and Avastin® will be presented in single-use vials as follows: 
 
x 100 mg of MB02 or Avastin® in a 4-mL volume. Each 100-mg (25 mg/mL) 
glass vial product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg 
sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate 
(dibasic, anhydrous), 1.6 mg polysorbate 20, and water for injection. 
x 400 mg of MB02 or Avastin® in a 16-mL volume. Each 400-mg (25 mg/mL) 
glass vial product is formulated in 960 mg α,α-trehalose dihydrate, 92.8 mg 
sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate 
(dibasic, anhydrous), 6.4 mg polysorbate 20, and water for injection. 
 
Combination Chemotherapy treatment will be presented in single use vials as follows: 


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x Paclitaxel vials of 300 mg (6 mg/mL) and 100 mg (6 mg/mL). 
x Carboplatin vials of 450 mg (10 mg/mL) and 150 mg (10 mg/mL). 
 
All study drugs will be manufactured and imported according to relevant regulatory 
requirements. MB02/ Avastin® vials must be stored in a refrigerator at 2qC to 8qC 
(36 ºF to 46ºF) in their outer carton to protect from light. Once prepared, infusion 
solutions of MB02 or Avastin® in polyvinylchloride or polyethylene bags containing 
0.9% sodium chloride injection (United States Pharmacopeia, USP), should be stored at 
2qC to 8ºC (36–46ºF) for no more than 24 hours before use. Paclitaxel/carboplatin will 
be stored and prepared according to SmPCs. 
 
7.4.3 
Packaging and Labeling 
 
Study packaging will be performed by Clinical Supplies Management (CSM) Europe 
SA, Mont-Saint-Guibert, Belgium. All packaging and labeling operations will be 
performed according to Good Manufacturing Practice for Medicinal Products and local 
regulatory requirements. MB02 and Avastin® are supplied as a concentrate for solution 
for infusion. They are provided in sterile, preservative-free, nonpyrogenic, type I glass 
vials with a rubber stopper. 
 
MB02 and Avastin® will be labeled with information in the same format and as required 
by the relevant regulatory and national requirements. Labeling will be performed 
according to Annex 13 of the Good Manufacturing Practice (GMP) guidelines of the 
European Commission, International Conference on Harmonisation (ICH), Good 
Clinical Practice (GCP) guidelines, and local law. 
 
Paclitaxel and Carboplatin will be supplied with their commercial packaging to which 
will be attached a study specification label and stamped. 
 
7.4.4 
Method of Assigning Subjects to Treatment Groups 
 
Subjects (i.e., the unique subject identifier [ID] consisting of center ID and subject ID) 
will be randomly allocated (1:1 ratio) to treatment according to a prespecified blocked 
randomization scheme. Randomization will be stratified by sex (male/female), smoking 
status (smoker/nonsmoker), disease diagnosis (newly diagnosed/recurrent disease) and 
stage (Stage IIIB/Stage IV). For stratification purposes, former smokers will be 
classified as smokers if they stopped less than 5 years ago and as nonsmokers if they 
have not smoked for the last 5 years or more, or have stopped prior to study and cannot 
provide information on when they stopped smoking. 
 
The randomization list will be prepared by INC Research by an independent unblinded 
randomization statistician. The randomization will be performed using a centralized 
Interactive Web Response System, Endpoint®. 


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7.4.5 
Selection of Doses in the Study 
 
The dose and infusion rates of test (MB02) and reference (Avastin®) medications that 
have been selected are the same as those approved for bevacizumab in the SmPC for 
first-line treatment of non-squamous NSCLC, i.e., 15 mg/kg given every 3 weeks as 
an IV infusion, which is the standard of care and posology for the disease under 
study. 
 
7.4.6 
Selection and Timing of Dose for Each Subject 
 
Randomization of subjects will take place on the same day (Day 1) or the day before the 
planned treatment dose administration (Day -1); should an unintended delay occur, the 
initial cycle of MB02 must start within 4 (-1/+3) days of randomization. Beyond this 
period, the imaging and laboratory tests must be repeated. Subsequent bevacizumab 
doses will be administered at 21 day intervals (-1/+3 days) due to holidays, etc. 
 
Further treatment cycles (i.e., Cycle 2 or subsequent) will be administered if the subject 
fulfils all of the following retreatment criteria: absolute neutrophil count more than 
1.5×109 /L; platelet count more than 100,000/PL, hemoglobin level (Hb) more than 
9 g/dL, controlled hypertension and proteinuria less than 2+ or if all other 
nonhematological related toxicities have resolved to ≤ grade 1 (except alopecia, 
anorexia, constipation, not optimally treated nausea and/or vomiting and non-clinically 
relevant isolated biochemical abnormalities) or to the subject’s baseline condition. 
 
Until the Week 18 assessment, reduction in MB02/Avastin® dose will not be permitted. 
Treatment (both MB02/Avastin® and chemotherapy) should be put on hold in the event 
of toxicities ≥ grade 3, that the investigator considers to be clinically significant and 
related to study treatment. The maximum permitted length of treatment hold is 14 days, 
equivalent to 5 weeks from last treatment dose. Treatment can be restarted when 
retreatment criteria are met. An MB02/Avastin® dose adjustment to weight change may 
or may not be implemented (under investigator’s discretion) if the subject’s body weight 
changes less than 10% from Baseline or from the weight of last dose adjustment, and 
must be compulsorily done if the subject’s body weight changes by 10% or more from 
Baseline or from the weight at the last dose adjustment. After Week 18, intended dose 
reduction of MB02/Avastin® is allowed if clinically necessary to a dose level of 
7.5 mg/kg. No further dose reduction of MB02/Avastin® is allowed. 
If a subject discontinues MB02/Avastin® treatment before completing 6 cycles of 
therapy and before the primary endpoint at Week 18, the subject must discontinue study 
treatment and proceed to End-of-Treatment Visit. 
 
Toxicities should be managed according to the relevant Avastin® SmPC. If grade 3 
toxicity recurs upon reintroduction of MB02/Avastin®, the investigator should consider 
the individual benefit versus the risk of continuing therapy. If the event occurs again 
upon a second reintroduction of MB02/Avastin®, treatment should be permanently 
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Additional information of dose levels is summarized in Section 7.4.1. 
7.4.7 
Blinding 
 
This is a randomized, double-blind study up to Week 52. 
 
The pharmacist at each study site and a specific clinical team from INC Research and 
the Sponsor will be unblinded to treatment assigned. Subjects as well as investigators, 
all other study staff, laboratories and the rest of the INC Research and Sponsor team 
will remain blinded to treatment assignment up to Week 52. The blind for a specific 
subject can be broken by the investigator (emergency code breaking) only if the 
investigator considers the information indispensable to the safety of the subject. 
 
All subjects whose treatment is unblinded by the investigator (break blind option, 
emergency code breaking) while on the study will be withdrawn at the moment of 
unblinding, with the reason for unblinding given as the reason for discontinuation from 
the study. 
 
7.4.8 
Previous and Concomitant Therapy 
 
7.4.8.1 Prohibited Medication/Therapy 
 
Any concomitant medications contraindicated according to the SmPC of any of the 
study drugs (Avastin®/MB02 or chemotherapy -Paclitaxel and Carboplatin-) are 
considered prohibited in this trial. 
 
As osteonecrosis of the jaw has been reported for subjects on bevacizumab and invasive 
dental procedures are an identified risk factor, a dental examination and appropriate 
preventive dentistry should be considered before the start of treatment, if clinically 
indicated. Procedures that involve direct osseous injury and placement of dental 
implants should be avoided if not strictly necessary. Caution should be exercised for 
subjects on intravenous bisphosphonates. 
 
7.4.8.2 
Permitted Medication 
 
Antihypertensive medications, antidiarrheal medications, and analgesics can be 
administered as required, according to the investigator’s discretion. 
 
Low molecular weight heparins are allowed and may be used for the treatment of deep 
vein thrombosis or pulmonary embolism, if they occur. 
 
Antiemetic premedication may be used for nausea and granulocyte colony-stimulating 
factor (G-CSF) according to the investigator’s judgement; corticosteroids and/or 
bisphosphonates are permitted for treatment of bone metastases. Megestrol acetate can 
be used for appetite stimulation. Erythropoietin is permitted, as are primary and 
secondary prophylaxis with granulocyte colony-stimulating factor. 


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As per paclitaxel SmPC, premedication with anti-histaminic drugs (H1 and H2) and 
steroids is recommended. 
 
7.4.9 
Treatment Compliance 
 
The investigator is ultimately responsible for supervising compliance with the 
instructions described in this study protocol. 
 
8 
TIMING OF STUDY PROCEDURES 
 
Subjects will provide written informed consent up to 28 days before first study drug 
administration and before any study-related procedures are performed. 
 
The planned study assessments are presented in Section 7.1.1. 
 
8.1 
Pretreatment 
 
8.1.1 
Screening Visit (Days -28 to -1; Visit 1) 
 
The following screening assessments will be made within the time periods specified: 
 
Up to 28 days before first study drug administration: 
 
x Written informed consent. 
x Record demographic data, such as ethnic origin, date of birth, and sex. 
x Collect full medical history and baseline conditions. 
x Collect full NSCLC history including prior antitumor therapies, as applicable. 
x Perform a standard 12-lead electrocardiogram (ECG). 
x Measure left ventricular ejection fraction by cardiac ultrasound or multigated 
acquisition scan. 
x Conduct brain CT (only in subjects with known or history of brain metastases). 
x Conduct tumor assessment using CT and/or MRI of chest, upper abdomen, and 
any other involved regions. Disease status and tumor response will be assessed 
per RECIST version 1.1 criteria. 
x Recording of AEs and recording/reporting of SAEs from signature of informed 
consent. 
 
Up to 14 days before first study drug administration 
 
x Perform a physical examination. 
x Determine ECOG/performance status. 
x Record supine vital signs (including blood pressure, pulse rate, respiratory rate 
and body temperature), weight and height (measured at screening only). 
x Collection of samples for urinalysis. If the urine protein-to-creatinine ratio ≥ 1, 
then a 24-hour urine test is to be conducted by a central laboratory. 


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x Determine status of known active viral infection, including but not limited to: 
hepatitis B, hepatitis C, or HIV. 
x Urine or serum pregnancy test (according to local requirements, female subjects 
of childbearing potential only). 
x Record concomitant medications taken up to 28 days before the planned date of 
the first dose of study drug. 
x Record surgeries and/or procedures (not study related) undergone up to 28 days 
before the planned date of the first dose of study drug. 
 
Up to 7 days before first study drug administration 
 
x Assess for eligibility against the inclusion and exclusion criteria. 
x Collection of samples for hematology, blood chemistry, and coagulation. 
 
Before the start of treatment a complete dental examination is mandatory in order to 
identify any invasive dental procedure. It is considered a risk factor for osteonecrosis of 
the jaw, reported for subjects on bevacizumab. Appropriate preventive dentistry should 
be considered, if clinically indicated (Section 7.4.8.1). 
 
8.2 
Treatment Period 
 
8.2.1 
Cycle 1 (-1/+3 Days) 
 
Randomization of subjects will take place on the same day or the day before the planned 
treatment dose administration (Day 1 or Day -1); should an unintended delay occur, the 
initial cycle of MB02 must start within 4 days (-1/+3 days) of randomization. 
 
The following procedures will be performed prior to dosing: 
 
x Physical examination. 
x Determination of ECOG performance status. 
x Recording of supine vital signs (including blood pressure, pulse rate, respiratory 
rate and body temperature) and weight. 
x Collection of samples for hematology, blood chemistry, coagulation, and 
urinalysis tests. (If screening laboratory assessments are done within 7 days of 
Cycle 1 Day 1 [first dose], they do not need to be repeated on Day 1.) 
x Urine or serum pregnancy test (according to local requirements; female subjects 
of childbearing potential only). 
x Collection of a sample for serum biomarkers (antidrug antibodies). 
x Review and recording of concomitant medications, procedures and/ or surgeries. 
x Review and recording of AEs and concomitant diseases. Recording/reporting of 
SAEs. 


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Once all procedures have been performed and, if everything is correct and adequate, 
chemotherapy will be administered followed by MB02 or Avastin® (15 mg/kg IV 
infusion) according to the randomization schedule which will be recorded in the eCRF. 
 
In addition to this, a Brain CT and/or CT Scan/MRI will be performed any time 
throughout the cycle if PD is suspected or if clinically indicated. Standard 12-lead ECG 
and left ventricular ejection fraction may also be measured by cardiac ultrasound or 
multigated acquisition scan, if clinically indicated. 
 
If the subject has died, this will be recorded in the eCRF. If the death has occurred 
because of an SAE, this will be reported as per Section 9.1.3.2. 
 
