Clinical trial NCT02272413
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim
Start date: 2015-07-08; Completion date: 2018-11-16
Enrollment: 671 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this phase III trial is to establish statistical equivalence in terms of efficacy (best overall response rate \[ORR\], proportion of patients with complete response \[CR\] plus partial response \[PR\]) until 18 weeks of first-line treatment with BI 695502 plus chemotherapy versus Avastin® plus chemotherapy followed by maintenance monotherapy with either BI 695502 or Avastin®.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 695502 intervention 2: Avastin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02191106-09
EudraCT No.:
BI Trial No.:
2014-002161-30 
1302.5 INVICTAN®-2
BI Investigational
Product(s):
BI 695502
Title:
A multicenter, randomized, double-blind Phase III trial to evaluate 
efficacy and safety of BI 695502 plus chemotherapy versus Avastin®
plus chemotherapy in patients with advanced nonsquamous Non-Small 
Cell Lung Cancer
Clinical Phase:
III
Trial Clinical 
Monitor:
Phone:
Fax:
Co-ordinating 
Investigator:
Office: 
Fax: 
Status:
Final Protocol (Revised Protocol based on global amendment 07)
Version and Date
Version:
8.0
Date: 17 January 2018
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TITLE PAGE


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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
Trial number:
Revision date:
17 January 2018
08 October 2014
1302.5
Title of trial:
A multicenter, randomized, double-blind Phase III trial to evaluate efficacy and safety 
of BI 695502 plus chemotherapy versus Avastin® plus chemotherapy in patients with 
advanced nonsquamous Non-Small Cell Lung Cancer
Co-ordinating 
Investigator:
Trial sites:
Multicenter trial conducted in approximately 250 clinical sites.
Clinical phase:
III
Objectives:
Primary objective:

The primary objective of this trial is to establish statistical equivalence in terms 
of efficacy (best overall response rate [ORR], proportion of patients with 
complete response [CR] plus partial response [PR]) until 18 weeks of first-line 
treatment with BI 695502 plus chemotherapy versus United States (US)-licensed 
Avastin® plus chemotherapy followed by maintenance monotherapy with either 
BI 695502 or US-licensed Avastin®.
Secondary objectives:

The secondary objectives of the trial are to evaluate further efficacy parameters 
(progression-free survival [PFS], overall survival [OS], duration of response) and 
the safety and tolerability of BI 695502 versus US-licensed Avastin®.


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BI Trial No.: 1302.5
Doc. No.: c02191106-09
Trial Protocol
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
Trial number:
Revision date:
17 January 2018
08 October 2014
1302.5
Methodology:
This is a Phase III, randomized, double-blind, multicenter, active comparator, parallel 
two-arm trial to compare BI 695502 plus paclitaxel and carboplatin (Arm B) versus 
US-licensed Avastin® plus paclitaxel and carboplatin (Arm A). After 4 to 6 induction 
cycles are given, all patients who do not have disease progression (i.e., patients with 
CR, PR or stable disease) will receive maintenance with BI 695502 or US-licensed 
Avastin® alone, per the original randomization. 
The fully blinded, pooled ORR will be closely monitored to verify the sample size 
assumptions. After approximately 200 patients (100 patients per arm) have had tumor 
response assessments performed until Week 18, an independent blinded statistician 
will perform a blinded evaluation to confirm the initially calculated sample size.
The trial will investigate the equivalence of efficacy, safety 
 
data in patients with previously untreated nonsquamous (ns) non-small cell lung 
cancer (NSCLC), randomized in a 1:1 ratio to Arm B and Arm A.
The main efficacy analysis will be based upon the evaluation of tumor response as 
determined by central imaging (independent blinded confirmation of tumor response) 
according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1).
Starting as of 21 Dec 2017, the Sponsor recommends that patients should be switched 
from BI 695502 to the reference product bevacizumab (IMP or commercially 
available Avastin®, both hereafter referred to as Avastin®) as soon as it is available 
at the respective clinical site. If Avastin® is not immediately available, the 
Investigators may temporarily allow continuation on BI 695502. The blind will be 
kept intact and all patients will continue the study with no additional visits in the 
scheduled visit cycle as per protocol.
No. of patients: 
total entered:
Approximately 660 patients will be randomized.
each treatment:
Approximately 330 patients randomized to each Arm B and A in a 1:1 ratio:

BI 695502/concentrate for solution for intravenous (i.v.) infusion (+ paclitaxel 
and carboplatin during induction cycles) (Arm B). 

US-licensed Avastin®/concentrate for solution for i.v. infusion (+ paclitaxel and 
carboplatin during induction cycles) (Arm A).
Pharmacokinetic 
sampling:
Plasma concentrations of BI 695502 or Avastin® measured throughout the treatment 
period.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
Trial number:
Revision date:
17 January 2018
08 October 2014
1302.5
Diagnosis:
Males and females with recurrent or metastatic disease (Stage IV), histologically or 
cytologically confirmed advanced nsNSCLC.
Main criteria
for inclusion:
Aged ≥18 years (for Japan only: Age ≥20 years at Screening)
No prior systemic therapy for metastatic disease. Prior systemic therapy and/or 
radiotherapy for locally advanced disease permitted if completed >12 months prior to 
Screening.
Patients harboring tumors without activating EGFR or ALK mutation. Patients with 
unknown or activating EGFR or ALK mutation may be included provided 
chemotherapy is the site standard of care.
Patients must have at least one measurable lesion according to RECIST 1.1 (based on 
independent central review), and an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1. 
Patients must have no known sensitivity to any of the trial drugs or their excipients
and must have adequate hepatic, renal, and bone marrow function.
Test product(s):
BI 695502/concentrate for solution for i.v. infusion
dose:
15 mg/kg every 3 weeks (21 days)
mode of admin.: Intravenous infusion administered over 90 minutes for the first infusion; if well 
tolerated, administered over 60 minutes for the second infusion and subsequently 
administered over 30 minutes.
Comparator products:
US-licensed Avastin®/concentrate for solution for i.v. infusion 
dose:
15 mg/kg every 3 weeks (21 days)
mode of admin.: Intravenous infusion administered over 90 minutes for the first infusion; if well 
tolerated, administered over 60 minutes for the second infusion and subsequently 
administered over 30 minutes.
Additional protocol 
medication:
Starting as of 21 Dec 2017, the Sponsor recommends that patients should be switched 
from BI 695502 to Avastin®, following the same dose and administration procedure 
as per the Avastin® label, with the exception of the use of filters which must continue 
to be used.
Associated products:
Paclitaxel/carboplatin regimen: 
Paclitaxel 200 mg/m2 (i.v. infusion, administered according to regular institutional 
practice) followed by carboplatin target area under the curve (AUC) 6 mg/mL·minute 
(30- to 60-minute i.v. infusion) every 3 weeks (21 days) for up to 6 cycles with 
adequate pre- and concomitant medication.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
Trial number:
Revision date:
17 January 2018
08 October 2014
1302.5
Duration of treatment:
Treatment with BI 695502 or US-licensed Avastin®, plus chemotherapy (up to 
6 induction cycles) every 3 weeks (21 days, 1 cycle) followed by continued use of 
BI 695502 or Avastin® as a single agent for responding or stabilized patients 
(maintenance cycles) every 3 weeks (21 days, 1 cycle) until disease progression, 
death, withdrawal of consent, or unacceptable toxicity, whichever occurs earlier. 
Criteria for efficacy:
Primary efficacy endpoint:

Best ORR based on unconfirmed response assessment as assessed by central 
imaging review until 18 weeks after the start of treatment.
Secondary efficacy endpoints:

Progression-free survival defined as the time from randomization until 
disease progression as per investigator assessment or death.

Overall survival defined as the time from randomization until death from 
any cause.

Duration of response defined as the time from first documented CR or PR 
until time of progression as per investigator assessment.
Other efficacy endpoints:

Best ORR based on unconfirmed response assessments as per investigator 
assessment until 18 weeks after start of treatment.

Best ORR based on unconfirmed response assessments as per investigator 
assessment until progression or death.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
Trial number:
Revision date:
17 January 2018
08 October 2014
1302.5
Criteria for safety:

The proportion of patients with the following selected adverse events (AEs) 
for comparability assessment of BI 695502 and US-licensed Avastin®
(secondary endpoint): anaphylactic reactions/hypersensitivity 
reactions/infusion-related reactions; arterial and venous thromboembolic 
events; febrile neutropenia; gastrointestinal perforations; hypertension; 
proteinuria; pulmonary hemorrhage; other hemorrhages; wound-healing 
complications/abscess/fistulas.

The proportion of patients with AEs.

The proportion of patients with AEs related to trial treatment.

The proportion of patients with Grade 3 or 4 AEs according to National 
Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) version 4.0.

The proportion of patients with Grade 3 or 4 AEs according to NCI-CTCAE 
version 4.0 related to trial treatment.

The proportion of patients with protocol-specified adverse events of special 
interest.

The proportion of patients with AEs potentially related to immunogenicity 
will also be evaluated.

Physical examination, vital signs, weight, 12-lead electrocardiogram, 
laboratory findings.
Statistical methods:
The primary endpoint will be best ORR, based on unconfirmed response assessment, 
as assessed by central imaging review until 18 weeks after the start of treatment.
Stratification of patient randomization will be based on sex (male versus female), 
smoking status (never smoked versus current/past smoker), NSCLC stage at 
screening (recurrent disease versus Stage IV) and ethnicity (East Asian origin versus 
non East Asian).
Primary efficacy analysis:
Equivalence of BI 695502 to US-licensed Avastin® will be measured based on the 
ratio in best ORR (employing a log binomial regression model with subsequent 
transformation to ratio of proportions) and a margin of (0.736, 1.359) on the ORR 
ratio scale. The null hypothesis will be rejected in favor of equivalence if the 90% 
confidence interval (CI) for the ratio in best ORR between the treatments falls 
completely within the range defined by the equivalence margin; i.e., the comparison 
will be based on two one-sided tests with a 5% type I error rate. The primary analysis 
will be based on the full analysis set according to the intention-to-treat principle. 
The equivalence margin (0.736, 1.359) for ORR ratio is based on a meta-analysis that 
included the following three studies: Sandler et al 2006 (R07-1161), Niho et al 2012 
(R14_0473), and Johnson et al 2004 (R04-4661).  


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
Trial number:
Revision date:
17 January 2018
08 October 2014
1302.5
Statistical methods 
(contd.):
Secondary analyses:
Progression-free survival, OS, and duration of response will be assessed by a 
Cox-proportional hazards model using the same adjustment factors as for best ORR.
Safety analysis
All reported terms for AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). No statistical testing will be performed for AEs. For all AE 
and serious AE tables, patients will be counted at most once for each preferred term 
and each system organ class. Adverse events will be summarized by the number and 
percentage of patients experiencing events by system organ class, preferred term and 
severity.  
 
The analysis of the primary efficacy endpoint is not impacted by the switch from 
BI 695502 to Avastin® as all patients had already completed the Week 18 
assessments at the time of the transition. 
The main analyses will cover the period up until patients were switched from 
BI 695502 to Avastin® in the BI 695502 group and data will be analyzed to the 
extent available. Appropriate censoring methods will be applied at the time of 
switching and will be defined in the TSAP. Adverse events will be presented by 
underlying treatment and taking the corresponding exposure into account.
Additionally, after the transition from BI 695502 to Avastin® in the BI 695502 
group, the impact of switching will be assessed based on the occurrence of relevant 
adverse events after the transition, i.e. anaphylactic reactions/hypersensitivity 
reactions/infusion-related reactions and the occurrence of anti-drug antibodies by 
comparing switched patients and patients receiving continuous treatment with
Avastin®.