8.2.2 
Cycle 2 (-1/+3 Days) 
 
Cycle 2 will take place 21 days (-1/+3 days) after first administration of study drug. 
The following procedures will be performed prior to dosing: 
x Physical examination. 
x Determination of ECOG performance status. 
x Recording of supine vital signs (including blood pressure, pulse rate, respiratory 
rate and body temperature) and weight. 
x Collection of samples for hematology, blood chemistry, coagulation, and 
urinalysis tests to be conducted by a central laboratory. 
x Urine or serum pregnancy test (according to local requirements; female subjects 
of childbearing potential only). 
x Collection of a sample for serum biomarkers (antidrug antibodies). 
x Review and recording of concomitant medications, procedures and/ or surgeries. 
x Review and recording of AEs and concomitant diseases. Recording/reporting of 
SAEs. 
 
Once all procedures have been performed and, if everything is correct and adequate, 
chemotherapy will be administered followed by MB02 or Avastin® (15 mg/kg IV 
infusion) according to the randomization schedule which will be recorded in the eCRF. 
 
At Week 6 (±3 days) from Cycle 1 Day 1 and/or any time throughout the cycle if 
clinically indicated, a CT Scan/ MRI of chest, upper abdomen and any other involved 
regions should be conducted. Disease status and tumor response will be assessed per 
RECIST version 1.1 criteria. 
 
In addition to this, a Brain CT and/or CT Scan/ MRI will be performed any time 
throughout the cycle if PD is suspected or if clinically indicated. Standard 12-lead ECG 
and left ventricular ejection fraction may also be measured by cardiac ultrasound or 
multigated acquisition scan, if clinically indicated. 


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If the subject has died, this will be recorded in the eCRF. If the death has occurred 
because of an SAE, this will be reported as per Section 9.1.3.2. 
 
8.2.3 
Cycle 3 (-1/+3 Days) 
 
Cycle 3 visit will take place 21 days (-1/+3 days) after second administration of study 
drug. 
 
The following procedures will be performed prior to dosing: 
 
x Physical examination. 
x Determination of ECOG performance status. 
x Recording of supine vital signs (including blood pressure, pulse rate, respiratory 
rate and body temperature) and weight. 
x Collection of samples for hematology, blood chemistry, coagulation, and 
urinalysis tests to be conducted by a central laboratory. 
x Urine or serum pregnancy test (according to local requirements; female subjects 
of childbearing potential only). 
x Standard 12-lead ECG. 
x Review and recording of concomitant medications, procedures and/ or surgeries. 
x Review and recording of AEs and concomitant diseases. Recording/reporting of 
SAEs. 
 
Once all procedures have been performed and, if everything is correct and adequate, 
chemotherapy will be administered followed by MB02 or Avastin® (15 mg/kg IV 
infusion) according to the randomization schedule which will be recorded in the eCRF. 
 
In addition to this, a Brain CT and/or CT Scan/MRI will be performed any time 
throughout the cycle if PD is suspected or if clinically indicated. Standard 12-lead ECG 
and left ventricular ejection fraction may also be measured by cardiac ultrasound or 
multigated acquisition scan, if clinically indicated. 
 
If the subject has died, this will be recorded in the eCRF. If the death has occurred 
because of an SAE, this will be reported as per Section 9.1.3.2. 
 
8.2.4 
Cycle 4 (-1/+3 Days) 
 
Cycle 4 visit will take place 21 days (-1/+3 days) after third administration of study 
drug. 
 
The following procedures will be performed prior to dosing: 
 
x Physical examination. 
x Determination of ECOG performance status. 


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x Recording of supine vital signs (including blood pressure, pulse rate, respiratory 
rate and body temperature) and weight. 
x Collection of samples for hematology, blood chemistry, coagulation, and 
urinalysis tests to be conducted by a central laboratory. 
x Urine or serum pregnancy test (according to local requirements; female subjects 
of childbearing potential only). 
x Collection of a sample for serum biomarkers (antidrug antibodies). 
x Review and recording of concomitant medications, procedures and/ or surgeries. 
x Review and recording of AEs and concomitant diseases. Recording/reporting of 
SAEs. 
 
Once all procedures have been performed and, if everything is correct and adequate, 
chemotherapy will be administered followed by MB02 or Avastin® (15 mg/kg IV 
infusion) according to the randomization schedule which will be recorded in the eCRF. 
 
At Week 12 (±3 days) from Cycle 1 Day 1 and/or any time throughout the cycle if 
clinically indicated, a CT Scan/ MRI of chest, upper abdomen and any other involved 
regions should be conducted. Disease status and tumor response will be assessed per 
RECIST version 1.1 criteria. 
 
In addition to this, a Brain CT will be performed any time throughout the cycle if PD is 
suspected or if clinically indicated. Standard 12-lead ECG and left ventricular ejection 
fraction may also be measured by cardiac ultrasound or multigated acquisition scan, if 
clinically indicated. 
 
If the subject has died, this will be recorded in the eCRF. If the death has occurred 
because of an SAE, this will be reported as per Section 9.1.3.2. 
 
8.2.5 
Cycle 5 (-1/+3 Days) 
 
Cycle 5 visit will take place 21 days (-1/+3 days) after fourth administration of study 
drug. 
 
The following procedures will be performed prior to dosing: 
 
x Physical examination. 
x Determination of ECOG performance status. 
x Recording of supine vital signs (including blood pressure, pulse rate, respiratory 
rate and body temperature) and weight. 
x Collection of samples for hematology, blood chemistry, coagulation, and 
urinalysis tests to be conducted by a central laboratory. 
x Urine or serum pregnancy test (according to local requirements; female subjects 
of childbearing potential only). 
x Standard 12-lead ECG. 


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x Review and recording of concomitant medications, procedures and/ or surgeries. 
x Review and recording of AEs and concomitant diseases. Recording/reporting of 
SAEs. 
 
Once all procedures have been performed and, if everything is correct and adequate, 
chemotherapy will be administered followed by MB02 or Avastin® (15 mg/kg IV 
infusion) according to the randomization schedule which will be recorded in the eCRF. 
 
In addition to this, a Brain CT and/ or a CT Scan/ MRI will be performed any time 
throughout the cycle if PD is suspected or if clinically indicated. Standard 12-lead ECG 
and left ventricular ejection fraction may also be measured by cardiac ultrasound or 
multigated acquisition scan, if clinically indicated. 
 
If the subject has died, this will be recorded in the eCRF. If the death has occurred 
because of an SAE, this will be reported as per Section 9.1.3.2. 
 
8.2.6 
Cycle 6 (-1/+3 Days) 
 
Cycle 6 visit will take place 21 days (-1/+3 days) after fifth administration of study 
drug. 
 
The following procedures will be performed prior to dosing: 
 
x Physical examination. 
x Determination of ECOG performance status. 
x Recording of supine vital signs (including blood pressure, pulse rate, respiratory 
rate and body temperature) and weight. 
x Collection of samples for hematology, blood chemistry, coagulation, and 
urinalysis tests to be conducted by a central laboratory. 
x Urine or serum pregnancy test (according to local requirements; female subjects 
of childbearing potential only). 
x Review and recording of concomitant medications, procedures and/ or surgeries. 
x Review and recording of AEs and concomitant diseases. Recording/reporting of 
SAEs. 
 
Once all procedures have been performed and, if everything is correct and adequate, 
chemotherapy will be administered followed by MB02 or Avastin® (15 mg/kg IV 
infusion) according to the randomization schedule which will be recorded in the eCRF. 
 
At Week 18 (±1 week) from Cycle 1 Day 1 and/or any time throughout the cycle if 
clinically indicated, a CT Scan/ MRI of chest, upper abdomen and any other involved 
regions should be conducted. Disease status and tumor response will be assessed per 
RECIST version 1.1 criteria. 


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In addition to this, a Brain CT will be performed any time throughout the cycle if PD is 
suspected or if clinically indicated. Left ventricular ejection fraction may also be 
measured by cardiac ultrasound or multigated acquisition scan, if clinically indicated. 
 
Also, a standard 12-lead ECG will be performed at Week 18 (±1 week), and it may be 
repeated at any time if clinically indicated. 
 
If the subject has died, this will be recorded in the eCRF. If the death has occurred 
because of an SAE, this will be reported as per Section 9.1.3.2. 
 
8.2.7 
Additional Cycles Until Treatment Withdrawal (From Week 19 (Cycle 7) 
onwards, Then Every 3 Weeks; -1/+3 Days) 
 
Subjects who complete 6 cycles can continue to receive MB02 or Avastin® 
monotherapy until disease progression, unacceptable toxicity, death or Week 
52,whichever occurs first. The study ends at Week 52. After Week 52, all subjects 
(including those randomized to Avastin® during the study) will be offered the 
opportunity to continue receiving biosimilar MB02 monotherapy until disease 
progression, unacceptable toxicity, lost to follow-up, withdrawal of consent, initiation of 
any new treatment or death. For specific information about post Week 52 procedures 
refer to section 8.6 
 
Additional Cycles will be scheduled at intervals of 3 weeks (-1/+3 days). 
 
The following procedures will be performed prior to each monotherapy dosing: 
 
x Physical examination. 
x Determination of ECOG performance status. 
x Recording of supine vital signs (including blood pressure, pulse rate, respiratory 
rate and body temperature) and weight. 
x Collection of samples for hematology, blood chemistry, coagulation, and 
urinalysis tests to be conducted by a central laboratory. 
x Urine or serum pregnancy test (according to local requirements, female subjects 
of childbearing potential only). 
x Collection of a sample for serum biomarkers (antidrug antibodies). One sample 
needs to be collected before Cycle 7 dosing and another sample needs to be 
collected before Cycle 12 dosing, as applicable. 
x Review and recording of concomitant medications, procedures and/ or surgeries. 
x Review and recording of AEs and concomitant diseases. Recording/reporting of 
SAEs. 
 
Once all procedures have been performed and, if everything is correct and adequate, 
MB02 or Avastin® monotherapy (15 mg/kg IV infusion) will be administered according 
to the randomization schedule which will be recorded in the eCRF. 


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Every 9 weeks (±5 days) from Week 18 and/or, any time throughout the cycles if 
clinically indicated, a CT Scan/ MRI of chest, upper abdomen and any other involved 
regions should be conducted including a brain CT (only in subjects with known or 
history of brain metastases). A brain CT may also be performed at any time throughout 
the cycle if PD is suspected or if it is clinically indicated. Disease status and tumor 
response will be assessed per RECIST version 1.1 criteria. 
 
Standard 12-lead ECG and left ventricular ejection fraction may also be measured by 
cardiac ultrasound or multigated acquisition scan, if clinically indicated. 
 
If the subject has died, this will be recorded in the eCRF. If the death has occurred 
because of an SAE, this will be reported as per Section 9.1.3.2. 
 
8.3 
End of Treatment Visit (Within 3 Weeks of Completion of Last Cycle; 
±5 Days) 
 
The End-of-Treatment Visit will take place within 3 weeks of completion of the last 
treatment cycle (±5 days), unless the subjects starts any subsequent antitumor therapy in 
which case the End-of-Treatment Visit should be performed immediately before the 
start of the new therapy (ideally the day before or the same day). The following 
procedures will be performed: 
 
x Physical examination. 
x Determination of ECOG performance status. 
x Recording of supine vital signs (including blood pressure, pulse rate, respiratory 
rate, and body temperature) and weight. 
x Collection of samples for hematology, blood chemistry, coagulation, and 
urinalysis tests to be conducted by a central laboratory. 
x Urine or serum pregnancy test (according to local requirements; female subjects 
of childbearing potential only). 
x Standard 12-lead ECG. 
x Measurement of left ventricular ejection fraction by cardiac ultrasound or 
multigated acquisition scan, if not done in the previous 6 weeks. 
x Brain CT scan (only in subjects with known or history of brain metastases, or if 
clinically indicated). 
x A CT Scan/MRI of chest, upper abdomen and any other involved regions if not 
performed within the prior 4 weeks. Disease status and tumor response will be 
assessed per RECIST version 1.1 criteria. 
x Collection of samples for serum biomarkers (antidrug antibodies), if not 
performed within the previous 3 weeks. 
x Review and recording of concomitant medications, procedures and/ or surgeries. 
x Review and recording of AEs and concomitant diseases. Recording/reporting of 
SAEs. 


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All these evaluations need only be repeated for parameters for which no measurement is 
available within 10 days before the End of Treatment Visit, or for those parameters for 
which values were out of range in the last assessment (grade ≥2) and were considered to 
be treatment related. These evaluations should be conducted when the medical condition 
of the subject allows. 
 
If the subject has died, this will be recorded in the eCRF. If the death has occurred 
because of an SAE, this will be reported as per Section 9.1.3.2. 
 
8.4 
Additional Follow-up Visits 
 
8.4.1 
Subjects Who Discontinue Treatment Without Radiological Disease 
Progression Before Week 52 (9 Week Intervals; ±7 Days) 
 
Subjects who discontinue treatment without radiological disease progression before 
Week 52 and do not withdraw consent will be followed up every 9 weeks (± 7 days) 
from End-of-Treatment Visit until disease progression, new antitumor therapy, subject 
decision, death, or until the Week 52 End-of-Study Visit, whichever occurs first. The 
following procedures will be performed at each Follow-up Visit: 
 
x Physical examination. 
x Determination of ECOG performance status. 
x Recording of supine vital signs (including blood pressure, pulse rate, respiratory 
rate and body temperature) and weight. 
x A CT Scan/ MRI of chest, upper abdomen and any other involved regions if not 
performed within the prior 4 weeks. Disease status and tumor response will be 
assessed per RECIST version 1.1 criteria. 
x Collection of samples for serum biomarkers (antidrug antibodies). These 
samples will be collected at the beginning of Week 4, at the beginning of 
Week 10, at the beginning of Week 19, at the beginning of Week 34, as 
applicable depending on when the treatment is discontinued. 
x Review and recording of concomitant medications, procedures and/ or surgeries 
considered related to any study drugs will be reviewed and collected. 
x Review and recording of AEs and concomitant diseases. Recording/reporting of 
SAEs. Adverse events/SAEs ongoing at the End-of-Treatment Visit will be 
followed until resolution or stabilization. From 30 days after last dose onwards, 
AEs will be recorded and SAEs will be recorded and reported only if they are 
considered at least possibly related to treatment. 
x Recording any other antitumor therapy treatments initiated will be recorded in 
the eCRF. 
 
Those subjects who report disease progression during follow-up visits will be followed 
as per Section 8.4.2. 


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If the subject has died, this will be recorded in the eCRF. If the death has occurred 
because of an SAE, this will be reported as per Section 9.1.3.2. 
 
When all of these procedures have been performed, the next visit will be scheduled, if 
applicable. 
 
8.4.2 
Subjects with Radiological Progression or New Antitumor Therapy 
Initiated (3 Months Intervals; ±14 Days) 
 
After radiological progression is documented or a new antitumor therapy is started, 
subjects will be followed up at least every 12 weeks (±14 days) until death or Week 52 
(End-of-Study Visit), whichever occurs first. Tumor assessment will not be conducted. 
Documented telephone calls are acceptable in this survival follow-up. 
 
The following procedures will be performed at each Follow-up Visit: 
 
x Review and recording of concomitant medications, procedures, and/ or surgeries 
considered related to any study drugs will be reviewed and collected. 
x Review and recording of AEs and concomitant diseases. Recording/reporting of 
SAEs. Adverse events/SAEs ongoing at the End-of-Treatment Visit will be 
followed until resolution or stabilization. From 30 days after last dose onwards, 
AEs will be recorded and SAEs will be recorded and reported only if they are 
considered at least possibly related to treatment. 
x Recording any other antitumor therapy initiated will be recorded in the eCRF. 
x If the subject has died, this will be recorded in the eCRF. If the death has 
occurred because of an SAE, this will be reported as per Section 9.1.3.2. 
 
8.5 
Week 52 End-of-Study Visit (±7 Days) 
 
The End-of-Study Visit will take place 52 weeks (±7 days) after first study drug 
administration. The following procedures will be performed at the Week 52 End-of- 
Study Visit: 
 
x Physical examination. 
x Determine of ECOG performance status. 
x Recording of vital signs (including blood pressure, pulse rate, respiratory rate 
and body temperature) and weight. 
x Standard 12-lead ECG. 
x Brain CT scan (only in subjects with known or history of brain metastases, or if 
clinically indicated). 
x In those subjects who have not shown disease progression (not started any new 
antitumor therapy) a CT Scan/MRI of chest, upper abdomen and any other 
involved regions must be done if it was not performed within the previous 
4 weeks. Disease status and tumor response will be assessed per RECIST 
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x Collection of samples for serum biomarkers (antidrug antibodies). This sample 
needs to be collected at the end of Week 52. 
x Review and recording of concomitant medications, procedures and/ or surgeries. 
If this visit is performed after 30 days from last dose, only those considered 
related to any study drugs will be reviewed and collected. 
x Review and recording of AEs and concomitant diseases. If this visit is 
performed after 30 days from last dose, only those considered related to any 
study drugs will be reviewed and collected. 
x Any other antitumor therapy treatments initiated will be recorded in the eCRF. 
 
All these evaluations will be repeated for parameters for which no measurement within 
the previous 10 days is available. 
 
If the subject has died, this will be recorded in the eCRF. If the death has occurred 
because of an SAE, this will be reported as per Section 9.1.3.2. 
 
After Week 52, all subjects (including those randomized to Avastin® during the study) 
will be offered to continue receiving biosimilar MB02 monotherapy until disease 
progression, unacceptable toxicity or death. 
 
8.6 
Post Week 52 Period Procedures for Subjects That Are Responding to 
Treatment 
 
After Week 52, all subjects (including those randomized to Avastin® during the study) 
will be offered the opportunity to continue receiving biosimilar MB02 monotherapy. 
The following will be required: 
 
x Subjects and investigators will remain blinded up to week 52 
x Subjects will be asked to re-consent to accept the potential risk of being 
switched to MB02 treatment, in case they were initially randomized to 
Avastin® 
x Subjects will receive MB02 labelled as clinical trial 
x Investigators will collect safety information during the time subjects are on 
MB02 treatment beyond Week 52 and will enter the information in the pertinent 
section of the eCRF and, in case of occurrence of any SAE; it will be processed 
and notified as per section 9.1.3.2. No other study assessments are required, it is 
lead to investigator’s discretion the performance of any further assessment 
according to local practice, but these will not be captured in the eCRF 
x Subjects will continue receiving biosimilar MB02 monotherapy until disease 
progression, unacceptable toxicity, lost to follow-up, withdrawal of consent, 
initiation of any new treatment or death. 
x Investigators are required to notify in advance of any patient at his/her site 
willing to proceed with post week 52 treatment. Likewise, investigators are 
required to confirm the continuation or discontinuation of the treatment in 
advance, per drug supply and logistics purposes. 


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8.7 
Duration of Treatment 
 
Cycle 1 starts on Day 1 with the first treatment administration, which will consist of 
paclitaxel infusion followed by carboplatin and then infusion of MB02 or Avastin®; this 
regimen will be applied for the first 6 cycles. 
 
After 6 cycles, (i.e., at the start of Cycle 7), subjects can continue to receive 
MB02/Avastin® monotherapy treatment every 3 weeks until evidence of disease 
progression or until unacceptable toxic effects develop. 
 
Treatment discontinuation can occur because of PD, unacceptable toxicity, withdrawal 
of consent, subject decision, lost to follow-up, protocol violation, death, investigator’s 
decision, or if subject becomes pregnant, whichever occurs first. The study will finish 
once the subject has reached 52 weeks after the first dose administration (when PFS and 
OS are assessed and the last ADA sample is taken) or, subject withdraws his/her 
consent, if subject is lost to follow-up, becomes pregnant or dies; once a protocol 
violation is reported. Sponsor may also terminate the study. 
 
After Week 52, all subjects (including those randomized to Avastin® during the study) 
will be offered the opportunity to continue receiving biosimilar MB02 monotherapy 
until disease progression, unacceptable toxicity, lost to follow-up, withdrawal of 
consent, initiation of any new treatment or death. For specific information about post 
Week 52 procedures, refer to Section 8.6. 
 
9 
EFFICACY, IMMUNOGENICITY, AND SAFETY VARIABLES 
 
Efficacy, immunogenicity, and safety variables will be assessed at the time points 
specified in the planned schedule of assessments, which is presented in Section 7.1.1. 
 
9.1 
Efficacy, Immunogenicity, and Safety Measurements Assessed 
 
9.1.1 
Efficacy Variables 
 
9.1.1.1 Tumor Assessments 
 
Tumor assessments will be performed using CT and/or MRI of the chest, upper 
abdomen, and any other involved regions; every effort will be made to ensure that the 
same method of assessment used at Screening is used at all subsequent time points. 
Tumor response will be assessed by the IRC using the RECIST v1.1 criteria to evaluate 
ORR. Disease status, PFS, and OS16 will be evaluated by investigators. The RECIST 
v1.1 (January 2009) guidelines for measurable, nonmeasurable, target and nontarget 
lesions and the objective tumor response criteria (CR, PR, stable disease [SD] or PD) 
are detailed in Section 16.2. 


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Baseline assessment should be performed up to 28 days before the start of study 
treatment and ideally as closely as possible to the start of study treatment; it should 
include all areas known for possible metastases. Thereafter, disease assessment should 
be repeated according to the time points presented in Section 7.1.1. Additional tumor 
assessments can be made at any time should the investigator consider this to be 
clinically indicated. Tumor measurements will also be performed during the Week 52 
End-of-Study Visit if not done within the previous 4 weeks. Operational details for the 
IRC are described in detail in the IRC charter 
 
Details regarding timing of tumor assessments are presented in Section 7.1.1. 
 
9.1.2 
Immunogenicity Variables 
 
Blood samples will be taken to determine serum biomarkers (antidrug antibodies) up to 
52 weeks after first study drug administration in all randomized subjects. Further details 
are provided in the laboratory manual; details regarding timing of immunogenicity 
assessments are presented in Section 7.1.1. 
 
9.1.3 
Safety Assessments 
 
Safety will be monitored by: incidence, nature, and severity of AEs, including adverse 
drug reactions graded according to NCI-CTCAE (version 4.03); incidence of clinical 
laboratory value abnormalities (hematology, clinical chemistry, and urinalysis); physical 
examination; ECOG/performance status, 12-lead ECG, vital sign assessment and brain 
CT (in subjects with history of brain metastases only). Details regarding timing of safety 
assessments are presented in Section 7.1.1. 
 
9.1.3.1 Adverse Events 
 
Adverse event definition 
 
An AE is defined as any untoward medical occurrence in a clinical study subject 
administered a medicinal product which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, including MB02, Avastin®, 
paclitaxel and carboplatin, whether or not it is related to the medicinal (investigational) 
product, including MB02, Avastin®, paclitaxel and carboplatin. This includes an 
exacerbation of pre-existing conditions or events, intercurrent illnesses or drug 
interaction that is not recorded elsewhere in the eCRF under specific efficacy 
assessments. Anticipated fluctuations of pre-existing conditions that do not represent a 
clinically significant exacerbation or worsening need not be considered AEs. 
 
It is the responsibility of the investigator to document all AEs that occur during the 
study. AEs will be elicited by asking the subject a nonleading question, for example, 


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“Have you experienced any new or changed symptoms since we last asked/since your 
last visit?” Adverse events should be reported on the appropriate page of the eCRF. 
 
Assessment of severity 
 
Adverse events will be collected and classified according to NCI-CTCAE version 
4.03.18 
 
Death itself is not an AE, but rather the outcome of an event, which should be described 
using medical terminology. Grade 5 (death) as an intensity criterion that should only be 
used in those cases where either no cause for death is known (e.g., sudden death, death 
NOS) or death occurs as an immediate outcome of a given event (e.g., allergic reaction, 
sepsis leading to immediate death). 
 
If there is a change in the grade of an AE, it must be recorded as a separate event. 
 
If changes to a subject’s left ventricular ejection fraction are judged to be grade 3, 
subjects will be managed according to appropriate protocols and referred to a 
cardiologist 
 
Assessment of causality 
 
Every effort will be made by the investigator to assess the relationship of the AE, if any, 
to the study drugs. Causality should be assessed using the categories presented in the 
following table: 


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Unrelated: 
Clinical event with an incompatible time relationship to study drug 
administration, and that could be explained by underlying disease or 
other drugs or chemicals or is incontrovertibly not related to the study 
drug. 
Unlikely: 
Clinical event whose time relationship to study drug administration 
makes a causal connection improbable but that could plausibly be 
explained by underlying disease or other drugs or chemicals. 
Possible: 
Clinical event with a reasonable time relationship to study drug 
administration, but that could also be explained by concurrent disease 
or other drugs or chemicals. 
Probable: 
Clinical event with a reasonable time relationship to study drug 
administration and is unlikely to be attributed to concurrent disease or 
other drugs or chemicals. 
Very 
Likely/Certain: 
Clinical event with plausible time relationship to study drug 
administration and that cannot be explained by concurrent disease or 
other drugs or chemicals. 
Unknown: 
The event cannot be judged because information is insufficient or 
contradictory or data cannot be supplemented or verified. 
 
Action taken 
 
The investigator will describe the action taken in the appropriate section of the eCRF. 
All medication given as treatment will be reported in the appropriate page of the eCRF. 
 
Follow-up of adverse events 
 
All investigators should follow-up subjects with AEs until the event is resolved or until, 
in the opinion of the investigator, the event is stabilized or determined to be chronic. 
Details of AE follow-up or resolution must be documented in the eCRF. 
 
Subjects should be followed up until 30 days after last cycle, and any AEs that occur 
during this time should be reported according to the procedures outlined below. 
Additionally, for those subjects who proceed with post Week 52 treatment, any AE 
occurring during this time should, also, be reported according to the procedures 
outlined below. 
 
All subjects with unresolved AEs at the end of the study, except those who dropped out 
before randomization or starting active treatment, must be included in a safety follow- 
up visit to check response of AEs. 
 
Follow-up can be waived in specific cases after consultation with the Sponsor. This 
permission must be documented per case and retained in the Sponsor File. 