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FLOW CHART 1.1 – CYCLE 1 UP TO CYCLE 6
Trial Period
Screening
Treatment
Induction
Induction/Maintenance
Visit
0
1
2
3
4
5
6
Cycle
NA
1
2
3
4
5
6
Informed consent
X
Assessment of eligibility (including EGFR and ALK mutation status2)
X
X
Demographics
X
Medical and surgical history including surgery for lung cancer
X
Smoking status
X
Infection screen (hepatitis B, hepatitis C, TB), optional HIV test3
X
LABORATORY/SAFETY ASSESSMENTS4
Serum pregnancy test5
X
Urine pregnancy test6
X
X
X
Physical examination (including height at Screening only) and weight
X
X
X
X
X
X
X
Vital signs7
X
X
X
X
X
X
X
Laboratory tests (serum chemistry, hematology, urinalysis, coagulation)8
X
X
X
X
X
X
X
12-lead ECG9
X
X
X
Previous and concomitant therapy/medication
X
X
X
X
X
X
X
Adverse events10
X
X
X
X
X
X
X
DISEASE ASSESSMENTS
Tumor assessment (CT11 MRI scan ± PET scan12)
X13
X14
X14
ECOG PS
X
X
X
X
Survival
X--------------------------------------------------------------------------------------X
OTHER ASSESSMENTS


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FLOW CHART 1.1 – CYCLE 1 UP TO CYCLE 6 (continued)
Trial Period
Screening
Treatment
Induction
Induction/Maintenance
Visit
0
1
2
3
4
5
6
Cycle
NA
1
2
3
4
5
6
TRIAL MEDICATION
Contact IXRS®17
X
X
X
X
X
X
X
Randomization
X
Trial medication infusion18
X19
X
X
X
X
X
Paclitaxel premedication
X
X
X
X20
X20
X20
Paclitaxel/carboplatin administration
X
X
X
X20
(X)20
(X)20
ALK = anaplastic lymphoma receptor tyrosine kinase; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal 
growth factor receptor; HIV = human immunodeficiency virus; IXRS® = Interactive Telephone and Web Response System; MRI = magnetic resonance imaging; NA = not 
applicable; PET = positron emission tomography; PS = performance status; TB = tuberculosis.
1.
Clinical assessments will be performed within 3 days before trial medication infusion.
2.
EGFR and ALK mutation status will be evaluated at Screening according to local practice.
3.
Hepatitis B and C testing to be performed at Screening unless obtained within 6 months prior to Screening. Screening for HIV and TB (purified protein derivative or 
QuantiFERON) to be performed according to local practice and local regulatory guidance.
4.
Laboratory samples must be drawn prior to infusions of premedication and trial medication.
5.
Only for females of childbearing potential (for definition, see Section 3.3.2, inclusion criterion #11). Serum pregnancy test will be performed at Screening and at subsequent 
visits if a urine pregnancy test is positive.
6.
Only for females of childbearing potential. Urine pregnancy test will be performed every 6 weeks. Serum pregnancy test will be performed if a urine pregnancy test is 
positive.
7.
Sitting blood pressure (5 minutes rest before start of measurement), respiratory rate, pulse, and body temperature. Two or more blood pressure readings should be taken at 
2 minute intervals and averaged. If the first 2 diastolic readings differ by more than 5 mmHg, then an additional reading should be obtained, and averaged.
8.
All trial-required laboratory tests will be analyzed by the central laboratory, unless specified in the protocol. For laboratory results that are required for decisions on 
chemotherapy administration, laboratory testing should be performed per standard-of-care, based on the site's regular practice. Blood samples may be analyzed locally, but 
will not be collected.
9.
Patients should rest for at least 5 minutes in a supine position before ECG evaluations. Two consecutive recordings may be made at Screening, and before starting Cycle 3 and 
Cycle 5. The first of the consecutive ECGs is mandatory. The second of the consecutive ECGs is optional, at the discretion of the Investigator in case of clinical significance. 
Additional ECGs will be performed if clinically indicated.


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10. All adverse events, regardless of relatedness, will be collected from the time of informed consent until up to 18 weeks after the last administration of trial medication. Adverse 
events continuing at the Safety Follow-up (SFU) visit must be followed until recovery or in case of persistency, sufficient characterization has been achieved and the 
investigator and medical monitor agree to not pursue them further.
11. CT scan with i.v. contrast of chest and abdomen, including adrenal glands and the entire liver, if applicable. In case of an iodine i.v.-contrast contraindication (renal 
insufficiency, allergy, hyperthyroidism etc), an abdomen MRI with contrast (gadolinium) will be performed with a non-contrast chest CT scan. Tumor assessment will be 
performed every 6 weeks (±3 days) during therapy. 
12. A PET scan can be performed in addition to the CT scan, at Screening and at the End of Treatment visit. Combined PET-CT scans may be used only if performed with 
contrast and if resolution is sufficient to allow accurate and consistent comparison of lesion measurements with subsequent CT scans.
13. The screening tumor assessment should be performed within 21 days prior to randomization. Patients should have at least one measurable lesion according to RECIST 1.1 
based on independent central review, to be confirmed prior to randomization (see Section 3.3.2).
14. The tumor assessment should be performed prior to trial medication administration. During the induction phase, tumor assessments should be performed before treatment 
administration of Cycles 3 and 5. If an induction therapy cycle is delayed, the tumor assessment will also be delayed.
17. IXRS® will be used for randomization, and at each visit to assign the correct vial for the allocated treatment group and the medication identification.
18. Administration of BI 695502/US-licensed Avastin® will occur on Day 1 of each cycle (every 21 days) prior to administration of paclitaxel and carboplatin.
19. Cycle 1 treatment to be administered within 4 days after randomization.
20. If the patient cannot tolerate more than 3 cycles of chemotherapy treatment, maintenance treatment with US-licensed Avastin®/BI 695502 monotherapy can be started.


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FLOW CHART 1.2 – CYCLE 7 ONWARDS
Treatment - Maintenance
EOT16
Switch Visit prior 
to Avastin® 
administration21
Non-treatment 
period17, 20
SFU18
Survival19
Visit
7
8
9
10
Cycle
7
8
9
10 and 
onwards
LABORATORY/SAFETY 
ASSESSMENTS2
Serum pregnancy test3
X
X
Urine pregnancy test3
X
X
X4
X
Physical examination (including 
weight)
X
X
X
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
Laboratory tests (serum chemistry, 
hematology, urinalysis, coagulation)
X
X
X
X
X
X
X
12-lead ECG6
X
X7
X
X
X
Concomitant therapy/medication
X
X
X
X
X
X
X
X
Adverse events8
X
X
X
X
X
X
X
X
Date of initiation of second-line 
therapy (if applicable).
X
DISEASE ASSESSMENTS
Tumor assessment
(CT9/MRI scan ± PET scan10)
X11
X7
X
X22
X
ECOG PS
X
X7
X
X
X
Survival
X------------------------------------------------------------------------------------------------------------------------------------------------------------------X
TRIAL MEDICATION


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Treatment - Maintenance
EOT16
Switch Visit prior 
to Avastin® 
administration21
Non-treatment 
period17, 20
SFU18
Survival19
Visit
7
8
9
10
Cycle
7
8
9
10 and 
onwards
Contact IXRS®14
X
X
X
X
X
Trial medication infusion15, 23
X
X
X
X
X
CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; IXRS® = Interactive Telephone and Web 
Response System; MRI = magnetic resonance imaging; PET = positron emission tomography; PS = performance status; SFU = Safety Follow-up.
1.
Clinical assessments will be performed within 3 days before trial medication infusion.
2.
Laboratory samples must be drawn prior to infusions of premedication and trial medication.
3.
Only for females of childbearing potential. Urine pregnancy test will be performed every 6 weeks. A serum pregnancy test should be performed if urine pregnancy test is 
positive.
4.
Urine pregnancy test will be performed every 6 weeks from Cycle 11 onwards.
5.
Sitting blood pressure (5 minutes rest before start of measurement), respiratory rate, pulse, and body temperature. Two or more blood pressure readings should be taken at 
2 minute intervals and averaged. If the first 2 diastolic readings differ by more than 5 mmHg, then an additional reading should be obtained, and averaged.
6.
Patients should rest for at least 5 minutes in a supine position prior to 12-lead ECG evaluations. Two consecutive recordings may be made. The first of the consecutive ECGs 
is mandatory. The second of the consecutive ECGs is optional, at the discretion of the Investigator in case of clinical significance. Additional ECGs will be performed if 
clinically indicated.
7.
From Cycle 10 onwards, the following assessments should be performed every 3 cycles (approximately 9 weeks): 12-lead ECGs, tumor assessments (at least every 3 cycles or 
per investigator discretion), ECOG PS.
 
8.
All adverse events (AEs), regardless of relatedness, will be collected from the time of informed consent until up to 18 weeks after the last administration of trial medication or 
discontinuation of Avastin®, whichever occurs later. Adverse events continuing at the SFU visit must be followed until recovery or in case of persistency, sufficient 
characterization has been achieved and the investigator and medical monitor agree to not pursue them further.
9.
CT scan with i.v. contrast of chest and abdomen, including adrenal glands and the entire liver, if applicable. In case of an iodine i.v.-contrast contraindication (renal 
insufficiency, allergy, hyperthyroidism etc), an abdomen MRI with contrast (gadolinium) will be performed with a non-contrast chest CT scan. After Week 18, for patients 
receiving maintenance therapy and/or during the non-treatment period tumor assessment will be performed per the investigator’s discretion, or a minimum of every 9 weeks 
(±3 days), and at the EOT visit. If a maintenance therapy cycle is delayed, the tumor assessment will also be delayed.
10. A PET scan can be performed in addition to the CT scan, at the EOT visit. Combined PET-CT scans may be used only if performed with contrast and if resolution is sufficient 
to allow accurate and consistent comparison of lesion measurements with subsequent CT scans.


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11. The tumor assessment should be performed prior to trial medication administration. In case of a treatment cycle delay (i.e. due to toxicity), imaging assessment (e.g. CT, MRI) 
for the primary endpoint will be performed at Week 18 ±14 days (fixed time point), regardless of the number of cycles administered to date.
14. IXRS® will be used at each visit to assign the correct vial for the allocated treatment group and the medication identification.
15. Administration of BI 695502/Avastin® will occur on Day 1 of each cycle (every 21 days).
16. For all patients who receive at least one infusion of BI 695502 or Avastin® the EOT visit will be performed within 21 days after the last administration of trial medication.
17. For all patients who discontinue BI 695502/Avastin® for reasons other than disease progression and do not withdraw consent, visits will occur every 3 weeks after the End of 
Treatment visit until initiation of new treatment, disease progression, or death. 
18. All patients who received at least one infusion of BI 695502 or US-licensed Avastin® will attend a SFU visit 18 weeks after the last administration of trial medication prior to 
the switch visit. If the patient continues to receive treatment with Avastin® beyond 18 weeks post last IMP dose, then no SFU visit will be performed.
19. After the SFU visit or discontinuation of Avastin®, whichever occurs later, all patients will be monitored for survival every 3 months via telephone call until death, see 
Section 6.2.3.
20. If a patient remains in the non-treatment period beyond 18 weeks post last dose of trial medication, he/she will be treated according to standard of care, and assessed for tumor 
progression every 6 to 9 weeks according to clinical judgment. Tumor assessments and all AEs, regardless of relatedness, will be collected at these visits. The date of 
initiation of second-line therapy should be recorded (if applicable).
21. During the Switch Visit (the next scheduled cycle visit per protocol following 21 Dec 2017), assessments not already scheduled should be performed prior to Avastin® 
administration.
22. To be performed only if a tumor assessment was not performed within the previous 4 weeks.
23. Starting as of 21 Dec 2017, the Sponsor recommends that patients should be switched from BI 695502 to Avastin®; therefore, from this date onward, patients should receive 
Avastin® at the Cycle Visits, as soon as Avastin® is available at the clinical site. If Avastin® is not immediately available, the Investigators may temporarily allow 
continuation on BI 695502.


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TABLE OF CONTENTS
TITLE PAGE .......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .................................................2
FLOW CHART 1.1 – CYCLE 1 UP TO CYCLE 6..........................................8
FLOW CHART 1.2 – CYCLE 7 ONWARDS.................................................11
TABLE OF CONTENTS ..................................................................................14
ABBREVIATIONS............................................................................................18
1.
INTRODUCTION .............................................................................20
1.1
MEDICAL BACKGROUND..............................................................................20
1.2
DRUG PROFILE.................................................................................................21
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT...................................................................................23
2.1
RATIONALE FOR PERFORMING THE TRIAL..........................................23
2.2
TRIAL OBJECTIVES.........................................................................................24
2.2.1
Primary objective.................................................................................................24
2.2.2
Secondary objectives............................................................................................24
2.3
BENEFIT - RISK ASSESSMENT......................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION .......27
3.1
OVERALL TRIAL DESIGN AND PLAN ........................................................27
3.1.1
Administrative structure of the trial ..................................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP............................................................................................30
3.3
SELECTION OF TRIAL POPULATION ........................................................30
3.3.1
Main diagnosis for study entry ...........................................................................30
3.3.2
Inclusion criteria ..................................................................................................31
3.3.3
Exclusion criteria .................................................................................................32
3.3.4
Removal of patients from therapy or assessments............................................34
3.3.4.1
Removal of individual patients ..............................................................................34
3.3.4.2
Discontinuation of the trial by the sponsor............................................................35
4.
TREATMENTS .................................................................................36
4.1
TREATMENTS TO BE ADMINISTERED......................................................36
4.1.1
Identity of Boehringer Ingelheim investigational product and comparator 
product..................................................................................................................36
4.1.2
Method of assigning patients to treatment groups............................................36
4.1.3
Selection of doses in the trial...............................................................................37
4.1.4
Drug assignment and administration of doses for each patient.......................38
4.1.4.1
Chemotherapy........................................................................................................39
4.1.5
Blinding and procedures for unblinding............................................................41