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Documentation and reporting of adverse events 
 
Adverse events should be reported and documented in accordance with the procedures 
outlined below; AEs will be recorded in the eCRF from the signing of the informed 
consent form (ICF) until 30 days after last cycle, for those subjects that do not proceed 
with post Week 52 treatment. For those subjects that continue to post Week 52 
treatment, any AE occurring during this time will also be recorded in the eCRF. Any 
AEs occurring more than 30 days after last cycle of drug administration should also be 
recorded in the eCRF if they are considered at least possibly related to the study drugs 
by the investigator. The following data should be documented for each AE: 
 
x Description of the symptom event. 
x Classification as ‘serious’ or ‘not serious’. 
x Severity. 
x Date of first occurrence and date of resolution (if applicable). 
x Action taken. 
x Causal relationship. 
x Outcome of event (unknown, recovered, not yet recovered, recovered with 
sequelae, death [with date and cause reported]). 
 
9.1.3.2 Serious Adverse Events 
 
Serious adverse event definition 
 
An SAE is any untoward medical occurrence or effect that, at any dose, 
 
x Results in death. 
x Is life threatening (an AE is life threatening if the subject was at immediate risk 
of death from the event as it occurred, i.e., it does not include a reaction that 
might have caused death if it had occurred in a more serious form). 
x Requires or prolongs inpatient hospitalization. (Complications occurring during 
hospitalization are AEs and are SAEs if they cause prolongation of the current 
hospitalization. Hospitalization for elective treatment of a pre-existing non- 
worsening condition is not, however, considered an AE. The details of such 
hospitalizations must be recorded on the medical history or physical examination 
page of the eCRF). 
x Results in persistent or significant disability/incapacity. (An AE is incapacitating 
or disabling if it results in a substantial and/or permanent disruption of the 
subject’s ability to carry out normal life functions). 
x Results in a congenital anomaly/birth defect. 
 
In addition, medical and scientific judgement is required to decide if prompt notification 
is required in situations other than those defined for SAEs above. This may include any 
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but may have jeopardized the subject or required intervention to prevent 1 of the 
outcomes listed above, or that would suggest any significant hazard, contraindication, 
side effect, or precaution that may be associated with the use of the investigational 
product. These events should be collected in the eCRF under the seriousness criteria 
“Important Medical Event”. 
 
Disease progression is a worsening of a subject’s condition attributable to the disease  
for which the study medication is being given. This may be an increase in severity of the 
disease or increase in the symptoms of the disease. The development of new, or 
progression of existing metastases of the primary cancer under study should be 
considered as disease progression and not an AE. Events that are unequivocally due to 
disease progression should not be reported as AEs during the study. The development of 
a new cancer should be regarded as an AE and reported accordingly. Generally, it will 
also meet at least 1 of the serious criteria. New cancers are those that are not the primary 
reason for the administration of the study treatment and have been identified after the 
subject’s inclusion in the study. They do not include metastases of the original cancer. 
 
Reporting of serious adverse events 
 
All SAEs will be recorded in the eCRF and reported from signing of the ICF until 
30 days after last cycle of any drug from the protocol treatment schedule, for those 
subjects that do not proceed with post Week 52 treatment. For those subjects that 
continue to post Week 52 treatment, any SAE occurring during this time, will also be 
recorded in the eCRF and reported. Any SAEs occurring or more than 30 days after last 
cycle of drug administration should also be recorded in the eCRF and reported if they 
are considered at least possibly related to the protocol treatment by the investigator. An 
SAE form must be sent to INC Research by email (PDF) or faxed within 24 hours for 
the attention of the Safety Department. 
 
Full details for SAE reporting and contact information can be found in the Investigator 
Manual. 
 
The investigator should not wait to receive additional information to fully document the 
event before notification of an SAE, even though additional information may be 
requested. Where applicable, information from relevant laboratory results, hospital case 
records, and autopsy reports should be obtained and transmitted to the Sponsor’s Safety 
Department within 24 hours. 
 
Instances of death, congenital abnormality, or event that are of such clinical concern as 
to influence the overall assessment of safety, if brought to the attention of the 
investigator at any time after cessation of study drug administration and linked by the 
investigator to this study, should be reported to the Sponsor’s Safety Department within 
24 hours. 
 
All SAEs must be reported, with the exception of: 


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x Hospitalization for administration of study treatments. Hospitalization or 
prolonged hospitalization for a complication of study treatment administration 
will be reported as an SAE. 
x Hospitalization for diagnostic investigations (e.g., scans, endoscopy, sampling 
for laboratory tests, bone marrow sampling) that are not related to an AE. 
x Prolonged hospitalization for technical, practical, or social reasons, in absence of 
an AE. 
x Hospitalization for a procedure that was planned before study participation 
(i.e., before registration or randomization). This should be recorded in the 
source documents. Prolonged hospitalization for a complication of such 
procedures remains a reportable SAE. 
x Hospitalization for ≤24 hour (attendance at Emergency Room). 
x Death due to PD, either while on treatment or during the follow-up period; this 
information will be included in the “Death” module of the eCRF. 
 
Hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE. 
 
The Sponsor or Sponsor designee will promptly notify all relevant investigators and the 
regulatory authorities of findings that could adversely affect the safety of subjects, 
impact on the conduct of the study or alter the independent ethics committee 
(IEC)/institutional review board (IRB) approval/favorable opinion of the study. In 
addition, The Sponsor or Sponsor designee, will expedite the reporting to all concerned 
investigators, to the IECs/IRBs, where required, and to the regulatory authorities of all 
adverse reactions that are both serious and unexpected. 
 
Follow-up of serious adverse events 
 
All SAEs will be followed clinically until they are resolved or until a stable situation 
has been reached. Depending on the event, follow-up may require additional tests or 
medical procedures as indicated, and/or referral to a medical specialist. Follow-up 
information on SAEs should be reported until recovery or until a stable situation has 
been reached. 
 
The final outcome of the SAE should be reported in a final SAE report. 
 
Reporting of pregnancy 
 
Details of the procedures to be followed if a pregnancy occurs are provided in 
Section 7.3.4.2. 
 
Pregnancies of a female subject or the female partner of a male subject, occurring at 
least, while the subject is on protocol treatment or during the Follow-up period, should 
be reported to the Sponsor’s Safety Department. Pregnancies must be reported to 


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Pharmacovigilance by email/fax within 24 hours after the event was known to the 
investigator, using the pregnancy report form. 
 
The investigator will follow the female subject until completion of the pregnancy, and 
must notify the Sponsor of the outcome of the pregnancy within 5 days or as specified 
below. The investigator will provide Follow-up information as agreed with scheduled 
revisions calendar. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as an 
SAE (i.e., spontaneous or therapeutic abortion, stillbirth, neonatal death, or congenital 
anomaly - including that in an aborted fetus), the investigator should follow the 
procedures for reporting SAEs. In the case of a live “normal” birth, the Sponsor should 
be informed as soon as the information is available. All neonatal deaths that occur 
within 30 days of birth should be reported, without regard to causality, as SAEs. 
 
In addition, any infant death after 30 days from birth that the investigator suspects to be 
related to in utero exposure to the investigational medicinal product(s) should also be 
reported. 
 
The investigator is encouraged to provide outcome information of the pregnancy of the 
female partner of a male subject, if this information is available to the investigator and 
the female partner gives her permission. 
 
9.1.3.3 Unexpected Adverse Reactions 
 
Unexpected Adverse Reaction Definition 
 
An unexpected adverse reaction is any untoward and unintended response that is related 
to the administration of the study drug at any dose that is not consistent with the 
applicable product information (e.g., investigators brochure for an unauthorized 
investigational medicinal product or SmPC for an authorized product). 
 
All suspected unexpected serious adverse reactions (SUSARs) will be the subject of 
expedited reporting. The Sponsor and/or INC Research shall ensure that all relevant 
information about a SUSAR that is fatal or life-threatening is reported to the relevant 
competent authorities and IEC/IRB within 7 days after knowledge by the Sponsor of 
such a case and that relevant follow up information is communicated within an 
additional 8 days. All other SUSARs will be reported to the relevant competent 
authorities and IEC/IRB within 15 days after knowledge by the Sponsor of such a case. 
All investigators should follow up SUSARs until the events are resolved or until, in the 
opinion of the investigator, the events are stabilized or determined to be chronic. 


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Warnings and Precautions 
 
Warnings and precautions are presented in the MB02 investigator’s brochure (version 
5.0; dated 31 MAY 2017). 
 
9.1.3.4 Clinical Laboratory Evaluation 
 
Hematology, clinical chemistry, coagulation, and urine laboratory analyses will be 
performed at a central laboratory, as described in the laboratory manual. Details of 
sample collection methodology, sample processing, and shipping are also presented in 
the laboratory manual. Local site laboratories may be utilized, in addition to the central 
laboratory, if more rapid results are required for retreatment decisions or subject safety. 
If a local site laboratory sample is taken, then part of the blood sample obtained for 
local site laboratory assessment should also be sent to the central laboratory for analysis. 
Local site laboratory results obtained during the study will not be captured in the eCRF 
unless the investigator determines they are needed to clarify why a treatment decision 
was made or an AE was recorded. Laboratory parameters of interest will be graded 
according to NCI-CTCAE version 4.0318 to allow for comparison of AEs and laboratory 
parameters. 
 
The following laboratory safety tests will be performed: 
 
Hematology 
 
Complete blood count, including hemoglobin, hematocrit, white blood cell (WBC) 
count (with 5-part differential), red blood cell count (RBC) and platelet count. 
 
Clinical Chemistry 
 
Bicarbonate (HCO3), calcium, phosphorus, magnesium, albumin, glucose, serum 
creatinine, total protein, and blood urea nitrogen. Liver function tests: AST, ALT, 
lactate dehydrogenase, alkaline phosphatase, and total and direct bilirubin. 
 
Coagulation 
 
International normalized ratio, prothrombin time, partial thromboplastin time and 
fibrinogen. 
 
Urinalysis 
 
At screening, a single urine sample will be sent to central laboratory for microscopy 
including protein, protein-to-creatinine ratio, specific gravity, glucose, and blood. If 
protein-to-creatinine ratio is ≥ 1, then a 24-hour urine sample will be shipped to central 
laboratory and must demonstrate < 1 g of protein in 24 hours. 


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For routine on-study assessments, dipstick is sufficient as long as the urine protein 
result is less than 2+ (urinalysis is also acceptable). If dipstick urine protein is ≥ 2+, 
24-hour urine must demonstrate < 1 g of protein in 24 hours as assessed by a central 
laboratory. 
 
9.1.3.5 Other Laboratory Variables 
 
Screening for pregnancy (female subjects of childbearing potential only) will be 
performed (serum or urine β human chorionic gonadotrophin [β-HCG]) at Screening 
and before each cycle of treatment. 
 
9.1.3.6 Vital Signs 
 
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate and body 
temperature) will be recorded in a standardized manner using manual methods of 
measurement after the subject has rested in a supine position for 5 minutes. Weight and 
height will be recorded in metric units (height at Screening only). 
 
Inadequately controlled hypertension is defined as systolic blood pressure > 140 mm Hg 
and/or diastolic blood pressure > 90 mm Hg on antihypertensive medications. If 
medically significant hypertension cannot be controlled with antihypertensive therapy, 
or if the subject develops hypertensive crisis or hypertensive encephalopathy, 
MB02/Avastin® should be permanently discontinued. 
 
9.1.3.7 Physical Examination 
 
A complete physical examination will be performed. The following items and body 
systems will be assessed: general appearance; eyes, ears, nose and throat, head and 
neck; chest and lungs; cardiovascular; abdomen; musculoskeletal; lymphatic; 
dermatologic; neurologic; and extremities. A complete dental examination will also be 
performed at screening in order to identify any invasive dental procedure. It is 
considered a risk factor for osteonecrosis of the jaw, reported for subjects on 
bevacizumab. 
 
Appropriate preventive dentistry should be considered before the start of treatment, if 
clinically indicated. Procedures that involve direct osseous injury and placement of 
dental implants should be avoided if not strictly necessary. Caution should be exercised 
for subjects receiving intravenous bisphosphonates. 
 
9.1.3.8 Eastern Cooperative Oncology Group Performance Status 
 
Eastern Cooperative Oncology Group performance status will be recorded according to 
the grades presented in Table 1. 


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Table 1 Summary of Eastern Cooperative Oncology Group (ECOG) Performance 
Status 
 
Grade 
ECOG/performance status 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Source: http://ecog-acrin.org/resources/ecog-performance-status. Accessed: 07 April 2017 
 
 
9.1.3.9 12-Lead Electrocardiogram 
 
A standard 12-lead ECG will be performed at Screening, at Cycle 3 (before dosing), 
Cycle 5 (before dosing), Cycle 6 (Week 18), End-of-Treatment Visit, at Week 52 (Cycle 
18 predose) and any time if clinically indicated at the investigator’s discretion. 
 
PR interval, QRS complex duration, QT interval, and QT interval corrected according to 
Fridericia’s formula will be calculated. The ECG measurements will be made with the 
subject in a supine position and having rested in this position for at least 10 minutes 
before each time point. 
 
Paper ECG traces will be recorded on a single A4 page at a standard paper speed of 
25 mm/sec, calibrated to 1 cm/mV or to 0.5 cm/mV if the amplitude of the QRS 
complex requires, with a lead II rhythm strip. 
 
Any ECG with results falling outside the normal ranges may be repeated at the 
discretion of the investigator. If any results falling outside the normal ranges are deemed 
not clinically significant by the investigator, or appropriately qualified designee, this 
should be clearly stated on the hard copies of the ECG and signed and dated by the 
investigator. If an ECG trace indicates an abnormality that is measured by the 
equipment but is deemed normal by the investigator, this should be clearly stated on the 
ECG trace as normal and signed and dated by the investigator or appropriately qualified 
designee. If the ECG trace indicates an abnormality that is present but deemed as not 
clinically significant by the investigator or appropriately qualified designee, then this 
should be clearly stated on the ECG trace as “NCS” and signed and dated by the 
investigator or appropriately qualified designee. If any results falling outside the normal 


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ranges are deemed clinically significant by the investigator or appropriately qualified 
designee these should be recorded in the eCRF as an AE/SAE. 
 
9.1.3.10 Cardiac Ultrasound or Multigated Acquisition Scan 
 
Left ventricular ejection fraction will be measured by cardiac ultrasound or multigated 
acquisition scan at Screening and End-of-Treatment Visits (if not done in previous 6 
weeks). It can also be measured during any treatment cycle if clinically indicated. 
 
9.1.3.11 Brain CT Scan 
 
A brain CT scan will be performed only in subjects with known or history of brain 
metastases, and whenever is clinically indicated. Brain CT scan procedures are 
presented in the laboratory manual. 
 
9.1.3.12 Survival Status 
 
Any deaths will be recorded on the appropriate pages of the eCRF. 
 
9.2 
Data Safety Monitoring Board 
 
To enhance the safety and integrity of the study data, a DSMB consisting of 
independent experts will be convened to review periodically the accumulating safety 
data for the study. The initial safety review by the DSMB will occur after the first 25% 
of subjects have been randomized and received study drug. The DSMB will provide a 
recommendation on study continuation, modification or termination, should a concern 
regarding safety arise. The specific responsibilities and composition of the DSMB are 
outlined in a separate document, the DSMB charter, which also includes details of 
outputs provided for the meetings. The DSMB will meet at the times described in the 
DSMB charter for periodic safety reviews; the DSMB can also request ad hoc meetings 
with the Sponsor should any safety concerns arise. 
 
9.2.1 
Appropriateness of Measurements 
 
The efficacy and safety assessments planned for this study are widely used and 
generally recognized as reliable, accurate, and relevant to the disease condition. 
 
10 
STATISTICAL METHODS 
 
10.1 
Statistical and Analytical Plans 
 
A detailed SAP will be created and finalized before database lock. 
 
A blinded data review meeting will be convened to finalize assignments to the analysis 
sets, including the per-protocol set (PPS) shortly after all subjects have completed the 
scheduled procedures at Week 18 and data cleaning up to the Week 18 visit has been 


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completed. An additional blinded data review meeting will be held on clean data shortly 
before the database lock (once all subjects have completed the study). 
 
10.1.1 Datasets or Populations Analyzed 
 
Intention-to-treat analysis Set 
 
The ITT analysis set will consist of all randomized subjects. Subjects from the ITT 
population will be analyzed under the randomized treatment group. 
 
Per-Protocol Set 
 
The PPS with regards to the primary endpoint will consist of all subjects in the ITT 
population who complete at least the first 6 cycles of treatment and for whom no major 
protocol deviations affecting efficacy occur until Week 18. For protocol deviations refer 
to Section 10.3. 
 
Subjects from the PPS will be analyzed under the randomized treatment group. 
 
Safety Analysis Set 
 
The SAF will consist of all randomized subjects who received at least 1 administration 
of study drug. Subjects will be analyzed under the actual treatment received. 
 
10.1.2 Demographic and Other Baseline Characteristics 
 
Demographic and other baseline characteristics (e.g., age, sex, race, height, body 
weight, body mass index) will be summarized for the ITT population, PPS, and SAF. 
 
10.1.3 Efficacy Variables 
 
Unless otherwise stated, efficacy analyses will be performed on the ITT population. 
 
10.1.3.1 Definition of Primary Efficacy Endpoint 
 
Objective response rate: OR will be assigned for subjects if they experience either CR 
or PR per RECIST v1.1 at Week 18, as assessed by independent review. The ORR at 
Week 18 will be calculated as the proportion of subjects with OR, and the RR of the 
ORRs (MB02/Avastin®), and risk difference (RD) of the ORRs (MB02 minus Avastin®) 
will be used to determine if MB02 is equivalent to Avastin®. Any subjects who 
discontinue study treatment before Week 18 will be classed as non-responders in the 
final analysis of the primary efficacy endpoint (both for RR and RD analysis). Based on 
the recommendations of 2 different agencies, both Risk Ratio (FDA) and Risk 
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10.1.3.1.1 
Analysis on primary endpoint using risk ratio 
 
Per the US FDA recommendation the equivalence analysis will be based on the risk 
ratio (Type II meeting of 30th June 2017 and 31st July 2017 follow-up letter). Further to 
this, based on FDA recommendation (Type II meeting of 4th October 2018), the 
equivalence margin [0.73, 1.36] will be used to ascertain clinical equivalence of the 
primary efficacy endpoint. 
 
The statistical hypotheses associated with the primary analysis of ORR at Week 18 
using risk ratio is: 
x H0: (ORR MB02 / ORRAvastin ≤ 0.73) or (ORRMB02 / ORRAvastin ≥ 1.36) 
x 
H1: 0.73 < (ORRMB02 / ORRAvastin) < 1.36, 
where ORRMB02 and ORRAvastin are the ORRs for MB02 and Avastin®, respectively. 
 
The ORR estimate will be adjusted for the randomization strata sex (male/female), 
smoking status (smoker/nonsmoker), disease diagnosis (newly diagnosed/recurrent 
disease) and disease stage (Stage IIIB/Stage IV) using the Cochran- Mantel-Haenszel 
estimate of the RR and corresponding 2-sided 90% CI. The primary analysis will be 
conducted in the ITT population. For additional equivalence criteria on the primary 
endpoint required by regulatory bodies (i.e., PMDA), a 2-sided 95% CI for RR will 
also be provided in the ITT population. 
 
10.1.3.1.2 
Analysis on primary endpoint using risk difference 
 
The EMA requested that the difference in ORRs should be used as the primary efficacy 
analysis (Follow-up Scientific Advice – 22nd June 2017). Hence, this additional analysis 
will be performed and included as part of the primary efficacy analysis. 
 
The statistical hypotheses associated with the primary analysis of ORR at Week 18 
using risk difference is: 
x H0: (ORRMB02 - ORRAvastin ≤ -12%) or (ORRMB02 - ORRAvastin ≥ +12%) 
x 
H1: -12% < (ORRMB02 - ORRAvastin) < +12%, 
where ORRMB02 and ORRAvastin are the ORRs for MB02 and Avastin®, respectively. 
 
The ORR estimate will be adjusted for the randomization strata sex (male/female), 
smoking status (smoker/nonsmoker), disease diagnosis (newly diagnosed/recurrent 
disease) and stage (Stage IIIB/Stage IV) using the Cochran- Mantel-Haenszel estimate 
of the RD and corresponding 2-sided 90% CI. This primary analysis will be conducted 
in the ITT population. For additional equivalence criteria on the primary endpoint 
required by regulatory bodies (i.e., PMDA), a 2-sided 95% CI for RD will also be 
provided in the ITT population. 


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10.1.3.1.3 
Sensitivity and supportive analyses for Primary Efficacy Endpoint 
 
In order to evaluate the robustness of the primary analysis, additional evaluations will 
be performed as follows: 
 
i) 
PPS analysis: The analysis of the primary endpoint (both RD and RR) will 
be repeated using the PPS as sensitivity analysis. 
 
Other sensitivity analyses will be discussed in the SAP. For each sensitivity analysis the 
estimate and 90% CI will be reported for treatment effect and interaction term (if 
applicable). 
 
For sensitivity analyses not involving interactions, a forest plot including the treatment 
effect derived from each analysis and the 90% CI will be plotted using as reference the 
treatment effect from the main primary analysis. 
 
10.1.3.2 Definition and Analysis of Secondary Efficacy Endpoints 
 
1. Progression Free Survival: PFS will be defined as the time from 
randomization to subsequent confirmed progression per RECIST version 1.1, 
or death, measured in weeks. Further details on how to build this       
endpoint will be provided in the SAP. Analyses will occur at Week 18 and 
Week 52; at each analysis, all subject data accrued during the study up to 
this point will be included to inform survival. Thus, at Week 18, any subjects 
with data occurring after Week 18 will be incorporated into the analyses of 
survival time. 
 
1.1) Kaplan-Meier figures and estimates will be presented stratified by 
treatment group. The log-rank test will be used to compare the survival 
distributions of MB02 vs Avastin®. 
1.2) If available, for descriptive purposes, the estimate of the median PFS (in 
weeks) as well the 90% CIs will be presented, comparing the PFS 
distributions of the 2 treatments. This analysis will be performed at cutoff 
points at Week 18 and Week 52 (12 months). 
 
1.3) The Cox proportional hazards model will be used to estimate the hazard 
ratio and its 90% CI of MB02 compared with Avastin® at Week 18 and at 
Week 52 (12 months). The main Cox proportional hazards model will 
include treatment group, with sex, smoking status, disease diagnosis, and 
disease stage as covariates. The proportional hazard assumption will be 
evaluated on all covariates (i.e., treatment and stratification factors) by 
graphical inspection of the Schoenfeld residuals and by Grambsch and 
Therneau test as well.21 In the case of nonproportional hazards, other 
analyses will be implemented (e.g., stratified Cox regression). 


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2. Overall Survival: OS will be defined as the time from randomization to 
subsequent death, measured in weeks. Subjects that do not die during the 
study will be censored at the date of last contact (further details will be 
provided in the SAP). Similar to PFS, OS analyses will occur at Week 18 
and Week 52; at each analysis, all subject data accrued during the study up 
to this point will be included to inform survival. Thus, at Week 18, any 
subjects with data occurring after Week 18 will be incorporated into the 
analyses of survival time. 
 
2.1) Kaplan-Meier figures and estimates will be presented stratified by 
treatment group. The log-rank test will be used to compare the survival 
distributions of MB02 vs Avastin®. 
 
2.2) If available, for descriptive purposes, the estimate of the median OS 
time (in weeks) as well the 90% CIs will be presented for the 2 treatment 
groups. This analysis will be performed at cutoff points at Week 18 and 
Week 52 (12 months). 
 
2.3) The Cox proportional hazards model will be used to estimate the hazard 
ratio and its 90% CI between Avastin® and MB02 at Week 18 and Week 52 
(12 months). The main Cox proportional hazards model will include 
treatment, with sex, smoking status, disease diagnosis, and disease stage as 
covariates. Model diagnostic will follow the same procedure implemented on 
Cox regression for PFS outcome. 
 
The effects of other baseline variables on the efficacy endpoints may be investigated in 
subgroup analyses. 
 
10.1.4 Immunogenicity Variables 
 
For immunogenicity, incidence of ADAs to bevacizumab, their neutralizing potential, 
and titer of positive will be summarized in the SAF using by frequency of ADA- 
positive samples for each time point and overall for each treatment separately and may 
be compared between treatments. Analysis of immunogenicity endpoints will be 
conducted by an external provider. 
 
10.1.5 Safety Variables 
 
Descriptive analysis of safety variables will be performed on the SAF. Further 
information will be provided in the SAP. 
 
Incidence of AEs and their characteristics (frequency, severity, causality, seriousness, 
and action taken) in the treatment groups will be compared. Adverse events will be 
classified according to NCI-CTCAE version 4.03. 


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Physical examination, ECOG/performance status, vital signs, body weight, laboratory 
test results (including immunogenicity and pregnancy test), 12-lead ECG, brain CT, 
tumor assessment, concomitant medications, and actual values and their changes from 
Baseline (as appropriate) will be displayed using summary statistics by treatment at 
each measurement time point. 
 
Laboratory parameters of interest will also be graded according to NCI-CTCAE version 
4.03 to allow for comparison of AEs and laboratory parameters. 
 
10.1.6 Schedule of Analyses 
 
No interim analyses are planned; however, there will be data reviews during the study. 
Safety and tolerability interim data recorded during the study period will be reviewed by 
an independent DSMB for preliminary safety and tolerability assessments at specific 
intervals. The timing of the DSMB reviews will be described in the DSMB charter. 
 
The main analysis will be performed once the primary endpoint has been achieved, i.e., 
once the last randomized subject has completed the study up to Week 18, and any tumor 
review has occurred. A further analysis will be conducted once all subjects have 
completed/terminated the study (maximum 52 weeks). Further details of these analyses 
will be included in the SAP, including procedures incorporated in order to maintain 
blinding for the Week 18 analysis. 
 
10.1.7 Handling of Missing Data 
 
Further details will be provided in the SAP. 
 