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4.1.5.1
Blinding..................................................................................................................41
4.1.5.2
Procedures for emergency unblinding ...................................................................41
4.1.6
Packaging, labelling, and re-supply....................................................................42
4.1.7
Storage conditions................................................................................................42
4.1.8
Drug accountability..............................................................................................42
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT......................................................................................................43
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) ......43
4.2.2
Restrictions ...........................................................................................................44
4.2.2.1
Restrictions regarding concomitant treatment .......................................................44
4.2.2.2
Restrictions on diet and life style...........................................................................46
4.3
TREATMENT COMPLIANCE.........................................................................47
5.
VARIABLES AND THEIR ASSESSMENT...................................48
5.1
EFFICACY...........................................................................................................48
5.1.1
Endpoints of efficacy............................................................................................48
5.1.2
Assessment of efficacy..........................................................................................48
5.1.2.1
Response rate .........................................................................................................48
5.1.2.2
Duration of response..............................................................................................49
5.1.2.3
Progression-free survival .......................................................................................49
5.1.2.4
Overall survival......................................................................................................50
5.2
SAFETY................................................................................................................50
5.2.1
Endpoints of safety...............................................................................................50
5.2.2
Assessment of adverse events..............................................................................50
5.2.2.1
Definitions of adverse events.................................................................................50
5.2.2.2
Adverse event and serious adverse event reporting...............................................52
5.2.3
Assessment of safety laboratory parameters.....................................................54
5.2.4
Electrocardiogram ...............................................................................................55
5.2.5
Assessment of other safety parameters ..............................................................56
5.4
APPROPRIATENESS OF MEASUREMENTS...............................................58


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6.
INVESTIGATIONAL PLAN ...........................................................64
6.1
VISIT SCHEDULE..............................................................................................64
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ..................65
6.2.1
Screening period...................................................................................................65
6.2.2
Treatment period .................................................................................................66
6.2.3
End of trial and follow-up period.......................................................................69
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE...................................................................................72
7.1
STATISTICAL DESIGN - MODEL..................................................................72
7.2
NULL AND ALTERNATIVE HYPOTHESES ................................................72
7.3
PLANNED ANALYSES......................................................................................74
7.3.1
Primary analyses..................................................................................................75
7.3.1.1
Primary ORR ratio analyses...................................................................................75
7.3.1.2
Sensitivity analyses for the primary endpoint best ORR.......................................76
7.3.2
Secondary analyses ..............................................................................................76
7.3.3
Other analyses ......................................................................................................76
7.3.4
Safety analyses......................................................................................................77
7.3.5
Interim analyses ...................................................................................................77
7.3.5.1
DSMB analyses......................................................................................................77
7.3.5.2
Blinded review of sample size assumption............................................................78
7.3.5.3
Primary analysis time point and follow-up analysis time point.............................78
7.4
HANDLING OF MISSING DATA ....................................................................79
7.4.1
Efficacy endpoints................................................................................................79
7.4.2
Pharmacokinetic parameters..............................................................................79
7.4.3
Safety and other endpoints..................................................................................79
7.5
RANDOMIZATION............................................................................................79
7.6
DETERMINATION OF SAMPLE SIZE ..........................................................81
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS..........................................................................................82
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ............................................................................................................82
8.2
DATA QUALITY ASSURANCE .......................................................................84
8.3
RECORDS............................................................................................................84
8.3.1
Source documents ................................................................................................84
8.3.2
Direct access to source data and documents......................................................84


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8.3.3
Storage of records ................................................................................................85
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS 85
8.4.1
Listedness..............................................................................................................85
8.4.2
Expedited reporting to health authorities and IECs/IRBs...............................85
8.5
STATEMENT OF CONFIDENTIALITY.........................................................85
8.6
COMPLETION OF TRIAL................................................................................86
8.7
PROTOCOL VIOLATIONS ..............................................................................86
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY...............................................................................86
9.
REFERENCES...................................................................................87
9.1
PUBLISHED REFERENCES.............................................................................87
9.2
UNPUBLISHED REFERENCES.......................................................................90
10.
APPENDICES....................................................................................91
10.1
GUIDELINES FOR EVALUATION OF OBJECTIVE TUMOR 
RESPONSE USING RECIST 1.1 CRITERIA (RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS).....................................................................91
10.2
GUIDELINES FOR BI 695502/ AVASTIN® PREPARATION AND 
ADMINISTRATION ...........................................................................................99
10.3
CHEMOTHERAPY REGIMENS AND RECOMMENDATIONS FOR 
DOSE MODIFICATIONS IN CASES OF TOXICITY.................................101
10.4
CLINICAL EVALUATION OF LIVER INJURY .........................................106
10.4.1
Introduction........................................................................................................106
10.4.2
Procedures ..........................................................................................................106
10.5
TUMOR, NODE, METASTASIS (TNM) STAGING.....................................108
10.6
DETAILS OF THE STATISTICAL CONCEPT FOR CLINICAL 
SIMILARITY ASSESSMENT..........................................................................110
10.6.1
Equivalence Margin...........................................................................................110
10.6.2
Statistical model and equivalence test..............................................................111
10.6.3
Sample Size.........................................................................................................113
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)......................114


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
 
CA
Competent authority
CI
Confidence interval
CL
Clearance
CR
Complete response
CRA
Clinical Research Associate
CRF
Case report form
CRO
Contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
CT
Computed tomography
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
EGFR
Epidermal growth factor receptor
ELISA
Enzyme-linked immunosorbent assay
EOT
End of Treatment
FAS
Full analysis set
FDG
fludeoxyglucose
GCP
Good Clinical Practice
GI
Gastrointestinal
GFR
Glomerular filtration rate
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IMP
Investigational medicinal product
INVICTAN®-2
Trial name of the study
IRB
Institutional Review Board


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ISF
Investigator Site File
i.v.
intravenous
IXRS®
Interactive Telephone and Web Response System
LFT
Liver function test
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NE
Not evaluable 
nsNSCLC
Nonsquamous non-small cell lung cancer
NSAIDs
Nonsteroidal anti-inflammatory drugs
NSCLC
Non-small cell lung cancer
NTL
Non-target lesion
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression-free survival
PH
Proportional hazards
PPD
Purified protein derivative
PPS
Per-protocol set
PR
Partial response
PS 
Performance status
RECIST
Response Evaluation Criteria in Solid Tumors
REP
Residual effect period
RPLS
Reversible posterior leukoencephalopathy syndrome
SAE
Serious adverse event
SD
Stable disease
SFU
Safety follow-up
SPC
Summary of Product Characteristics
SOP
Standard operating procedure
TB
Tuberculosis
TL
Target lesion
TOST
Two one-sided tests
TNM
Tumor, node, metastasis
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
US
United States
Vc
Volume of distribution
VEGF
Vascular endothelial growth factor


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Worldwide, lung cancer is the most common cause of cancer-related death in men and 
women, and is responsible for almost 1.4 million deaths annually (R13_1113). 
Approximately 85% of these patients have non–small cell lung cancer (NSCLC). Only 15.9% 
of all lung cancer patients are alive 5 years or more after diagnosis.
The stage of disease is often advanced at the time of diagnosis with 30% to 40% of NSCLC 
cases being classified as Stage IV (P14-01224). The prognosis of patients with advanced 
stage disease is poor. Patients with clinical Stage IV disease have an historical median 
survival of 6 months (R11-0052) with best supportive care; in patients fit enough to receive 
chemotherapy recent combination regimens have improved survival to about 8 to 10 months. 
The addition of bevacizumab has further prolonged survival in nonsquamous NSCLC 
(nsNSCLC) to about 12 months.
A tissue diagnosis is frequently performed and may guide therapy when a target agent is 
available, because recent advances have shown that optimal therapy depends on the histology 
of NSCLC (squamous versus nonsquamous histology) and whether there are certain 
mutations in the tumor. Patients with mutations in the epidermal growth factor receptor 
(EGFR) and the anaplastic lymphoma kinase (ALK) gene can benefit from a variety of oral 
tyrosine kinase inhibitors (R09-0256, R12-1015, R13-1390). Of note, tumors with these 
mutations typically have nonsquamous histology. Additionally, the presence of the EGFR 
mutation appears to vary by ethnic origin of the patient; approximately 15% of patients in the 
United States (US) and European Union (EU) have an EGFR mutation while the rate is 
roughly double that in East Asia (R07-1194). 
Patients with no known mutations or with a mutation but no access to the targeted agent are
generally treated with cytotoxic chemotherapy as their first-line treatment. Contemporary 
first-line chemotherapy usually, but not exclusively, combines a platinum agent (cisplatin or 
carboplatin) with another cytotoxic agent (R09-5804). Platinum agents may be combined 
with compounds such as pemetrexed, gemcitabine, taxanes or vinorelbine (R08-4164). 
Nonplatinum-based regimens such as gemcitabine and vinorelbine or gemcitabine and 
docetaxel are also accepted options (R13-5402). 
The Eastern Cooperative Oncology Group (ECOG) conducted a randomized clinical trial 
comparing four platinum-based, two-drug chemotherapy regimens in more than 
1100 patients. The regimens included in this trial were cisplatin and paclitaxel, cisplatin and 
gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. The median survival was 
8 months, with no significant differences in overall survival (OS) among the groups 
(R04-1314).
The platinum-doublet regimens have slightly different toxicities, convenience and costs, and 
this can direct the choice of the physician in selecting the preferred therapy for their patients. 
Thus, the standard of care in 2014 for patients without a known mutation or with a mutation 
but no access to the targeted agent is initially a two-drug combination usually using a


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platinum agent for 4 to 6 cycles. This is referred to as initial systemic chemotherapy or 
occasionally as “induction” therapy. For those patients with nonsquamous histology, and no 
risk of major bleeding, the addition of bevacizumab showed a benefit in survival and has 
become standard of care.
Regarding the optimal number of ‘induction’ cycles of chemotherapy, in trials comparing 
4 or 6 cycles of chemotherapy, no survival benefit was shown with the administration of 
more than 4 cycles (R13-5426). In the last session of 2011, the American Society of Clinical 
Oncology panel of experts recommended not to administer more than 4 cycles in 
nonresponding patients. Finally, in two recently published trials, all patients were given a 
maximum of 4 cycles of chemotherapy followed by maintenance treatment. In Patel’s trial, in 
the arm using 4 cycles of chemotherapy/bevacizumab followed by maintenance with 
bevacizumab alone, OS was 13 months i.e., similar to that reported in Sandler’s trial in which 
patients received an average of 5 induction cycles (R13-5425). In the ATLAS trial, in which 
all responding and stabilized patients received maintenance treatment, OS was 13.6 months in 
the arm receiving bevacizumab alone (R13-5424).
Specific targeted therapies have been developed for the treatment of advanced NSCLC 
(R05-1052). Bevacizumab, a recombinant monoclonal antibody that targets the vascular 
endothelial growth factor (VEGF), was approved in 2006 by the US Food and Drug 
Administration (FDA) for patients with unresectable, locally advanced, recurrent, or 
metastatic nsNSCLC.
The ECOG recommends treatment with bevacizumab in combination with paclitaxel and 
carboplatin for selected patients with advanced nsNSCLC based on the results of the 
Phase III ECOG 4599 trial (R07-1161). In this study, the addition of bevacizumab 
significantly increased the response rate (35% versus 15%, p<0.001), median 
progression-free survival (PFS) (6.2 versus 4.5 months, p<0.001) and median survival 
(12.3 versus 10.3 months, p=0.003).
Selection criteria for the use of bevacizumab included, besides nonsquamous histology, no 
recent history of hemoptysis, and ECOG performance status (PS) 0 to 1. Bevacizumab should 
be used with caution in case of high risk of thrombocytopenia, and potential possible 
bleeding.
Accordingly, carboplatin and paclitaxel with bevacizumab represents one of the frequently 
used first-line regimens suitable for nonmutated EGFR and ALK nsNSCLC.
1.2
DRUG PROFILE
BI 695502, a monoclonal antibody, is being developed as a proposed biosimilar product to 
the bevacizumab product Avastin® approved in the EU and in the US (R15 -1223, 
R18-0043). BI 695502 is a genetically engineered humanized monoclonal antibody directed 
against human VEGF that selectively binds with high affinity to VEGF and neutralizes 
VEGF’s biologic activity through a steric blockade of the binding of VEGF to its receptors 
on the surface of endothelial cells.