10.2 
Determination of Sample Size 
 
Based on the recommendations of 2 different agencies, 2 different analyses will be 
performed: 1 based on Risk Ratio (FDA) and 1 based on Risk Difference (EMA). 
Hence, the sample size calculation should ensure that sufficient power is retained on 
both analyses. No multiplicity correction will be applied. 
The determination of equivalence will be based on the ITT population. Per protocol 
population will be used as a supportive population for evaluating sensitivity of main 
analysis. 
 
Risk Ratio 
The US Food and Drug Administration (FDA) requires a primary endpoint of risk ratio 
based on ORR, with an equivalence margin of [0.73, 1.36]. In order to gain an 
understanding of the clinical effect of the reference treatment, Avastin®, a meta-analysis 
has been conducted to ascertain the expected ORR for the reference arm, including the 
following references: Sandler et al. (N Engl J Med 2006;533:2542-50), Johnson et al. (J 
Clin Oncol 2004;22:2184-91), Niho et al. (Lung Cancer 2012;76:362-7), Reck et al. 




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10.3 
Protocol Deviations 
 
Major protocol deviations may include, but are not limited to: 
 
x Randomization criteria violations. 
x Inclusion/Exclusion criteria violations. 
x Inadequate compliance with study drug. 
x Prohibited medications taken. 
x Significant deviations from the study drug administration schedule. 
x No valid evaluation of the primary efficacy endpoint. 
x Other protocol deviations that could affect subjects' efficacy outcomes. 
 
The final list of major protocol deviations will be defined during the blinded data review 
meeting. 
 
11 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
11.1 
Audit and Inspection 
 
Study centers and study documentation may be subject to Quality Assurance audit 
during the course of the study by the Sponsor or its nominated representative. In 
addition, inspections may be conducted by regulatory authorities at their discretion. 
 
11.2 
Monitoring 
 
Data for each subject will be recorded on an eCRF. Data collection must be completed 
for each subject who signs an ICF and is administered study drug; the minimum 
information collected (i.e., for Screen Failure subjects) will be ICF, inclusion/exclusion 
criteria, disease medical history, vital signs, demographics, and AEs. Any reason for 
screening failure should be recorded. 
 
In accordance with GCP and ICH guidelines, the study monitor will carry out source 
document verification at regular intervals to ensure that the data collected in the eCRF 
are accurate and reliable. 
 
The investigator must permit the monitor, the IEC/IRB, the Sponsor’s internal auditors, 
and representatives from regulatory authorities direct access to all study-related 
documents and pertinent hospital or medical records for confirmation of data contained 
within the eCRFs. 
 
11.3 
Data Management and Coding 
 
INC Research will be responsible for activities associated with the data management of 
this study. This will include setting up a relevant database and data transfer 
mechanisms, along with appropriate validation of data and resolution of queries. Data 


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generated within this clinical study will be handled according to the relevant standard 
operating procedures of the data management and biostatistics departments of INC 
Research. 
 
Study centers will enter data directly into an electronic data capture (EDC) system by 
completing the eCRF via a secure internet connection. Data entered into the eCRF must 
be verifiable against source documents at the study center. Data to be recorded directly 
on the eCRF will be identified and the eCRF will be considered the source document for 
these data. Any changes to the data entered into the EDC system will be recorded in the 
audit trail and will be FDA CFR 21 Part 11 compliant. Subject identifiers will be used to 
prevent identification of individual subjects. 
 
Medical coding will use Medical Dictionary for Regulatory Activities (MedDRA) for 
concomitant diseases and AEs and WHO Drug for medications. 
 
Missing or inconsistent data will be queried in writing to the investigator through the 
EDC for clarification and until resolution. Subsequent modifications to the database will 
be documented. 


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12 
RECORDS AND SUPPLIES 
 
12.1 
Drug Accountability 
 
On receipt of the study drug (including rescue medication, if relevant), the investigator 
(or deputy) will conduct an inventory of the supplies and verify that study drug supplies 
are received intact and in the correct amounts before completing a supplies receipt. The 
investigator will retain a copy of this receipt at the study center and return the original 
receipt to the study monitor. The monitor may check the study supplies at each study 
center at any time during the study. 
 
It is the responsibility of the study monitor to verify that the investigator (or deputy 
investigator) has correctly documented the amount of the study drug received, 
dispensed, and returned on the dispensing log that will be provided. A full drug 
accountability log will be maintained at the study center at all times. If study centers 
have appropriate facilities, they should destroy unused expired medication according to 
local regulations. If they do not have appropriate facilities, the study monitor will 
arrange collection of unused study drug for destruction. The study monitor will also 
perform an inventory of study drug at the close-out visit to the study center. All 
discrepancies must be accounted for and documented. 
 
12.2 
Financing and Insurance 
 
Financing and insurance of this study will be outlined in a separate agreement between 
INC Research and the Sponsor. 


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13 
ETHICS 
 
13.1 
Independent Ethics Committee or Institutional Review Board 
 
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the subjects, and any other relevant study documentation will be 
submitted to the appropriate IEC/IRB. Written approval of the study and all relevant 
study information must be obtained before the study center can be initiated or the study 
drug is released to the investigator. Any necessary extensions or renewals of IEC/IRB 
approval must be obtained for changes to the study such as amendments to the protocol, 
the ICF, or other study documentation. The written approval of the IEC/IRB with the 
approved ICF must be filed in the study files. 
 
The investigator will report promptly to the IEC/IRB any new information that may 
adversely affect the safety of the subjects or the conduct of the study. The investigator 
will submit written summaries of the study status to the IEC/IRB as required. On 
completion of the study, the IEC/IRB will be notified that the study has ended. 
 
13.2 
Regulatory Authorities 
 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and 
approval before the beginning of the study. On completion of the study, the regulatory 
authorities will be notified that the study has ended. 
 
13.3 
Ethical Conduct of the Study 
 
The investigator(s) and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, GCP, ICH 
guidelines, and the applicable national and local laws and regulatory requirements. 
 
13.4 
Informed Consent 
 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s) and must adhere to GCP. 
 
The investigator is responsible for ensuring that no subject undergoes any study related 
examination or activity before that subject has given written informed consent to 
participate in the study. 
 
The investigator or designated personnel will inform the subject of the objectives, 
methods, anticipated benefits, and potential risks and inconveniences of the study. The 
subject should be given every opportunity to ask for clarification of any points s/he does 
not understand and, if necessary, ask for more information. At the end of the interview, 
the subject will be given ample time to consider the study. Subjects will be required to 
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by the investigator in the investigators study file. A signed and dated copy of the 
subject ICF will be provided to the subject or their authorized representative. 
 
It should be emphasized that the subject may refuse to enter the study or to withdraw 
from the study at any time, without consequences for their further care or penalty or loss 
of benefits to which the subject is otherwise entitled. Subjects who refuse to give or who 
withdraw written informed consent should not be included or continue in the study. 
 
If new information becomes available that may be relevant to the subject’s willingness 
to continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) 
(and regulatory authorities, if required). The study subjects will be informed about this 
new information and reconsent will be obtained. 
 
13.5 
Subject Confidentiality 
 
Monitors, auditors, and other authorized agents of the Sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the US FDA, as well as that of any other 
applicable agency(ies), will be granted direct access to the study subjects’ original 
medical records for verification of clinical study procedures and/or data, without 
violating the confidentiality of the subjects to the extent permitted by the law and 
regulations. In any presentations of the results of this study or in publications, the 
subjects’ identities will remain confidential. 


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14 
REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced. After completion of the study 
(end of study defined is the date of the last visit of the last subject), all documents and 
data relating to the study will be kept in an orderly manner by the investigator in a 
secure study file. This file will be available for inspection by the Sponsor or its 
representatives. Essential documents should be retained for 2 years after the final 
marketing approval in an ICH region or for at least 2 years after the discontinuation of 
clinical development of the investigational product or longer if required by local 
regulations. It is the responsibility of the Sponsor to inform the study center when these 
documents no longer need to be retained. The investigator must contact the Sponsor 
before destroying any study related documentation. In addition, all subject medical 
records and other source documentation will be kept for the maximum time permitted 
by the hospital, institution, or medical practice. 
 
The Sponsor must review and approve any results of the study or abstracts for 
professional meetings prepared by the investigator(s). Published data must not 
compromise the objectives of the study. Data from individual study centers in 
multicenter studies must not be published separately. 


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15 
REFERENCES 
 
1. 
Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 
2011;61:69–90. 
 
2. 
Forman D, Bray F, Brewster DH, et al. Cancer Incidence in Five Continents. Lyon, 
France: IARC Press, 2013. 
 
3. 
Willett CG, Boucher Y, Di Tomaso E, et al. Direct evidence that the VEGF-specific 
antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 
2004;10:145–7. 
 
4. 
Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic 
angiogenesis: therapeutic implications. Semin Oncol. 2002;29(6 Suppl 16):10–4. 
 
5. 
Avastin® Summary of Product Characteristics. Available at: 
http://www medicines.org.uk/emc/medicine/15748/SPC/. Accessed 07 April 2017. 
 
6. 
MB02 Investigator’s Brochure. Version 7.0; 16 July 2018. 
 
7. 
CDER/CBER, FDA. Guidance for Industry - Scientific Considerations in Demonstrating 
Biosimilarity to a Reference Product: Draft Guidance. 2012. 
 
8. 
CHMP, EMA. Guideline on similar biological medicinal products containing 
biotechnology-derived proteins as active substance: non-clinical and clinical issues 
(EMEA/CHMP/BMWP/42832/2005).   2006. 
 
9. 
CHMP, EMA. Guideline on similar biological medicinal products containing monoclonal 
antibodies – non-clinical and clinical issues: EMA/CHMP/BMWP/403543/2010. 2012. 
 
10. 
Carboplatin Summary of Product Characteristics. Available at: https://www.gelbe- 
liste.de/produkte/Carboplatin-Bendalis-10-mg-ml-Konzentrat-zur-Herstellung-einer- 
Infusionsloesung_546307/fachinformation. Gelbe-Liste Pharmindex. Accessed 23 Nov 
2018. 
 
11. 
Carboplatin Summary of Product Characteristics. Available at: 
http://www.tevauk.com/mediafile/id/40602.pdf. Teva Pharmaceuticals Europe B.V. 
Version 3.0, 26 April 2016. 
 
12. 
Carboplatin Summary of Product Characteristics. 
http://www medicines.org.uk/emc/product/3787/smpc. Accessed 23 Nov 2018. 
 
13. 
Paclitaxel Summary of Product Characteristics. Available at: 
https://www.teva.de/assets/products/de/label/Paclitaxel- 
GRY%206%20mg%20ml%20Konzentrat%20zur%20Herstellung%20einer%20Infusionsl 
osung%20-%202.pdf?pzn=399054. Teva GmbH Version 2, Sep 2017. 
 
14. 
Paclitaxel Summary of Product Characteristics. Available at: 
http://www.tevauk.com/mediafile/id/40077.pdf. Teva UK Ltd. Accessed 23 Nov 2018. 


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15. 
Paclitaxel Summary of Product Characteristics. Available at: 
http://www medicines.org.uk/emc/product/6362/smpc. Actavis UK Ltd. Accessed 16 
June 2017. 
 
16. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47. 
 
17. 
The Criteria Committee of the New York Heart Association. (1994). Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). Boston: 
Little, Brown & Co. pp. 253–256. 
 
18. 
US Department of Health and Human Services. Common Terminology Criteria for 
Adverse Events (CTCAE). Version 4.03. Available at: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 
14_QuickReference_5x7.pdf. Published 14 Jun 2010. Accessed 05 Apr 2017. 
 
19. 
US Department of Health and Human Services. Guidance for Industry: Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics. Available at: 
https://www fda.gov/downloads/drugsGuidanceComplianceRegulatoryInformation/Guida 
nce/UCM071590.pdf. Accessed 13 April 2017. 
 
20. 
Expert Committee on Biological Standardization, WHO. Guidelines on evaluation of 
similar biotherapeutic products (SBPs). 2009. 
 
21. 
Grambsch, PM and TM Therneau. Proportional hazards tests and diagnostics based on 
weighted residuals. Biometrika. 1994:81(3):515–526. 
 
22. 
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for 
non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-50. 
 
23. 
Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing 
bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in 
previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin 
Oncol. 2004;22:2184–91. 
 
24. 
Niho S, Kunitoh H, Nokihara H, et al. Randomized phase II study of first-line 
carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced 
non-squamous non-small-cell lung cancer. Lung Cancer. 2012;76:362-267. 
 
25. 
Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and 
bevacizumab or placebo as first-line therapy for non-squamous non-small-cell lung 
cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010;21:1804–9. 
 
26. 
Zhou C, Wu YL, Chen G, et al. BEYOND: A Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel 
Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent 
Nonsquamous Non–Small-Cell Lung Cancer. J Clin Oncol. 2015;33:2197-2204. 


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16 
APPENDICES 


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16.1 Investigator Signature Page 
 
 
Protocol Title: 
STELLA – A Randomized, Multicenter, Multinational, Double-blind 
Study to Assess the Efficacy and Safety of MB02 (Bevacizumab 
Biosimilar drug) versus Avastin® in Combination with Carboplatin and 
Paclitaxel for the Treatment of Subjects with Stage IIIB/IV Non-squamous 
Non-Small Cell Lung Cancer (NSCLC) 
Protocol Number: 
MB02-C-02-17 
 
 
Confidentiality and cGCP Compliance Statement 
 
I, the undersigned, have reviewed this protocol (and amendments), including 
appendices, and I will conduct the study as described in compliance with this protocol 
(and amendments), GCP, and relevant ICH guidelines. 
 
Once the protocol has been approved by the IEC/IRB, I will not modify this protocol 
without obtaining previous approval of mAbxience and of the IEC/IRB. I will submit 
the protocol amendments and/or any ICF modifications to mAbxience and IEC/IRB, 
and approval will be obtained before any amendments are implemented. 
 
I understand that all information obtained during the conduct of the study with regard to 
the subjects’ state of health will be regarded as confidential. No subjects’ names will be 
disclosed. All subjects will be identified by assigned numbers on all eCRFs, laboratory 
samples, or source documents forwarded to the Sponsor. Clinical information may be 
reviewed by the Sponsor or its agents or regulatory agencies. Agreement must be 
obtained from the subject before disclosure of subject information to a third party. 
 
Information developed in this clinical study may be disclosed by mAbxience, to other 
clinical investigators, regulatory agencies, or other health authority or government 
agencies as required. 
 
 
 
Investigator Signature 
Date 
Printed Name 
 
Institution 


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16.2 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Guidelines (January 2009) 
 
The following paragraphs are a quick reference to RECIST criteria (version 1.1). The 
complete criteria are included in the published RECIST document also available at 
http://www.eortc.be/RECIST. 
1) Measurability of tumor lesions at Baseline 
1.1)  Definitions 
Measurable disease. the presence of at least 1 measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
 
Measurable lesions. tumor lesions that can be accurately measured in at least 1 
dimension (longest diameter to be recorded) as ≥ 20 mm with chest x-ray, and as 
≥10 mm with CT or clinical examination [using calipers]. Malignant lymph nodes must 
be ≥ 15 mm in the short axis to be considered measurable; only the short axis will be 
measured and followed. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters) by use of a ruler or calipers. Tumor lesions situated in 
a previously irradiated area, or in an area subjected to other loco-regional therapy, are 
usually not considered measurable unless there has been demonstrated progression in 
the lesion. 
 
Non-measurable lesions. All other lesions (or sites of disease), including small lesions 
are considered non-measurable disease. Bone lesions without a measurable soft tissue 
component, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis or pulmonitis, inflammatory breast disease, lymphangitic involvement of lung or 
skin and abdominal masses followed by clinical examination are all non-measurable. 
Nodes that have a short axis less than 10 mm at baseline are considered nonpathological 
and should not be recorded or followed. 
 
Target lesions. When more than 1 measurable tumor lesion or malignant lymph node is 
present at baseline all lesions up to a maximum of 5 lesions total (and a maximum of 2 
lesions per organ) representative of all involved organs should be identified as target 
lesions and will be recorded and measured at baseline. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter), and be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. Note that pathological nodes must meet the criterion of a short 
axis of ≥ 15 mm by CT, and only the short axis of these nodes will contribute to the 
baseline sum. At baseline, the sum of the target lesions (longest diameter of tumor 
lesions plus short axis of lymph nodes: overall maximum of 5) is to be calculated and 
recorded. 


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Nontarget lesions. All non-measurable lesions (or sites of disease) including 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm), plus any measurable 
lesions over and above those listed as target lesions are considered nontarget lesions. 
Measurements are not required but these lesions should be noted at baseline and should 
be followed as “present” or “absent”. 
 
All Baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
2.1 Methods of measurements 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during Follow-up. Assessments 
should be identified on a calendar schedule and should not be affected by delays in 
therapy, which may be treatment arm dependent. While on study, all target lesions 
recorded at baseline should have their actual measurements recorded on the eCRF at 
each subsequent evaluation, even when very small (e.g. 2 mm). If it is the opinion of the 
radiologist that the lesion has probably disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned. For lesions that fragment/split, 
add together the longest diameters of the fragmented portions; for lesions that coalesce, 
measure the maximal longest diameter for the “merged lesion”. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm as assessed using calipers (e.g. skin nodules). For the case of 
skin lesions, documentation by color photography including a ruler to estimate the size 
of the lesion is recommended. If feasible, imaging is preferred. 
 
Chest X-ray. Chest CT is preferred over chest x-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than x-ray, particularly in identifying 
new lesions. However, lesions more than 20 mm on chest x-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
 
CT, MRI. CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability of 
lesions on CT based on the assumption that CT slice thickness is 5 mm or less. When 
CT have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for 
body scans). Although positron emission tomography (PET) is not considered adequate 
to measure lesions, PET-CT may be used providing that the measures are obtained from 
the CT and the CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast). 


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Tumor markers. Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a subject to be considered in CR. 
 
2.2 Measurability of tumor lesions at End-of-Treatment/Follow-up 
For the endpoint of best overall response, each subject will have their BEST 
RESPONSE from the start of study treatment until the end of treatment classified as 
outlined below: 
 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point at least 4 weeks later. Refer to the table below. 
2.1)  Response categories. 
Complete Response (CR): disappearance of all target and nontarget lesions and 
normalization of tumor markers. Pathological lymph nodes must have short axis 
measures less than 10 mm (Note: Continue to record the measurement even if < 10 mm 
and considered CR). Tumor markers must have normalized. Residual lesions (other than 
nodes < 10 mm) thought to be nonmalignant should be further investigated (by cytology 
or PET) before CR can be accepted. 
 
Partial Response (PR): At least a 30% decrease in the sum of measures (longest 
diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as 
reference the baseline sum of diameters. Nontarget lesions must be non-PD. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum of diameters on study. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured 
lesions taking as references the smallest sum of diameters recorded on study (including 
at baseline) AND an absolute increase of ≥ 5 mm. Appearance of new lesions will also 
constitute PD (including lesions in previously unassessed areas). In exceptional 
circumstances, unequivocal progression of nontarget disease may be accepted as 
evidence of disease progression, where the overall tumor burden has increased 
sufficiently to merit discontinuation of treatment, for example where the tumor burden 
appears to have increased by at least 73% in volume (which is the increase in volume 
when all dimensions of a single lesion increase by 20%). Modest increases in the size of 
1 or more nontarget lesions are NOT considered unequivocal progression. If the 
evidence of PD is equivocal (target or nontarget), treatment may continue until the next 
assessment, but on further documentation, the earlier date must be used. 


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Table 1: Integration of Target, Nontarget and New Lesions into Response Assessment 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall 
Response 
Best  Response  for  this  category  also 
requires 
Subjects with Target lesions ± nontarget lesions 
CR 
CR 
No 
CR 
Normalization  of  tumor  markers,  tumor 
nodes < 10 mm 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/  
not all evaluated 
No 
PR 
SD 
Non-PD/  
not all evaluated 
No 
SD 
Documented at least once ≥ 6-8 wks. from 
baseline 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
Subjects with Nontarget lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumor markers, all tumor 
nodes < 10 mm 
No Target 
Non-CR/non-PD 
No 
Non-CR/ 
non-PD 
No Target 
Not all evaluated 
No 
NE 
No Target 
Unequivocal PD 
Any 
PD 
No Target 
Any 
Yes 
PD 
Note: Subjects with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease 
progression [or evidence of unequivocal disease progression] at that time should be reported as “symptomatic deterioration”  This is a 
reason for stopping therapy, but is NOT objective PD  Every effort should be made to document the objective progression even after 
discontinuation of treatment  
 
Complete response or PR may be claimed only if the criteria for each are met at a 
subsequent time point at least 4 weeks later. The best overall response can be 
interpreted as below: 


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Response:  
First time point 
 
 
Subsequent time point 
BEST overall response 
Also requires 
 
CR 
 
CR 
CR 
Normalization of tumor 
markers, tumor nodes < 
10 mm 
CR 
PR 
SD, PD or PR (see comment*) 
CR 
SD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for 
SD duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for 
SD duration met, otherwise NE 
NE 
NE 
NE 
* may consider PR providing initial “CR” likely PR on subsequent review – then original CR should be corrected  
Recurrence of lesion after true CR is PD  
 
2.2)  Date of progression 
This is defined as the first day when the RECIST (version 1.1) criteria for PD are met. 
In the cases of subjects with only nonmeasurable disease, care must be taken to 
explicitly describe the findings which would qualify for PD for those subjects. 
 
1) 
Reporting of tumor response 
All subjects included in the study must be assessed for response to treatment, even if 
there is a major protocol treatment deviation or if they are ineligible, or not followed/re- 
evaluated. Each subject will be assigned 1 of the following categories: CR, PR, SD, 
progressive disease, early death from malignant disease, early death from toxicity, early 
death from other cause or unknown (not assessable, insufficient data). 
 
Early death is defined as any death occurring before the first per protocol time point of 
tumor re-evaluation. The responsible investigator will decide if the cause of death is 
malignant disease, toxicity, or other cause. 
 
Subjects for whom response is not confirmed will be classified as "unknown", unless 
they meet the criteria for SD (or the criteria for PR in case of an unconfirmed CR). 
Subjects’ response will also be classified as "unknown" if insufficient data were 
collected to allow evaluation per these criteria. 
Refer to the second table in Section 2.1 of this appendix. 


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2) 
Response duration 
Response duration will be measured from the time measurement criteria for CR/PR 
(whichever is first recorded) are first met until the first date that recurrent or progressive 
disease is objectively documented. 
3) 
Stable disease duration 
Stable disease duration will be measured from the time of start of treatment (or 
randomization for randomized studies) until the criteria for progression is met. 


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16.3
American Joint Committee on Cancer; Lung Cancer Staging, 7th edition


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Source: 
http://cancerstaging.org/references-tools/quickreferences/documents/lungmedium.pdf


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16.4
Protocol Amendment 2 Summary of Changes
This section details the changes made to final protocol MB02-C-02-17 version 3.0, 
Amendment 1 dated 03 Dec 2018, with Amendment 2 to the protocol. The integrated 
protocol, MB02-C-02-17 version 4.0, including Amendment 2, was issued on 24 May 2019.
The main reason to issue the present amendment is clarify the procedures applicable to
Subjects that are responding to treatment at week 52 and are offered the opportunity to be 
treated with biosimilar MB02 monotherapy until disease progression, unacceptable toxicity, 
or death. 
Overview of Changes
1. Clarification in section 3 Protocol Synopsis, study design paragraph: removing the
wording no further study assessments will be performed beyond Week 52 and adding
that the opportunity to continue treatment for subjects beyond Week 52 is only for
subjects that are responding to study treatment. It refers to a new section Section 8.6,
where the details are explained for this situation.
2. Incorporation of Section 8.6 to clarify the specific procedure applicable beyond week
Week 52.
3. Schedule of Assessment table 7.1.1. update incorporating specific
information to be collected beyond Week 52.
4. Clarification in Section 8.6 specifying that only Subjects that are benefiting from
study treatment at Week 52 will be offered the possibility to continue treatment with
biosimilar MB02 monotherapy.
Changes to the Protocol Text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. Additions to the protocol text are shown in bold and 
deletions are shown in strike through text. Minor editorial and grammatical corrections are 
not specified. 
Section 3, Protocol Synopsis
Study Design: 
The study ends at Week 52; no further study assessments will be made after this time. A, 
after Week 52, all subjects (including those randomized to Avastin® during the study) will be 
offered the opportunity to continue receiving biosimilar MB02 monotherapy until disease 
progression, unacceptable toxicity, lost to follow-up, withdrawal of consent, initiation of
any new treatment or deathdisease progression, unacceptable toxicity or death, as required. 
For specific information about post Week 52 procedures refer to Section 8.6.
Number of Subjects: 
Based on recommendation of two different agencies, two different analyses will be 
performed: one based on Risk Ratio (United States [US] Food and Drug Administration 
[FDA]) and one based on Risk Difference (RD; European Medicines Agency [EMA]). 
Risk Ratio: 
The United States (US) FDA requires a primary endpoint of risk ratio (RR) based on ORR, 
with an equivalence margin of [0.73, 1.36]. 