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BI 695502 is produced in Chinese hamster ovary cells. It is manufactured using standard 
mammalian cell culture techniques, followed by a series of protein purification steps, 
including several chromatography steps as well as steps for removal and inactivation of 
potential viruses. Bevacizumab has shown antitumor activity and clinical benefit in 
combination with chemotherapy and Avastin® is approved for use in metastatic colorectal 
cancer (US, EU), advanced NSCLC (US, EU), metastatic renal cell cancer (US, EU), 
metastatic breast cancer (EU only), advanced epithelial ovarian, fallopian tube, or primary 
peritoneal cancer (EU, US), metastatic cervical cancer (US, EU), and as a single agent for
glioblastoma (US only) (R15-1223, R18-0043). The local approval status for Avastin® can 
differ in countries outside of the US and the EU.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
BI 695502 is being developed as a proposed biosimilar to Avastin® (bevacizumab), which is 
planned to meet the need for alternatives to high-priced biologic agents in oncology 
treatments. The planned clinical development follows the currently understood concepts from 
published guidance documents and statements from regulatory authorities for biosimilar 
monoclonal antibody development. The general approach is to demonstrate in a homogenous 
population a high degree of similarity (i.e., statistical similarity) between the biosimilar and 
originator compound, at first in pharmacokinetic (PK)/pharmacodynamic and secondly in 
clinical efficacy, using a suitable endpoint, while also demonstrating a high degree of similarity 
(but not necessarily statistical similarity) for safety and immunogenicity.
The addition of bevacizumab to chemotherapy has been shown to be effective in nsNSCLC in 
terms of benefit in overall response rate (ORR), PFS and OS. The planned trial design 
follows that of three randomized trials using the same class of cytotoxic drugs, and dose of 
bevacizumab in patients with tumors of the same histology (Sandler et al 2006 [R07-1161],
Niho et al 2012 [R14-0473], Johnson et al 2013 [R13-5424]). The weighted ORR, based on a 
total N of 1005 patients (bevacizumab: 530, chemotherapy alone: 475) is 43.3% for the 
bevacizumab 15 mg/kg plus chemotherapy group versus 20.0% for the chemotherapy alone 
group, resulting in a ORR ratio for bevacizumab versus chemotherapy alone of 2.220 with a 
90% confidence interval (CI) of (1.847, 2.668). Such observation and feasibility 
considerations are the basis of the statistical rationale for the proposed clinical trial (see 
Section 7.2). A Phase I trial in healthy volunteers has already established pair-wise PK 
similarity between BI 695502, US-licensed Avastin®, and EU-approved Avastin® following 
one intravenous (i.v.) infusion (Trial 1302.1). 
In this pivotal Phase III trial, patients with nsNSCLC will be randomly assigned to receive 
either BI 695502 or US-licensed Avastin®, plus chemotherapy according to standard of care
(see Section 3.1 for details).
Since the introduction of bevacizumab in the therapeutic armamentarium, other targeted 
agents have become standard of care for patients with tumor-expressing activating mutations 
in EGFR and ALK receptor. Patients harboring tumors with unknown or activating EGFR 
and/or ALK mutation may be included provided chemotherapy is the site standard of care.
The trial will be conducted in compliance with the Clinical Trial Protocol (CTP), the 
International Conference on Harmonisation (ICH) guidelines, Good Clinical Practice (GCP)
and with all applicable and current regulatory requirements.


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2.2
TRIAL OBJECTIVES
2.2.1
Primary objective
The primary objective of this trial is to establish statistical equivalence in terms of efficacy 
(best ORR, proportion of patients with complete response [CR] plus partial response [PR], 
not required to be confirmed by a subsequent assessment) until 18 weeks of first-line 
treatment with BI 695502 plus chemotherapy versus US-licensed Avastin® plus 
chemotherapy followed by maintenance monotherapy with either BI 695502 or US-licensed
Avastin®.
2.2.2
Secondary objectives
The secondary objectives of the trial are to evaluate further efficacy parameters (progression-
free survival [PFS], overall survival [OS], duration of response) and the safety and 
tolerability of BI 695502 versus US-licensed Avastin®.
2.3
BENEFIT - RISK ASSESSMENT
Patients enrolled into this equivalence trial are expected to derive similar benefit and risk 
from the trial treatment across both arms. This is based on the similarity observed during pre-
clinical, analytical, functional and toxicological testing between the investigational medicinal 
product and the comparator. 
Patient risk will be minimized by implementing conservative eligibility criteria, regular and 
long-term safety monitoring, including immunogenicity testing. 
Although rare, the potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations of selected liver laboratory parameters to 
ensure patients´ safety.
There is an increased risk of gastrointestinal (GI) perforation in patients treated with 
Avastin®. The incidence of GI perforation ranged from 0.3% to 2.4% across clinical studies 
(R15-1223, R18-0043). Typical symptoms may include abdominal pain, nausea, emesis, 
constipation, and fever. Perforation can be complicated by intra-abdominal abscess and 
fistula formation. The majority of cases occurred within the first 50 days of initiation of 
Avastin®. The investigator is required to monitor the patients at regular intervals throughout 
the trial for any new or worsening symptoms or signs that may be suggestive of GI 
perforation.
Animal studies have shown that Avastin® impairs wound healing and an increased risk of 
wound healing complications has been observed in patients with metastatic colorectal cancer 


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who underwent surgery during the course of Avastin®. Therefore no major surgery is 
permitted within 28 days prior to the first dose of BI 695502/US-licensed Avastin®. If 
elective surgery is required during the course of the trial, then the trial medication should be 
discontinued at least 28 days prior to the procedure. Patients who undergo elective surgery 
during the trial or patients with anticipated elective surgery will be excluded from the trial.
Treatment with Avastin® has been shown to be associated with an increased risk of 
hemorrhage (including hemoptysis, GI bleeding, hematemesis, central nervous system 
hemorrhage, epistaxis, and vaginal bleeding) and arterial thromboembolic events (including 
cerebral infarction, transient ischemic attacks, myocardial infarction, and angina). Patients 
who have had a thrombotic or hemorrhagic event within 6 months prior to Screening will not 
be permitted to enter the trial. No anticoagulation therapy is allowed within 10 days of the 
first dose of trial medication or during the trial except for venous access or daily aspirin up to 
325 mg.
The use of Avastin® has been shown to be associated with an increased risk of reversible 
posterior leukoencephalopathy syndrome (RPLS). The investigator is required to monitor the 
patients at regular intervals throughout the trial for any new or worsening neurological 
symptoms or signs that may be suggestive of RPLS (typical symptoms are diverse and 
include headache, seizure, lethargy, confusion, blindness, and other visual and neurologic 
disturbances). If a patient develops new or worsening neurological signs or symptoms, he/she 
will be evaluated for RPLS. Magnetic resonance imaging (MRI) is necessary to confirm the 
diagnosis of RPLS. Any patient who is suspected of developing RPLS will be discontinued 
from the trial and the adverse event (AE) will be followed closely (see Section 5.2.2.2).
Symptoms usually resolve or improve within days, although some patients have experienced 
ongoing neurologic sequelae.
The incidence of severe hypertension increases in patients receiving Avastin®. Patients with 
systolic/diastolic blood pressure >150/100 mmHg (in the presence or absence of a stable 
regimen of antihypertensive therapy) are excluded from this trial. Blood pressure will be 
monitored every 3 weeks during the trial. Patients who develop hypertension should be 
treated with appropriate antihypertensive therapy at the investigator’s discretion and should 
continue to have their blood pressure regularly monitored.
Repeat dose toxicity studies in animals have shown that Avastin® may have an adverse effect 
on female fertility. In a Phase III trial in the adjuvant treatment of patients with colon cancer, 
a substudy with premenopausal women has shown a higher incidence of new cases of ovarian 
failure in the Avastin® group compared to the control group. After discontinuation of 
Avastin® treatment, ovarian function recovered in the majority (R15-1223, R18-0043). The 
investigator should discuss fertility preservation strategies with the patient prior to starting 
treatment in this trial, as appropriate.
Due consideration has been given to previous experience with Avastin® in NSCLC patients 
and toxicity management advice (e.g., for hypersensitivity reactions) is provided in this CTP. 
A Data Safety Monitoring Board (DSMB) was established to review the safety and efficacy 
data of BI 695502 compared with data for the active comparator and to review accumulating 


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safety data at regular intervals throughout the trial (see Section 7.3.5 for further details). For 
details of blinding, please refer to Section 4.1.5.1.
Trial 1302.1 was a Phase 1 randomized, single-blind, single-dose, two-stage, parallel-arm, 
active comparator trial. In total, 91 healthy, male subjects were treated: 30 subjects were 
administered 1 mg/kg BI 695502, 31 subjects were administered 1 mg/kg EU-approved 
Avastin®, and 30 subjects were administered 1 mg/kg US-licensed Avastin®. Based on the 
PK results obtained from this trial, similarity could be demonstrated for all comparisons of 
the trial medications. No serious adverse events (SAEs), severe AEs, or other significant AEs 
were reported and no subject discontinued trial medication due to an AE. A total of 
73 (80.2%) subjects reported at least one AE. Fewer subjects reported AEs for US-licensed 
Avastin® (70.0%) than for BI 695502 (86.7%) and EU-approved Avastin® (83.9%). No 
Grade 3, 4, or 5 AEs were reported and the majority of AEs were Grade 1 for all three trial 
medications. By preferred term the most frequently reported AEs were upper respiratory tract 
infection and headache. Overall, there was no relevant difference in the safety results for the 
three trial medications and no safety concerns were identified.
Based on extensive preclinical, analytical, functional and toxicological testing carried out 
prior to initiation of this trial, and the Phase 1 data described above, BI 695502, as a proposed 
biosimilar product, may be seen to provide similar efficacy, safety, immunogenicity and PK 
to Avastin® (US-licensed/EU-approved) in patients with advanced nsNSCLC. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a Phase III, randomized, double-blind, multicenter, active comparator, parallel 
two-arm trial. 
Approximately 660 patients (330 patients per arm) with advanced nsNSCLC will be 
randomized in a 1:1 ratio to receive either BI 695502 (Arm B) or US-licensed Avastin®
(Arm A) in combination with paclitaxel and carboplatin. Japan will randomize at least 10% 
of patients in the trial and this will be capped if needed.
Patients will receive treatment with 15 mg/kg of BI 695502 or US-licensed Avastin®
followed by standard combination chemotherapy consisting of paclitaxel 200 mg/m2
(according to regular institutional practice) followed by carboplatin target area under the 
curve (AUC) 6 mg/mL•min (30- to 60-minute infusion) with adequate pre- and concomitant 
medication every 3 weeks (each cycle) for up to 6 cycles (induction cycles).
After Cycle 4 to 6, if the patient has CR, PR or stable disease (SD), i.e., responding or 
stabilized patients, maintenance treatment with BI 695502/ US-licensed Avastin®
monotherapy can be started per the original randomization. Patients will then receive BI 
695502 or US-licensed Avastin® as a single agent until disease progression (according to 
Response Evaluation Criteria in Solid Tumors 1.1 [RECIST 1.1]), death, withdrawal of 
consent, or unacceptable toxicity, whichever occurs earlier.
A DSMB will review safety data from 40 patients (20 patients per treatment group) after 
3 cycles of treatment have been completed (see Section 7.3.5.1).
The fully blinded, pooled ORR will be closely monitored to verify the sample size 
assumptions. After approximately 200 patients (100 patients per arm) have had tumor 
response assessments performed until Week 18, an independent blinded statistician will 
perform a blinded evaluation to confirm the initially calculated sample size.
The primary endpoint of the trial is the best ORR (CR + PR, based on unconfirmed response 
assessment) until the Week 18 assessment. The primary analysis will be performed after all 
patients in the primary analysis population have had tumor response assessments performed 
until Week 18. This analysis will include the primary efficacy endpoint as well as all 
available secondary efficacy endpoints and safety data.
Patients will undergo visits and trial procedures as shown in Flow chart 1.1 and 
Flow chart 1.2.
Patients may return for unscheduled visits should their medical condition warrant urgent 
attention at the discretion of the investigator.
Starting as of 21 Dec 2017, the Sponsor recommends that patients should be switched from 
BI 695502 to the reference product bevacizumab (IMP or commercially available Avastin®, 
both hereafter referred to as Avastin®) as soon as it is available at the respective clinical site. 


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If Avastin® is not immediately available, the Investigators may temporarily allow 
continuation on BI 695502. The blind will be kept intact and all patients will continue the 
study with no additional visits in the scheduled visit cycle as per protocol.
All patients who receive at least one infusion of BI 695502 or US-licensed Avastin® should 
return for an End of Treatment (EOT) visit within 21 days after their last administration of BI 
695502 or Avastin® (see Section 3.3.4.1).
In addition, all patients should return for a Safety Follow-up (SFU) visit 18 weeks after their 
last administration of trial medication prior to the switch visit. If the patient continues to 
receive treatment with Avastin® beyond 18 weeks post last IP dose, then no SFU visit will be 
performed.
Patients who discontinue trial medication for reasons other than disease progression, but who 
do not withdraw consent will remain in the trial (non-treatment period) until initiation of a 
new treatment, disease progression, or death, whichever occurs earlier. Visits will be 
performed every 3 weeks (see Section 6.2.3) after the EOT visit. If a patient remains in the 
non-treatment period beyond 18 weeks post last dose of trial medication, he/she will be 
treated according to standard of care, and assessed for tumor progression every 6 to 9 weeks 
according to clinical judgment.
After the SFU visit or discontinuation of Avastin® (whichever occurs later), patients will be 
monitored for survival every 3 months until death or the end of the trial, whichever is earlier
(see Section 6.2.3).
An overview of the trial design is shown in Figure 3.1: 1.