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Data from the BEVZ92-A-01-13 study showed MB02 and Avastin® to have equivalent PK
in terms of AUC and similar efficacy in terms of tumor response in the sensitive population 
of metastatic colorectal patientssubjects. 
Section 7.1, Investigational Plan – Overall Study Design and Plan: Description
The study ends at Week 52; no further study assessments will be made after this time. A, 
after Week 52, all subjects (including those randomized to Avastin® during the study) will be 
offered the opportunity to continue receiving biosimilar MB02 monotherapy until disease 
progression, unacceptable toxicity, lost to follow-up, withdrawal of consent, initiation of
any new treatment or deathdisease progression, unacceptable toxicity, or death, as required 
. No further study related procedures are intended to be performed after Week 52; any 
assessments after Week 52 should be performed based on the investigator’s discretion and 
according to local standard practice. For specific information about post Week 52
procedures refer to Section 8.6.
Subjects who withdraw for any reason other than progression of disease (PD) or withdrawal 
of consent will be followed up every 9 weeks with tumor assessment until PD and/or the start 
of new antitumor treatment, subject decision, death, or Week 52 (End-of-Study Visit) 
whichever occurs first. 
The primary endpoint is ORR (i.e., complete response [CR] or partial response [PR] per 
RECIST version 1.1) at Week 18; an independent radiology review committee (IRC) will 
assess the primary efficacy endpoint using computed tomography (CT) and/or magnetic 
resonance imaging (MRI) according to RECIST version 1.1 criteria. 
A Data Safety Monitoring Board (DSMB) will assess the safety data periodically and will 
recommend to the Sponsor whether to continue, modify or stop the trial. 
x
Subjects with no radiological disease progression will be assessed for: tumor
evaluation, initiation of other treatments, physical examination, Eastern Cooperative
Oncology Group (ECOG) performance status, supine vital signs, concomitant
medications, surgeries, procedures, AEs/SAEs , concomitant diseases and
immunogenicity will be recorded in the electronic case report form (eCRF) at follow- 
up visits at intervals of 9 weeks up to disease progression and/or the start of new
antitumor treatment, death, or Week 52 (End-of-Study Visit).
After Week 52, all subjects (including those randomized to Avastin® during the study) will 
be offered to continue receiving biosimilar MB02 monotherapy until disease progression, 
unacceptable toxicity, lost to follow-up, withdrawal of consent, initiation of any new 
treatment or deathdisease progression, unacceptable toxicity, or death, as required ..For 
specific information about post Week 52 procedures refer to Section 8.6.
Section 7.71.1, Schedule of Assessments
New column added for post Week 52 visits detailing assessments to be performed: Re
consent risk of potential switch from Avastin® to MB02 if subjects were randomized to 
Avastin arm. Confirmation that subjects and investigators will remain blinded up to Week 
52. ( clarification added in footnote q) of Schedule of Assessment table.
Footnote: 
NSCLC = non small cell lung cancer; Abbreviations: ADA = antidrug antibodies; CT =
computed tomography, ECOG = Eastern Cooperative Oncology Group; HIV = human


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immunodeficiency virus; LVEF=left ventricular ejection fraction; NSCLC = non-small cell 
lung cancer; CT = computed tomography, ADA = antidrug antibodies; PD=progression of
disease; WOCBP=women of child bearingchildbearing potential; 
k For those patientssubjects who discontinue treatment without radiological disease 
progression, tumor assessment should be performed every 9 weeks (±5 days) until Week 52,
PD, start of new treatment, subject decision, or death, whichever occurs first. Once 
radiological disease progression is documented, subjects are no longer required to undergo 
additional tumor assessment. 
l Once patientsubject discontinues treatment, ADA sample will follow specified weeks as
scheduled. 
q Subjects will be asked to reconsent for the potential risk of switching treatment to
MB02 in case they have been randomized to Avastin ® treatment. Subjects will remain 
blinded.
Section 7.4.3, Packaging and Labelling
Study packaging will be performed by Clinical Supplies Management (CSM) Europe SA, 
Mont-Saint-Guibert, Belgium 
Section 7.4.7, Blinding
The pharmacist at each study site and a specific clinical team from INC Research and the 
Sponsor will be unblinded to treatment assigned. PatientsSubjects as well as investigators, all 
other study staff, laboratories and the rest of the INC Research and Sponsor team will remain 
blinded to treatment assignment up to Week 52. 
Section 7.4.8.1, Prohibited Medication/ Therapy
As osteonecrosis of the jaw has been reported for patientssubjects on bevacizumab and
invasive dental procedures are an identified risk factor, a dental examination and appropriate 
preventive dentistry should be considered before the start of treatment, if clinically indicated. 
Procedures that involve direct osseous injury and placement of dental implants should be 
avoided if not strictly necessary. Caution should be exercised for patientssubjects on
intravenous bisphosphonates. 
Section 8.1.1, Screening Visit (Days -28 to -1; Visit 1)
Up to 14 days before first study drug administration
x
Urine or serum pregnancy test (according to local requirements, female subjects of
child bearingchildbearing potential only).
Up to 7 days before first study drug administration
It is considered a risk factor for osteonecrosis of the jaw, reported for patientssubjects on
bevacizumab. Appropriate preventive dentistry should be considered, if clinically indicated 
(Section 7.4.8.1).
Section 8.2.1, Cycle 1 (-1/+3 Days)
x
Urine or serum pregnancy test (according to local requirements, female subjects of
child bearingchildbearing potential only).
Section 8.2.2, Cycle 2 (-1/+3 Days)
x
Urine or serum pregnancy test (according to local requirements, female subjects of
child bearingchildbearing potential only).


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Section 8.2.3, Cycle 3 (-1/+3 Days)
x
Urine or serum pregnancy test (according to local requirements, female subjects of
child bearingchildbearing potential only).
Section 8.2.4, Cycle 4 (-1/+3 Days)
x
Urine or serum pregnancy test (according to local requirements, female subjects of
child bearingchildbearing potential only).
Section 8.2.5, Cycle 5 (-1/+3 Days)
x
Urine or serum pregnancy test (according to local requirements, female subjects of
child bearingchildbearing potential only).
Section 8.2.6, Cycle 6 (-1/+3 Days)
x
Urine or serum pregnancy test (according to local requirements, female subjects of
child bearingchildbearing potential only).
Section 8.2.7, Additional Cycles Until Treatment Withdrawal (From Week 19 (Cycle 7) 
onwards, Then Every 3 Weeks; -1/+3 Days)
Subjects who complete 6 cycles can continue to receive MB02 or Avastin® monotherapy 
until disease progression, unacceptable toxicity, death or Week 52,whichever occurs first. 
The study ends at Week 52. After Week 52, all subjects (including those randomized to
Avastin® during the study) will be offered the opportunity to continue receiving 
biosimilar MB02 monotherapy until disease progression, unacceptable toxicity, lost to
follow-up, withdrawal of consent, initiation of any new treatment or death. For specific 
information about post Week 52 procedures refer to section 8.6
x
Urine or serum pregnancy test (according to local requirements, female subjects of
child bearingchildbearing potential only).
Section 8.3, End of Treatment Visit (Within 3 Weeks of Completion of Last Cycle; ±5 Days)
x
Urine or serum pregnancy test (according to local requirements, female subjects of
child bearingchildbearing potential only).
Section 8.4.1, Subjects Who Discontinue Treatment Without Radiological Disease 
Progression Before Week 52 (9 Week Intervals; ±7 Days)
Those patientssubjects who report disease progression during follow-up visits will be
followed as per Section 8.4.2.
Section 8.5, Week 52 End-of-Study Visit (±7 Days)
x
In those patientssubjects who have not shown disease progression (not started any
new antitumor therapy) a CT Scan/MRI of chest, upper abdomen and any other
involved regions must be done if it was not performed within the previous 4 weeks.
Disease status and tumor response will be assessed per RECIST version 1.1 criteria.
Section 8.6, Post Week 52 Period Procedures for Subjects That Are Responding to
Treatment


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New Section added 
After Week 52, all subjects (including those randomized to Avastin® during the 
study)will be offered the opportunity to continue receiving biosimilar MB02 
monotherapy. The following will be required:
x
Subjects and investigators will remain blinded up to week 52
x
Subjects will be asked to re-consent to accept the potential risk of being switched
to MB02 treatment, in case they were initially randomized to Avastin®
x
Subjects will receive MB02 labelled as clinical trial
x
Investigators will collect safety information during the time subjects are on
MB02 treatment beyond Week 52 and will enter the information in the pertinent
section of the eCRF and, in case of occurrence of any SAE, it will be processed
and notified as per section 9.1.3.2. No other study assessments are required, it is
leIW to investigator’s discretion the performance of any further assessment
according to local practice, but these will not be captured in the eCRF
x
Subjects will continue receiving biosimilar MB02 monotherapy until disease
progression, unacceptable toxicity, lost to follow-up, withdrawal of consent,
initiation of any new treatment or death.
x
Investigators are required to notify in advance of any patient at his/her site
willing to proceed with post week 52 treatment. Likewise, investigators are
required to confirm the continuation or discontinuation of the treatment in
advance, per drug supply and logistics purposes.
Section 8.7, Duration of Treatment
After Week 52, all subjects (including those randomized to Avastin® during the study) will be 
offered the opportunity to continue receiving biosimilar MB02 monotherapy until disease 
progression, unacceptable toxicity, lost to follow-up, withdrawal of consent, initiation of
any new treatment or death disease progression, unacceptable toxicity or death. For  
specific information about post Week 52 procedures, refer to Section 8.6.
Section 9.1.1, Tumor Assessment
Tumor response will be assessed by the IRC using the RECIST v1.1 criteria to evaluate ORR. 
Disease status, PFS, and OS16 will be evaluated by Investigatorsinvestigators. The RECIST 
v1.1 (January 2009) guidelines for measurable, nonmeasurable, target and nontarget lesions 
and the objective tumor response criteria (CR, PR, stable disease [SD] or PD) are detailed in
Section 16.2.
Section 9.1.3.1, Adverse Events
Follow-up of adverse events 
Subjects should be followed up until 30 days after last cycle, and any AEs that occur during 
this time should be reported according to the procedures outlined below. Additionally, for 
those subjects who proceed with post Week 52 treatment, any AE occurring during this 
time should, also, be reported according to the procedures outlined below.
Documentation and reporting of adverse events 
Adverse events should be reported and documented in accordance with the procedures 
outlined below; AEs will be recorded in the eCRF from the signing of the informed consent 
form (ICF) until 30 days after last cycle, for those subjects that do not proceed with post


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Week 52 treatment. For those subjects that continue to post Week 52 treatment, any AE 
occurring during this time, will also be recorded in the eCRF. Any AEs occurring more than 
30 days after last cycle of drug administration should also be recorded in the eCRF if they are 
considered at least possibly related to the study drugs by the investigator. The following data 
should be documented for each AE: 
 
Section 9.1.3.2, Serious Adverse Events 
Reporting of serious adverse events 
All SAEs will be recorded in the eCRF and reported from signing of the ICF until 30 days 
after last cycle of any drug from the protocol treatment schedule, for those subjects that do 
not proceed with post Week 52 treatment. For those subjects that continue to post Week 
52 treatment, any SAE occurring during this time, will also be recorded in the eCRF 
and reported. Any SAEs occurring or more than 30 days after last cycle of drug 
administration should also be recorded in the eCRF and reported if they are considered at 
least possibly related to the protocol treatment by the investigator. An SAE form must be sent 
to INC Research by email (PDF) or faxed within 24 hours for the attention of the Safety 
Department. 
 
Section 9.1.3.4, Clinical Laboratory Evaluation 
Local site laboratories may be utilized, in addition to the central laboratory, if more rapid 
results are required for re treatmentretreatment decisions or patientsubject safety. If a local 
site laboratory sample is taken, then part of the blood sample obtained for local site 
laboratory assessment should also be sent to the central laboratory for analysis. Local site 
laboratory results obtained during the study will not be captured in the eCRF unless the 
Investigatorinvestigator determines they are needed to clarify why a treatment decision was 
made or an AE was recorded. Laboratory parameters of interest will be graded according to 
NCI-CTCAE version 4.0318 to allow for comparison of AEs and laboratory parameters. 
 
Section 9.1.3.5, Other Laboratory Variables 
Screening for pregnancy (female subjects of child bearingchildbearing potential only) will 
be performed (serum or urine β human chorionic gonadotrophin [β-HCG]) at Screening and 
before each cycle of treatment. 
 
Section 9.1.3.6, Vital Signs 
If medically significant hypertension cannot be controlled with antihypertensive therapy, or if 
the patientsubject develops hypertensive crisis or hypertensive encephalopathy, 
MB02/Avastin® should be permanently discontinued. 
 
Section 9.1.3.7, Physical Examination 
It is considered a risk factor for osteonecrosis of the jaw, reported for patientssubjects on 
bevacizumab. 
 
Caution should be exercised for patientssubjects receiving intravenous bisphosphonates. 
 
Section 9.1.3.10, Cardiac Ultrasound or Multigated Acquisition Scan 
Left ventricular ejection fraction will be measured by cardiac ultrasound or multigated 
acquisition scan at Screening and End-of-Treatment Visits (if not done in previous 6 weeks). 
It can also be measured during any treatment cycle if clinically indicated. 



SAP_001.pdf: 
 
Protocol Title: 
MB02-C-02-17: STELLA – A Randomized, Multicenter, 
Multinational, Double-Blind Study to Assess the Efficacy 
and Safety of MB02 (Bevacizumab Biosimilar Drug) Versus 
Avastin® in Combination With Carboplatin and Paclitaxel 
for the Treatment of Subjects With Stage IIIB/IV Non-
squamous Non-Small Cell Lung Cancer (NSCLC). 
NCT Number: 
NCT03296163 
SAP version 
date: 
Version 2.0, 03 Apr 2020