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a
An early safety analysis will be reviewed after approximately 20 patients per arm have been treated for 3 cycles 
(40 patients). See Section 7.3.5.1 for details.
b.
Blinded sample size assumptions review to start when approximately 200 patients (100 patients per arm) have had 
tumor response assessments performed until Week 18 (see Section 7.3.5.2).
c.
The primary analysis will be performed after all patients in the primary analysis population have had tumor 
response assessments performed until Week 18 (see Section 7.3.5.3).
d.
A follow-up analysis will be conducted at a later time point, as required by the regulatory authorities (see 
Section 7.3.5.3).
Note:
Starting as of 21 Dec 2017, the Sponsor recommends that patients should be switched from BI 695502 to the 
reference product Avastin® as soon as it is available at the respective clinical site. If Avastin® is not immediately 
available, the Investigators may temporarily allow continuation on BI 695502. The blind will be kept intact and all 
patients will continue the study with no additional visits in the scheduled visit cycle as per protocol.
Figure 3.1: 1
Overview of trial design


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3.1.1
Administrative structure of the trial
Data will be reviewed by a DSMB (see Section 7.3.5). The DSMB will act in an advisory 
capacity to monitor patient safety and efficacy during the trial. The members will be selected 
on the basis of relevant experience and understanding of clinical research and the issues 
specific to the therapeutic area, as well as previous DSMB experience.
Details on the DSMB, including the analyses, the composition of the DSMB, the procedures, 
roles, responsibilities and their interactions will be described in the DSMB charter.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This is a Phase III, randomized, double-blind, multicenter, active comparator, parallel 
two-arm trial to compare the efficacy, safety and immunogenicity of BI 695502 to 
US-licensed Avastin® in patients with previously untreated advanced nsNSCLC.
Patients will initially be randomized in a 1:1 ratio to receive BI 695502 plus 
paclitaxel/carboplatin or US-licensed Avastin® plus paclitaxel/carboplatin. After 
approximately 200 patients (100 patients per arm) have had tumor response assessments 
performed until Week 18, an independent blinded statistician will perform a blinded 
evaluation to confirm the initially calculated sample size.
Paclitaxel + carboplatin + Avastin® is an accepted first-line chemotherapy regimen for 
patients with advanced nsNSCLC. This regimen conferred a significant improvement in OS, 
PFS, and response rate in patients with nsNSCLC and a good performance status (R07-1161).
This is a double-blind trial to minimize any bias that could be introduced by knowledge of the 
treatment by either the investigator or the patient. 
The primary focus of this trial is to demonstrate similarity of BI 695502 with US-licensed
Avastin®.
3.3
SELECTION OF TRIAL POPULATION
A log of all patients enrolled in the study (i.e., having given informed consent) will be 
maintained in the Investigator Site File (ISF) at the investigational site irrespective of 
whether they have been treated with investigational drug (BI 695502/US-licensed Avastin®)
or not.
3.3.1
Main diagnosis for study entry
The main requirements for trial entry include adult patients ≥18 years of age (for Japan only: 
Age ≥20 years at Screening), with recurrent or metastatic disease (Stage IV), histologically or 
cytologically confirmed advanced nsNSCLC. For patients with recurrent disease, cytotoxic 
chemotherapy treatment or radiotherapy for locally advanced tumor must have been stopped 
for at least 12 months prior to Screening. Patients harboring tumors without activating 
EGFR/ALK mutation will be eligible. Patients with unknown or activating EGFR/ALK


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mutation may be included provided chemotherapy is the site standard of care. Patients must 
have an ECOG PS of 0 or 1 and have at least one measurable lesion according to RECIST 
criteria 1.1. Patients must have no contraindication to Avastin® and must have adequate 
hepatic, renal, and bone marrow function.
3.3.2
Inclusion criteria
1.
Males and females aged ≥18 years (for Japan only: Age ≥20 years at Screening) with 
histologically or cytologically confirmed nsNSCLC. Mixed tumors should be 
categorized according to the predominant histology.
Note: NSCLC should be predominantly nonsquamous.
2.
Recurrent or metastatic disease (Stage IV) with an indication for therapy with 
paclitaxel + carboplatin + Avastin® (see Appendix 10.5).
3.
All patients must sign and date an Informed Consent Form consistent with ICH GCP 
guidelines and local legislation prior to participation in the trial (i.e., prior to any trial 
procedures, which include medication washout and restrictions) and be willing to 
follow the CTP.
4.
Patients harboring tumors without activating EGFR mutation. Patients with unknown 
or activating EGFR mutation may be included provided chemotherapy is the site 
standard of care. Despite EGFR mutational status, patients may enter the trial if the
site's best standard of care would be to administer such a chemotherapy regimen for 
that specific patient. However, if an EGFR test result is pending, and chemotherapy 
treatment would be switched in case of a mutational positive result, patients may not 
be included in this trial.
5.
Patients harboring tumors without activating ALK mutation. Patients with unknown 
or activating ALK mutation may be included provided chemotherapy is the site 
standard of care. Despite ALK mutational status, patients may enter the trial if the 
site's best standard of care would be to administer such a chemotherapy regimen for 
that specific patient. However, if an ALK test result is pending, and chemotherapy 
treatment would be switched in case of a mutational positive result, patients may not 
be included in this trial.
6.
At least one measurable lesion according to RECIST 1.1 based on independent central 
review. 
7.
ECOG PS 0 or 1.
8.
Adequate hepatic, renal, and bone marrow function: 
a.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≤2.5 x ULN. If liver metastases are present, ALT or AST ≤5 x ULN. 
b. Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN in the presence of hepatic 
and/or bone metastases).
c.
Serum bilirubin ≤1.5 x ULN, except in the case of known Gilbert's syndrome.
d. Serum creatinine ≤1.5 x upper limit of normal (ULN) or a creatinine clearance 
of ≥50 mL/min calculated by Cockroft-Gault formula.
e.
Proteinuria <2 g in 24 hours or an equivalent protein/creatinine ratio of 
<2000 mg/g creatinine (or <226 mg/mmol creatinine).


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f.
Absolute neutrophil count >1.5 x109/L. 
g. Platelet count >100 x109/L.
h. Hemoglobin ≥9 g/dL (without transfusion within 2 weeks prior to 
randomization).
9.
International normalized ratio ≤1.4 as analyzed locally. Partial thromboplastin time 
within normal limits according to local practice. Central laboratory analysis will be 
used for coagulation parameters where local analysis is not available.
10.
Life expectancy >6 months based on clinical investigator’s judgment.
11.
For participants of reproductive potential (males and females), use of a medically 
acceptable method of contraception during the trial, i.e., a combination of two forms 
of effective contraception (defined as hormonal contraception, intrauterine device, 
condom with spermicide, etc). All subjects (males and females of childbearing 
potential) must also agree to use an acceptable method of contraception (see above) 
for 6 months following completion or discontinuation from the trial medication. A list 
of contraception methods meeting these criteria is provided in the patient information.
Females will be defined as of childbearing potential if they have not undergone a
permanent contraceptive operation or they are not postmenopausal. Permanent 
contraceptive operation is defined as: hysterectomy, hysterosalpingectomy, or 
bilateral oophorectomy. The status of a female should be considered as 
postmenopausal when she has not had a period for 12 consecutive months without an 
alternative medical cause.
3.3.3
Exclusion criteria
1.
Prior therapy with monoclonal antibodies or small molecule inhibitors against VEGF 
or VEGF receptors, including Avastin®.
2.
Prior systemic therapy for metastatic disease.
3.
Prior systemic anticancer therapy or radiotherapy for locally advanced nsNSCLC if 
completed <12 months prior to Screening.
4.
Patients who have results pending for EGFR/ALK mutation status, to the 
investigator’s knowledge.
5.
Previous malignancy other than NSCLC in the last 5 years except for basal cell cancer 
of the skin or pre-invasive cancer of the cervix.
6.
Patients with known symptomatic brain metastasis:
a. Brain metastasis which is symptomatic at screening or randomization visits, or
b. Patients who have previously irradiated brain metastasis that has not been 
shown to be stable at least 1 month after completion of the radiation therapy 
(either by CT scan or MRI) at screening visit.
7.
Diagnosis of small cell carcinoma of the lung, squamous cell carcinoma of the lung, 
NSCLC NS (not specified) or NSCLC NOS (not otherwise specified).
8.
Patients with tumor/metastases cavitation, or invading into large blood vessels.
9.
Patients with tumor/metastases close to large blood vessels that may have an 
increased risk of bleeding, according to investigator’s judgment.


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10.
Any unresolved toxicity >Common Toxicity Criteria Grade 1 (except alopecia) from 
previous anticancer therapy (including radiotherapy). 
11.
History or evidence of inherited bleeding diathesis or coagulopathy with the risk of 
bleeding. Clinically non-significant minor bleeding is acceptable.
12.
A thrombotic or hemorrhagic event ≤6 months prior to Screening (includes 
hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, 
vaginal bleeding, cerebral infarction, transient ischemic attacks, myocardial 
infarction, angina, and coronary artery disease). 
13.
Current or recent (within 10 days of first dose of BI 695502/US-licensed Avastin®) 
regular use of aspirin (>325 mg/day) or other non-steroidal anti-inflammatory drugs 
(NSAIDs) with antiplatelet activity or treatment with dipyridamole, ticlopidine, 
clopidogrel or cilostazol.
14.
Current treatment with oral, inhaled or topical corticosteroids; the dose must not 
exceed 10 mg/day prednisolone or equivalent. During the 4 weeks prior to Day 1, the 
dose must be stable.
15.
Intravenous, intramuscular, intra-articular, or parenteral corticosteroids within 
6 weeks prior to Day 1 or throughout the trial, unless used for paclitaxel infusion 
premedication, according to regular institutional practice.
16.
Current or recent (within 10 days of first dose of BI 695502/US-licensed Avastin®) 
use of full-dose oral or parenteral anticoagulants or other thrombolytic agents for 
therapeutic (as opposed to prophylactic) purposes, clinically serious (as judged by the 
investigator) nonhealing wounds, or incompletely healed bone fracture.
17.
Live/attenuated vaccine within 12 weeks prior to the Screening Visit.
18.
History of myocardial infarction (≤6 months prior to Screening), unstable angina, 
New York Heart Association Grade II or greater, congestive heart failure, or serious 
cardiac arrhythmia requiring medication.
19.
Patients with a history of poorly controlled hypertension or with resting blood 
pressure >150/100 mmHg in the presence or absence of a stable regimen of 
antihypertensive therapy (see Section 5.2.5). 
20.
Any surgical procedure within 28 days prior to the first dose of 
BI 695502/US-licensed Avastin® or anticipated elective surgery during the trial
(see Table 4.2.2.1: 1 for details).
21.
History of active gastroduodenal ulcer(s).
22.
History of abdominal fistula as well as non-GI fistula, GI perforation or 
intra-abdominal abscess within 6 months prior to Screening.
23.
Active or chronic hepatitis B or C, ongoing human immunodeficiency virus (HIV) 
infection, or tuberculosis (TB) (see Section 5.2.3). Screening for HIV and TB 
(purified protein derivative [PPD] or QuantiFERON) to be performed according to 
local practice and local regulatory guidance. There should be no radiographic or 
clinical evidence of active TB. 
24.
Treatment within a clinical trial within 4 weeks prior to initiation of trial treatment. 
Patients who have received treatment with a drug that has not received regulatory 


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approval for any indication within 4 weeks or a minimum of 5 half-lives, whichever is 
longer, of the initial dose of trial medication.
25.
Patient considered unsuitable for inclusion by the investigator (e.g., inability to 
understand and/or comply with study requirements or presence of any condition 
which, in the opinion of the investigator, would not allow safe participation in the 
trial).
26.
Pregnant or lactating women.
27.
Known hypersensitivity to any of the trial drugs or their excipients.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
Patients may have already been pre-randomized to a treatment group at Screening (see 
Section 4.1.2 for details). Patients who do not meet all of the inclusion criteria or meet at least 
one of the exclusion criteria will not be randomized, and will be considered screen failures. 
The primary reason for the screen failure will be recorded on the electronic case report form 
(eCRF). Re-screening will be allowed on a case by case basis based on discussion with the 
medical monitor. Patients may be re-screened once in order to fulfil all the inclusion criteria, 
provided the patient would receive the bevacizumab + paclitaxel/carboplatin regimen in 
regular practice at the Investigator’s discretion.
Patients have the right to withdraw from this trial at any time for any reason. The investigator 
has the right to withdraw patients from the trial if further participation in the trial may not be 
in the best interest of the patient.
Patients will be discontinued from trial treatment for the following reasons:

Investigator decision due to an intolerable AE or laboratory value including but not 
limited to:

Patients who cannot tolerate at least 3 cycles of chemotherapy, or are given another 
backbone chemotherapy at any time. 

Progressive disease.

Life-threatening reaction, including anaphylaxis, hypersensitivity reaction, renal 
failure, severe cardiopulmonary event and severe muco-cutaneous reaction.

GI perforations (including fistula formation in the GI tract, intra-abdominal abscess).

Fistula formation involving an internal organ.

Wound dehiscence and wound healing complications requiring medical intervention.

Serious hemorrhage (i.e., requiring medical intervention).

Severe arterial thromboembolic events.

Hypertensive crisis or hypertensive encephalopathy.

RPLS.

Nephrotic syndrome.

Congestive heart failure, any degree.


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
Severe hypertension, moderate to severe proteinuria, or severe infusion reactions if the 
event cannot be adequately controlled within 14 days.

Repeated protocol violation after documented discussion with the medical monitor. 

Pregnancy in a female participant.

The sponsor or sponsor designee is to be notified immediately (see Section 5.2.2.2)

Any concomitant illness that prevents compliance.
Patients will be withdrawn from the trial for the following reasons:

The patient is unwilling to continue in the trial. 

The investigator or the sponsor, for any reason, stops the trial. 

Patient lost to follow-up despite reasonable efforts to make contact with the patient. The 
investigator/designee must make two telephone calls, after which a registered letter must 
be sent. The dates of the telephone calls and the registered letter will be documented in 
the source documents.
Patients discontinued from trial treatment or withdrawn from the trial will not be replaced, 
regardless of the reason for discontinuation/withdrawal.
It is understood by all concerned that an excessive rate of withdrawals can render the trial 
uninterpretable; therefore, unnecessary withdrawal of patients from the trial should be 
avoided. 
Should a patient decide to discontinue trial medication, all efforts must be made by the 
investigator to encourage patients to keep returning for trial visits to follow up for safety, but 
at a minimum to complete and report the observations as thoroughly as possible, and to 
complete the EOT visit within 21 days after the last trial medication administration. If 
applicable, the investigative staff will contact the patient (or a responsible relative or 
designee) to determine the reason for withdrawal from the trial. The primary reason for the 
withdrawal from the trial will be recorded on the appropriate pages of the eCRF.
All patients who receive at least one infusion of BI 695502 or US-licensed Avastin® should 
return for a Safety Follow-up (SFU) visit 18 weeks after their last administration of trial 
medication prior to the switch visit. If the patient continues to receive treatment with 
Avastin® beyond 18 weeks post last IP dose, then no SFU visit will be performed.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time including but not restricted to the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site.

Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial, or any other administrative reasons.

Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial.
The investigator/the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in the case of the third reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of Boehringer Ingelheim investigational product and comparator 
product
Details of the trial medications are provided in Table 4.1.1: 1.
Table 4.1.1: 1
Trial medication
Trial Medication
Dosage Forma
(Concentration)
Manufacturer
BI 695502, in solution consisting of:
BI 695502, disodium phosphate dihydrate, 
sodium dihydrogenphosphate dihydrate, 
trehalose dihydrate, polysorbate 20 and 
water for injection.
Concentrate for solution for 
infusion (25 mg/mL)
100 mg/4 mL or 
400 mg/16 mL solution in a 
single use vial
Boehringer Ingelheim 
Pharma GmbH & Co KG, 
Germany
US-licensed Avastin®, in solution 
consisting of:
Bevacizumab, trehalose dihydrate, 
disodium phosphate anhydrous, sodium 
dihydrogenphosphate monohydrate, 
polysorbate 20, water for injection.
Concentrate for solution for 
infusion (25 mg/mL)
100 mg/4 mL or 
400 mg/16 mL solution in a 
single use vial
Genentech, Inc., US
a.
The US label for Avastin® states “Solution for Infusion”, however as per the European official terminology of 
pharmaceutical dosage forms, “Concentrate for solution for infusion” is stated above.
Note:
Starting as of 21 Dec 2017, the Sponsor recommends that patients should be switched from BI 695502 to 
Avastin® as soon as it is available at the respective clinical site. If Avastin® is not immediately available, the 
Investigators may temporarily allow continuation on BI 695502. The blind will be kept intact and all patients will 
continue the study with no additional visits in the scheduled visit cycle as per protocol.
The packaging for BI 695502 and US-licensed Avastin® are different so to ensure the 
investigator and patient stay blinded, the infusion solutions will be prepared by an unblinded 
pharmacist or suitably qualified designee at each trial site (see Section 4.1.5.1). 
Details on BI 695502/US-licensed Avastin® preparation and administration are provided in 
Appendix 10.2.
For further details, see the product information for Avastin® (R15-1223, R18-0043) and/or 
the Pharmacy Manual.
4.1.2
Method of assigning patients to treatment groups
Patients may be pre-randomized to a treatment group based on their screening transaction via 
the Interactive Telephone and Web Response System (IXRS®). 
The Day 1 randomization or pre-randomization will depend on the trial site procedure. The 
process for randomization will be different depending on the country and respective trial 
medication shipping timelines. In countries where trial medication needs to be sent to sites in 
advance due to long shipping timelines (e.g., cross border shipments), or other reasons that 


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require trial medication provision to the sites prior to screening, trial medication will be 
provided to the sites in advance and patients will be randomized on Day 1. For countries 
where trial medication can be provided on short notice (short shipping times) 
pre-randomization will be performed at screening and trial medication will be shipped after 
pre-randomization only.
Eligible patients who meet all the inclusion criteria and do not meet any of the exclusion 
criteria will then be randomized to double-blind treatment with a 1:1 ratio according to the 
pre-randomization, if applicable. Patients who do not meet all of the inclusion criteria or meet 
at least one of the exclusion criteria will not be randomized, and will be considered screen 
failures. Day 1 of Cycle 1 is the first day of trial treatment and can occur up to 4 days after 
randomization. Patients will be randomly assigned in a blinded fashion to BI 695502 (Arm B)
or US-licensed Avastin® (Arm A). 
Patients will receive treatment with 15 mg/kg of BI 695502 or US-licensed Avastin®. The 
randomization will be performed by IXRS®. Patients will be randomized sequentially (to the 
lowest sequentially available randomization number).
Each vial of trial medication will be labeled with a unique medication identification number. 
This will be programmed into the IXRS®. At each applicable visit, the IXRS® will assign 
the correct vial for the allocated treatment group and visit and the medication identification 
will be linked to an individual patient. The medication identification assigned by the IXRS®
will then be linked to the patient number and trial site. 
Access to the randomization code will be controlled and documented. All persons directly 
involved in the conduct and analysis of the trial will have no access to the treatment 
allocation prior to database lock. The data of the primary analysis population will be 
unblinded at the time point of the primary analysis only for the team members involved in the 
analysis (including the sponsor and contract research organization [CRO]). For details on 
unblinding procedures, see Section 4.1.5.
4.1.3
Selection of doses in the trial
In the EU, US, and many other countries, Avastin® has received health authority approval 
for the treatment of nsNSCLC, in combination with carboplatin and paclitaxel, for first-line 
treatment of unresectable, locally advanced, recurrent or metastatic disease.
The dose of BI 695502 selected for this trial is based on the clinically effective dose of the 
currently available dosage form of Avastin®. 
The primary focus of this trial is to demonstrate equivalence of BI 695502 (proposed 
biosimilar to Avastin®) with US-licensed Avastin®. The recommended dose of Avastin®, 
administered as an i.v. infusion, is 15 mg/kg of body weight given once every 3 weeks. The 
dose should be recalculated prior to each infusion. Therefore, in this study, patients 
randomized to receive BI 695502 or US-licensed Avastin® will receive 15 mg/kg once every 
3 weeks (R15-1223, R18-0043). The same applies to Avastin® administration after the 
switch from BI 695502.


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Patients will receive the combined treatment (induction cycles) every 3 weeks for up to 
6 cycles. After evaluation of the last induction cycle, if the patient has CR, PR or SD, i.e., 
responding or stabilized patients, maintenance treatment with BI 695502/US-licensed 
Avastin® monotherapy can be started. Patients will then receive BI 695502 or Avastin® as a 
single agent every 3 weeks until disease progression (according to RECIST 1.1), death, 
withdrawal of consent, or unacceptable toxicity, whichever occurs earlier.
4.1.4
Drug assignment and administration of doses for each patient
BI 695502 and Avastin® will be provided by the sponsor and the chemotherapy will be 
provided by the site. 
Each patient will be randomized before Day 1 of Cycle 1 to receive one of two possible 
treatments: BI 695502 plus chemotherapy or US-licensed Avastin® plus chemotherapy.
BI 695502/US-licensed Avastin® infusion will be administered first, i.e., prior to 
administration of paclitaxel/carboplatin. The prepared infusion solution (see Section 4.1.1) 
will be administered as an i.v. infusion through a dedicated line. It must NOT be administered 
as an i.v. push or bolus. Drug infusions will take place under the close supervision of an 
experienced physician, and in an environment where full resuscitation facilities are 
immediately available. At the end of each infusion, the i.v. line must remain in place for at 
least 1 hour to allow administration of i.v. drugs, if necessary.
Patients may be hospitalized for observation at the discretion of the investigator (such 
instances of hospitalization will not be recorded as a serious adverse event [SAE]).
The recommended initial dose for the first BI 695502/US-licensed Avastin® infusion should 
be delivered over 90 minutes. If the first infusion is well tolerated, the second infusion may 
be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent 
infusions may be administered over 30 minutes. Drug administration start/stop and dosing 
amounts will be recorded in the eCRF.
For the first infusion after the switch visit, the same challenge should be done. The first 
infusion should be delivered over 90 minutes. If the first infusion is well tolerated, the second 
infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all 
subsequent infusions may be administered over 30 minutes.
BI 695502/US-licensed Avastin® dose modification is NOT permitted during this trial. Any 
deviation to the dose will be recorded in the eCRF. Slight variations in 
BI 695502/US-licensed Avastin® dose may occur due to a change in a patient’s body weight; 
dose deviations with a margin of <5% will NOT be considered protocol deviations. Dose 
modifications for chemotherapy are shown in Table 4.1.4.1: 1
In the event of a life-threatening reaction, including anaphylaxis, hypersensitivity reaction, 
renal failure, severe cardiopulmonary event and severe muco-cutaneous reaction, BI 695502
or Avastin® will be discontinued and no additional BI 695502 or Avastin® will be 
administered. Patients who experience any of these reactions will be discontinued from trial 
medication.


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If extravasation occurs during infusion of the trial medication, the infusion must be stopped. 
Restart the remainder of the infusion either in the area of the same arm which is proximal to 
the body or in the other arm. 
 
 
Patients who miss the allocated day for trial medication infusion will be contacted and 
another visit arranged as soon as practically possible in order to administer trial medication.
Refer to Appendix 10.3 for more information regarding chemotherapy regimens.
The treatment regimen for BI 695502/US-licensed Avastin® plus chemotherapy is provided 
in Table 4.1.4: 1.
Table 4.1.4: 1
BI 695502/US-licensed Avastin® plus paclitaxel and carboplatin
Immunochemotherapy 
regimen
Dose
Mode
Day 1
BI 695502/
US-licensed Avastin®
15 mg/kg
i.v.
X*
Paclitaxel
200 mg/m2
(administered according to regular institutional practice)
i.v.
X
Carboplatin
target AUC 6 mg/mL·min (30- to 60-minute infusion)
i.v. 
X
AUC = area under the curve; i.v. = intravenous
*
US-licensed Avastin®/BI 695502 infusion should be administered prior to paclitaxel and carboplatin.
BI 695502/US-licensed Avastin® dose and schedule will remain unchanged during the 
maintenance period when given as single agent. The same drug (BI 695502 or US-licensed 
Avastin®) will be continued during maintenance therapy based on the allocation at the time 
of randomization.
Starting as of 21 Dec 2017, the Sponsor recommends that patients should be switched from 
BI 695502 to the reference product Avastin® as soon as it is available at the respective 
clinical site. If Avastin® is not immediately available, the Investigators may temporarily 
allow continuation on BI 695502. The blind will be kept intact and all patients will continue 
the study with no additional visits in the scheduled visit cycle as per protocol.
4.1.4.1
Chemotherapy
Administration of backbone chemotherapy will be according to the standard preparation and 
infusion procedures of each investigational site. Patients should receive paclitaxel prior to 
carboplatin.
All patients will be treated with standard combination chemotherapy consisting of paclitaxel 
200 mg/m2 followed by carboplatin target AUC 6 mg/mL•min (30- to 60-minute infusion) 
every 3 weeks for up to 6 cycles with adequate pre- and concomitant medication. The initial 
dose of paclitaxel (Day 1, cycle 1) must be fixed to 200 mg/m² for all study patients, as well 


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as a dose of carboplatin to AUC: 6 mg/mL/min. In case of toxicity after this initial dose, the 
dose can be reduced according to the protocol guideline Table 4.1.4.1:1 and 10.3.1.
After 3 cycles, patients who cannot tolerate chemotherapy but are not progressing can start
maintenance treatment with BI 695502/US-licensed Avastin® monotherapy. However, if 
another backbone chemotherapy is initiated at any time or if the patient cannot tolerate at 
least 3 cycles of chemotherapy, then the patient will be discontinued from trial treatment.
The carboplatin dose will be calculated using the Calvert formula, taking into account the 
glomerular filtration rate (GFR) and given in dose of AUC:
Carboplatin-dosage in mg = (target AUC) x (GFR + 25) on Day 1 of each 3-week cycle
Glomerular filtration rate is to be based on the Cockroft-Gault formula for creatinine 
clearance:
          GFR (mL/min) =     C  x  (140-age [years])  x  (weight [kg])     
                                                   72  x  serum creatinine (mg/dL)
where C = 0.85 for female patients and C = 1.00 for male patients. 
The Cockcroft–Gault formula will be used to calculate the creatinine clearance/glomerular 
filtration rate (GFR) (required for the Calvert´s formula). As clinically recommended, GFR 
will be capped at 125 mL/min (even if the result obtained is higher) so as to avoid potential 
overdosing. Accordingly, the maximum total dose of carboplatin would be 900 mg per cycle.
All patients should be premedicated prior to paclitaxel administration in order to prevent 
severe hypersensitivity reactions. Such premedication may consist of dexamethasone, 
diphenhydramine (or its equivalent), and cimetidine/ranitidine (see Appendix 10.3). 
Doses of paclitaxel and carboplatin will be reduced for hematological and non-hematological 
toxicity effects (see Table 4.1.4.1: 1) for a maximum of two dose reductions. When a dose 
reduction is required, no dose re-escalation will be permitted. Chemotherapy dose reductions 
can be cumulative from cycle to cycle as required based on toxicity. Patients who do not 
tolerate the chemotherapy dose level -2 must discontinue treatment with chemotherapy.
Table 4.1.4.1: 1
Dose modifications of paclitaxel and carboplatin
0 (starting dose)
-1
-2
-3
Paclitaxel (mg/m2)
200
150
100
Off-treatment
Carboplatin (target AUC)
6
4.5
3
Off-treatment
Further details on the chemotherapy regimens and dose modifications are provided in 
Appendix 10.3.


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Drug toxicity will be assessed using the National Cancer Institute (NCI)-Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (R10-4848).
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is a double-blind trial. Patients, investigators, and trial personnel, except the unblinded 
pharmacist or designated person, will remain blinded with regard to the randomized treatment 
assignments until after final database lock. The data of the primary analysis population for 
biosimilarity will be unblinded at the time point of the primary analysis only for the team 
members involved in the analysis (including the sponsor and relevant CROs). In order to 
provide an additional fully blinded assessment of response a central evaluation process has 
been established.
The IXRS® will be used to manage randomization to treatment groups in a blinded manner. 
To randomize a patient, the investigator will contact the IXRS®. 
Access to the randomization code will be controlled and documented. All persons directly 
involved in the conduct and analysis of the trial will have no access to the treatment 
allocation prior to database lock for the primary analysis (see Section 4.1.2).
 
 
The data review will be performed by the DSMB with the support of an unblinded 
statistician. No unblinded data will be shared with trial personnel or sponsor personnel 
involved in data management.
No unblinding of sites or patients will be performed at the time of switching from BI 695502 
to Avastin® to ensure continued unbiased assessments. Moreover, knowledge about the 
initial treatment received would not impact the further treatment of patients, since after the 
introduction of the switch, all patients will receive Avastin®.
4.1.5.2
Procedures for emergency unblinding
In the event of an emergency, each trial site will be able to unblind patient treatment 
allocation via IXRS® (either the principal investigator or a designated medical
sub-investigator at the trial site). In the case of an AE, this may only occur in emergency 
situations when the identity of the trial medication must be known to the investigator in order 
to provide appropriate medical treatment or if required to assure the safety of trial 
participants. If unblinding is required in the interest of the safety of a patient and time allows, 
the investigator will discuss the matter with the CRO medical monitor before unblinding, 
whenever possible. If the code is broken for a patient (via the IXRS®) the sponsor’s trial 
clinical monitor must be informed immediately. The reason for opening the code break must 
be documented on the patient’s source documents and the appropriate eCRF page along with 
the date. 


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The process for breaking the blind will be handled through the IXRS®. Instructions for this 
will be described in the IXRS® user manual that will be provided to each site.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF. Relabeling of 
commercially available Avastin® for trial purposes is not required.
4.1.7
Storage conditions
All trial medications must be kept in a secure place under appropriate storage conditions and 
handled according to Good Manufacturing Practice and GCP. The medication must be stored 
in a refrigerator at a controlled temperature (2 to 8°C [36 to 46oF]). It should not be frozen or 
shaken. A temperature log with minimum/maximum readings must be maintained to make 
certain that the drug supplies are stored at the correct temperature. Vials will be kept in the 
outer carton in order to protect them from light. 
After the switch visit, the sites should monitor the storage conditions in accordance with local 
requirements.
4.1.8
Drug accountability
Drug supplies, which will be provided by the sponsor, must be kept in a secure, limited 
access storage area under the storage conditions defined by the sponsor, see Section 4.1.7. 
The unblinded pharmacist or the designated person will receive the investigational drugs 
delivered by the sponsor when the following requirements are fulfilled:

Approval of the CTP by the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC).

Availability of a signed and dated clinical trial contract between the sponsor and the Head 
of Trial Center.

Approval/notification of the regulatory authority, e.g., competent authority (CA).

Availability of the curriculum vitae (not older than 2 years) of the principal investigator.

Availability of a signed and dated CTP.

Availability of the proof of a medical licence for the principal investigator, if applicable.

Availability of the Form 1572 for sites in US.
The unblinded pharmacist or designated person must maintain records of the product’s 
delivery to the trial site, the inventory at the site, the use by each patient, and the return to the 
sponsor or alternative disposition of unused products. 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients. Once 
patients are switched from BI 695502 to Avastin®, the date of administration, the batch 
number, and expiry dates are to be recorded for Avastin®. The unblinded pharmacist or 
designated person will maintain records that document adequately that the patients were 
given the doses specified by the CTP and reconcile all investigational product(s) received 
from the sponsor. At the time of return to the sponsor and/or the CRO, the unblinded 


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pharmacist or designated person must verify that no remaining supplies are in the 
investigator’s possession.
The following text is only applicable for Japan:
The investigator/pharmacist/investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor representative after IRB/ethics committee 
approval of the study and completion of a clinical trial contract between the sponsor 
representative and the Head of Trial Center.
The investigator/pharmacist/investigational drug storage manager should return the unused 
and collected investigational drugs (including the empty boxes) to the sponsor after 
unblinding the trial.
In case investigational drugs are returned before unblinding of the trial, the 
investigator/pharmacist/investigational drug storage manager should seal the opened box 
(excluding empty boxes) for the patient, and before returning the unused and collected 
investigational drugs (including the empty boxes) to the sponsor. When returning the 
investigational drugs, the investigator/pharmacist/investigational drug storage manager 
should exercise utmost caution to assure that the sponsor representative and other relevant 
trial staff members remain blinded to the patient’s name on the package (box or label) of the 
investigational drugs.
Upon completion of the trial, the investigator/pharmacist/investigational storage manager 
submits to the sponsor representative a copy of the investigational drug dispensing and return 
log. When submitting the copy, the investigator/pharmacist/investigational drug storage 
manager should exercise caution to assure that the sponsor representative and other relevant 
trial staff members remain blind to the patient’s name.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
There are no recommended dose reductions or rescue medication for BI 695502/Avastin®.
BI 695502/Avastin® should be permanently discontinued in patients with GI perforations 
(including fistula formation in the GI tract, intra-abdominal abscess), fistula formation 
involving an internal organ; wound dehiscence and wound healing complications requiring 
medical intervention; serious hemorrhage (i.e., requiring medical intervention); severe arterial 
thromboembolic events; hypertensive crisis or hypertensive encephalopathy; RPLS; nephrotic 
syndrome; and congestive heart failure of any grade.
Patients with severe hypertension, moderate to severe proteinuria, or severe infusion 
reactions will not receive further treatment with Avastin® or BI 695502 if the event cannot 
be adequately controlled within 14 days. 


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For urinalysis, when the laboratory dipstick reports “2+” or greater, urine dipstick reading 
should undergo further assessment with a 24-hour urine collection either at the local 
laboratory or central laboratory, whichever the investigator deems more convenient. 
Avastin®/BI 695502 administration should be suspended for ≥ 2 g of proteinuria/24 hours 
and should resume when proteinuria is < 2 g/24 hours. If moderate proteinuria (≥2 g in
24 hours) cannot be controlled within 14 days, then the patient should discontinue the use of 
Avastin®/BI 695502.
If chemotherapy treatment is interrupted, e.g., due to toxicity, then BI 695502/Avastin®
should also be interrupted until chemotherapy treatment is resumed.
All concomitant medication/therapies will be recorded on the eCRF.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Restrictions on prior and concomitant medications during the course of the trial are described 
in Table 4.2.2.1: 1.
Other medication that is considered necessary for the patient’s safety (e.g., as a result of an 
AE) may be given at the investigator’s discretion. Investigators are encouraged to discuss the 
introduction of any of the medications listed in Table 4.2.2.1: 1 with the sponsor physician or 
CRO medical monitor. 
Caution must be taken in the concomitant use of any medication that may markedly affect 
renal function. Such medications may, however, be used with caution if deemed essential for 
treatment of a particular infection or continued if patients are using them prior to 
commencing the trial with no effect on renal function demonstrable on blood or urine testing.
Any concomitant medications will be recorded in the appropriate sections of the eCRF.


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Table 4.2.2.1: 1
Prior and concomitant treatments
Treatment
Restriction
Carboplatin + Paclitaxel
Refer to Appendix 10.3
Other anticancer regimens
Patients should not have received previous systemic treatment for their 
metastatic NSCLC. Patients who have received adjuvant chemotherapy are 
eligible if the last administration of the prior adjuvant regimen occurred 
>12 months prior to Screening. Prior systemic therapy for locally advanced 
nsNSCLC is permitted if completed >12 months prior to Screening. Other 
anticancer treatment is not permitted.
Radiotherapy
Palliative local radiation therapy (outside the only measurable lesion used 
for RECIST assessment) is acceptable, both previously and during the trial, 
at the Investigator´s discretion. However, any radiotherapy to the chest 
must have finished >12 months prior to screening. 
Previously irradiated brain metastasis must be shown to be stable at 
1 month after completion of radiation therapy (by CT or MRI) and before 
screening, the patient must be asymptomatic from brain metastasis, with a 
stable dose of oral corticosteroids ≤10 mg/day of prednisolone (or 
equivalent) during the last 4 weeks, no parenteral corticosteroids in the last 
6 weeks prior to Day 1 (see below item in this table), and with an indication 
of treatment with the study regimen (inclusion criterion #2). 
Patients must be recovered at screening from any adverse event (>grade 1, 
except alopecia) related to previous radiotherapy (exclusion criterion #10).
Intravenous, intramuscular, 
intra-articular, or parenteral 
corticosteroids
Not permitted within 6 weeks prior to Day 1 or throughout the trial, unless 
used for paclitaxel infusion premedication, according to regular institutional 
practice. 
Oral, inhaled, or topical
corticosteroids
If receiving current treatment with oral, inhaled, or topical corticosteroids 
(other than intra-articular or parenteral corticosteroids), the dose must not 
exceed 10 mg/day prednisolone or equivalent. During the 4 weeks prior to 
Day 1 the dose must be stable.
Oral or parenteral 
anticoagulants 
Full-dose oral or parenteral anticoagulants or thrombolytic agent for 
therapeutic (as opposed to prophylactic) purposes (including coumadin or 
warfarin) are not permitted within 10 days of the first dose of 
BI 695502/Avastin® or throughout the trial.
NSAIDs
The use of aspirin (>325 mg/day) or other NSAID with antiplatelet activity 
or treatment with dipyridamole, ticlopidine, clopidogrel and cilostazol 
within 10 days of first dose of BI 695502/Avastin® or throughout the trial. 
Acetaminophen (paracetamol) as well as natural and synthetic opioids 
could be used as pain relievers.
Monoclonal antibodies and 
small molecules
Any prior therapy with monoclonal antibodies or small molecule inhibitors 
against VEGF or VEGF receptors, including Avastin®, are not permitted.
Any drug/therapy that has not 
received regulatory approval 
for any indication
Treatment within a clinical trial within 4 weeks prior to initiation of trial 
treatment. Patients who have received treatment with a drug that has not 
received regulatory approval for any indication within 4 weeks or a 
minimum of 5 half-lives, whichever is longer, of the initial dose of trial 
medication. Simultaneous participation in non-interventional studies (e.g. 
observational studies) is allowed.


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Table 4.2.2.1: 1
Prior and concomitant treatments (continued)
Treatment
Restriction
Surgical procedures
Invasive procedures (major surgical procedure, open biopsy or significant 
traumatic injury) ≥28 days prior to the first dose of 
BI 695502/US-licensed Avastin®. 
Placement of a vascular access device and mediastinoscopy are not 
considered as major surgical procedures if performed more than 24 hours 
prior to BI 695502/US-licensed Avastin® administration.
Live/attenuated vaccine
Not permitted within 12 weeks prior to the Screening Visit.
Treatment
Permitted
Non-pharmacological treatments 
(e.g., physical therapy)
Permitted freely.
All supportive therapies (e.g., 
myeloid growth factors, blood 
transfusions)
Permitted as appropriate and according to site routine practice. 
Prophylactic use of growing factors is permitted according to regular 
institutional practice and the PI´s judgment.
Bisphosphonates
These are allowed, according to regular clinical institutional practice and 
PI´s discretion (e.g. pamidronate, zoledronate, and alendronate). Caution 
may be exerted as they may affect renal function. Nephrotoxicity can be
avoided by stringent adherence to infusion guidelines
nsNSCLC = nonsquamous non-small cell lung cancer; NSCLC = non-small cell lung cancer; VEGF = vascular endothelial 
growth factor; NSAID = non-steroidal anti-inflammatory drugs.
Any surgical procedure is not permitted within 28 days prior to the first dose of 
BI 695502/US-licensed Avastin® or for the duration of the trial.
For elective surgery during the trial the interval between termination of the 
BI 695502/Avastin® infusion and subsequent elective surgery should be at least 28 days. If 
emergency surgery is performed, precautions should be taken to minimize the potential risk 
of bleeding and thrombosis associated with this class of agents, infusion should be stopped 
and close monitoring for bleeding, wound healing and thromboembolic complications should 
be initiated. Patients with anticipated elective surgery will not be enrolled into the trial.
4.2.2.2
Restrictions on diet and life style
Patients should abstain from smoking and alcoholic beverages 48 hours prior to the first trial 
medication administration until Day 8. After that, smoking is permitted (<10 cigarettes or 
<3 cigars or <3 pipes/day). No more than two units of alcohol per day are permitted until the 
end of trial. One unit of alcohol is 10 mL (or 8 g) of pure alcohol. Accordingly it may be 
calculated by using the following formula: 
Alcohol units = Strength of the beverage (Alcohol by volume in %) x volume (mL) ÷ 1,000
In addition, patients should abstain from alcoholic beverages for 24 hours prior to each 
subsequent trial visit. 
Participation in contact sports (e.g., ice-hockey, rugby, martial arts) should be avoided during 
the course of the trial.


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4.3
TREATMENT COMPLIANCE
All drug infusions will be administered by the investigator or other designated trial personnel. 
This should guarantee full compliance is achieved, provided the patient attends each 
appropriate visit for the administration of trial medication.
The prescribed dosage, timing and mode of administration of trial medication may not be 
changed. Any deviation from the intended regimen must be recorded in the eCRF. 
Patients showing poor compliance as assessed by visit attendance for their drug infusions 
must be counseled on the importance of good compliance to the trial dosing regimen.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY
5.1.1
Endpoints of efficacy
Primary endpoint:

Best ORR, based on unconfirmed response assessment, as assessed by central 
imaging review until 18 weeks after the start of treatment. 
Secondary endpoints:

PFS defined as the time from randomization until disease progression as per 
investigator assessment or death.

OS defined as the time from randomization until death of any cause.

Duration of response defined as the time from first documented CR or PR until time 
of progression as per investigator assessment.
Other endpoints:

Best ORR, based on unconfirmed response assessment, as per investigator assessment
until 18 weeks after start of treatment.

Best ORR, based on unconfirmed response assessment, as per investigator assessment 
until progression or death.
5.1.2
Assessment of efficacy
The following assessments will be made at the time points indicated in Flow chart 1.1 and 
Flow chart 1.2.
5.1.2.1
Response rate
The response criteria evaluation will be carried out according to RECIST 1.1 (see 
Appendix 10.1). Objective response comprises those patients achieving a PR or CR until 
18 weeks after the start of treatment.
Each patient will be assigned to one of the following RECIST 1.1 categories based on 
independent central review, irrespective of protocol violations or missing data:

CR (complete response)

PR (partial response)

SD (stable disease)

PD (progressive disease)

NE (not evaluable, insufficient data).


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Complete response and PR do not need to be confirmed by a subsequent tumor assessment
(detailed rules are listed in the imaging charter). 
During the induction phase, the response evaluation against baseline will be performed using 
computed tomography (CT) or MRI scans at the time points indicated in Flow chart 1.1. 
During the induction phase, tumor assessments should be performed before treatment 
administration of Cycles 3 and 5.
Tumor assessment must be performed at Week 18 ±14 days (where Day 1 is the first day of 
Cycle 1) whether or not this assessment coincides with Cycle 7. 
After Week 18 (maintenance cycles with monotherapy), see Flow chart 1.2, tumor 
assessments should be performed at the investigator’s discretion, or at a minimum of every 
3 cycles (approximately every 9 weeks). Tumor assessments should be performed prior to 
trial treatment administration. If the cycle is delayed, tumor assessment will also be delayed. 
Consistency of consecutive CT or MRI scans should be ensured during all assessments for 
each patient, with the same technique being used for evaluating lesions throughout the 
treatment period. During the non-treatment period, tumor assessments should be performed at 
the investigator’s discretion, but at a minimum of every 9 weeks. 
A CT scan with i.v. contrast will be performed on the chest and abdomen, including the 
adrenals and the entire liver, if applicable. In case of an iodine i.v.-contrast contraindication
(renal insufficiency, allergy, hyperthyroidism etc), an abdomen MRI with contrast 
(gadolinium) should be performed with a non-contrast chest CT scan.
If a CT scan for tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast CT scan. 
CT scans must be used to measure lesions selected for response assessment.
A central review of all patient images will be performed until Week 18. Details will be 
described in the imaging charter. The results of the central review imaging data (independent 
blinded assessments of tumor response) will be used for the primary measure of response and 
will be the data used for the primary response analyses. The results of the investigator 
assessment will be used for sensitivity analysis (see Section 7.3.1.2).
5.1.2.2
Duration of response
Duration of response is the time from first documented CR or PR until time of progression as 
determined by investigator assessment.
5.1.2.3
Progression-free survival
Progression-free survival is defined as the time from randomization until disease progression
as determined by investigator assessment or death. Disease progression is assessed according 
to RECIST 1.1 (see Section 5.1.2.1 and Appendix 10.1). 


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5.1.2.4
Overall survival
Overall survival is defined as the time from randomization until death from any cause.
5.2
SAFETY
5.2.1
Endpoints of safety
The safety of BI 695502, compared to US-licensed Avastin®, will be evaluated by means of 
continuous AE monitoring, laboratory tests, physical examination, vital signs (blood pressure, 
pulse rate, respiratory rate, body temperature, and weight), 12-lead electrocardiogram (ECG) 
and tolerability.
Adverse events selected for comparability assessment (secondary endpoint)

The proportion of patients with the following selected AEs will be evaluated in 
comparability assessment of BI 695502 and US-licensed Avastin®: 
o
Anaphylactic reactions/hypersensitivity reactions/infusion-related reactions
o
Arterial and venous thromboembolic events
o
Febrile neutropenia
o
Gastrointestinal perforations
o
Hypertension
o
Proteinuria
o
Pulmonary hemorrhage
o
Other hemorrhages
o
Wound-healing complications/abscess/fistulas.
Other Endpoints:

The proportion of patients with AEs 

The proportion of patients with AEs related to trial treatment

The proportion of patients with Grade 3 or 4 AEs according to NCI-CTCAE version 4.0

The proportion of patients with Grade 3 or 4 AEs according to NCI-CTCAE version 4.0 
related to trial treatment

The proportion of patients with AEs potentially related to immunogenicity

The proportion of patients with adverse events of special interest (AESIs).
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An AE is defined as any untoward medical occurrence, including an exacerbation of a 
pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical 
product. The event does not necessarily have to have a causal relationship with this treatment.


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Serious adverse event
A SAE is defined as any AE which results in death, is immediately life-threatening, results in 
persistent or significant disability/incapacity, requires or prolongs patient hospitalization, is a 
congenital anomaly/birth defect, or is to be deemed serious for any other reason if it is an 
important medical event when based upon appropriate medical judgment which may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definitions.
Cancers with new histology are always considered serious. Progression of cancer (underlying 
disease) is exempted from reporting as an (S)AE.
Japan only: An AE that possibly leads to disability will be reported as a SAE. Every new 
occurrence of cancer will be reported as a SAE regardless of the duration between 
discontinuation of the drug and the occurrence of the cancer.
Intensity of adverse event
The intensity of AEs will be classified and recorded according to the NCI-CTCAE, 
version 4.0 (R10-4848), in the eCRF.
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the eCRF. 
Japan only: The reason for the decision on causal relationship needs to be provided in the 
eCRF.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
If a SAE is reported from a still-blinded trial, the causal relationship must be provided by the 
investigator for all potential trial drugs and trial design.
Worsening of pre-existing conditions
Worsening of pre-existing conditions will be recorded as an (S)AE in the eCRF.
Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the eCRF, if they are judged clinically relevant by the investigator.


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Protocol-specified adverse events of special interest
Protocol-specified AESIs are events of medical concern requiring monitoring and rapid 
communication.
The following are considered as protocol-specified AESI:

Patients showing the following laboratory abnormalities need to be followed up according 
to Appendix 10.4 of this CTP and the “DILI checklist” provided in the ISF:
o
Hepatic injury defined by the following alterations of liver parameters for patients 
with normal liver function at baseline: an elevation of AST and/or ALT ≥3 x ULN 
combined with an elevation of total bilirubin ≥2 times ULN measured in the same 
blood draw sample. 
o
Hepatic injury defined by the following alterations of liver parameters for patients 
with impaired liver function at baseline: an elevation of AST and/or ALT ≥5 x ULN
combined with an elevation of total bilirubin ≥2 times ULN measured in the same 
blood draw sample.
o
Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN

Anaphylactic reactions.

GI perforations.

Pulmonary hemorrhage.
Protocol-specified AESI can be classified as serious or non-serious but all AESI must be 
reported in an expedited manner similar to SAEs, even if they do not meet any of the 
seriousness criteria (i.e., non-serious AESI must also be reported on the SAE form and follow 
serious timelines). 
5.2.2.2
Adverse event and serious adverse event reporting
All AEs, serious and non-serious, as well as all protocol-defined AESI, occurring during the 
course of the clinical trial (i.e., from signing the informed consent onwards through the 
follow-up period) will be collected, documented and reported to the sponsor or sponsor 
designee by the investigator on the appropriate case report forms (CRFs)/eCRF/SAE 
reporting forms. The Residual Effect Period (REP) for BI 695502 is 112 days/16 weeks. 
Therefore, all events reported within 112 days/16 weeks of the last trial medication will be 
considered on-treatment. All AEs will be reported up until the end of the SFU visit (18 weeks 
after the last dose of trial medication) or until the patient discontinues Avastin®. The 
investigator does not need to actively monitor patients for AEs once the trial has ended. If a 
patient remains in the non-treatment period beyond 18 weeks post last dose of trial 
medication (beyond the SFU), all AEs, SAEs and AESI will be collected. However, if the 
investigator becomes aware of a SAE(s) occurring after the patient has completed the trial 
(including any protocol-required REP and/or follow-up), it should be reported by the 
investigator to the sponsor or sponsor designee if considered relevant by the investigator. 
Reporting will be done according to the specific definitions and instructions detailed in the 
‘AE Reporting’ section of the ISF. 
For each AE, the investigator will provide the onset date, end date, intensity, treatment 
required, outcome, seriousness, and action taken with the investigational drug. The 


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investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1. 
The investigator must report the following events via telephone/fax using the SAE form 
immediately (within 24 hours of awareness or the next business day whichever is shorter) to 
the sponsor or sponsor designee: SAEs, non-serious AEs which are relevant for a reported 
SAE, and any AESI. 
Disease progression in oncology trials is a study endpoint for analysis of efficacy and as such 
is exempted from reporting as a (S)AE. Progression of the subject’s underlying malignancy 
(nsNSCLC) will be recorded on the appropriate pages of the eCRF as part of efficacy data 
collection only and will not be reported on the SAE Form. It will therefore not be entered into 
the safety database (ARISg) and hence not get expeditiously reported. Death due to disease 
progression is also to be recorded on the appropriate eCRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the study drug(s) 
and the progression of the underlying malignancy, the event must be reported as a (S)AE on 
the on the SAE Form and on the eCRF.
Examples of exempted events of PD may be:
Progression of underlying malignancy (Progressive disease [PD]): if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by the 
respective response criteria. 
Hospitalization/Procedures due solely to the progression of underlying malignancy (PD)
Clinical symptoms and/or signs of progression (without confirmation by objective criteria 
e.g. imaging, clinical measurement): if the symptom can exclusively be determined to be 
due to the progression of the underlying malignancy and does meet the expected pattern of 
progression for the disease under study.
Exempted events are collected and tracked following a protocol-specified monitoring plan. 
Exempted events are monitored at appropriate intervals preferable by an independent 
committee such as a Data Monitoring Committee. See Section 8.4.2 for expedited reporting 
to health authorities and IECs/IRBs.
Except for trial endpoints, the investigator must immediately report to the sponsor all SAEs, 
regardless of whether the investigator believes that they are drug related.
Cancers with new histology are always considered serious and should be reported in an 
expedited manner by using an SAE form.
The telephone/fax numbers will be provided to each site in the ISF in a separate document to 
this CTP. With receipt of any further information to these events, a follow-up SAE report has 
to be provided. Serious AEs, nonserious AEs relevant to the SAE, and AESI must include a 
causal relationship assessment made by the investigator. 
Boehringer Ingelheim has set up a list of AEs which are defined to be always serious. In 
order to support the investigator with the identification of these “always SAEs”, if a 


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nonserious AE is identified to be serious per BI definition, a query will be raised. The 
investigator must verify the description and seriousness of the event. If the event description 
is correct, the item “serious” needs to be ticked and a SAE has to be reported in expedited 
fashion following the same procedure as above. The list of these AEs can be found in the ISF.
The SAE form is to be forwarded to the sponsor/sponsor designee. Specific contact details 
will be provided in the ISF. This immediate report is required irrespective of whether the
investigational product has been administered or not and irrespective of causal relationship. It 
also applies if new information to existing SAEs or protocol-specified AESI becomes 
available. 
Japan only: This information must be also reported immediately to the head of the trial site. 
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female patient has been 
enrolled into the clinical trial, after having taken trial medication, the investigator must report 
immediately any drug exposure during pregnancy to the sponsor/sponsor designee and the 
pregnant study participant must be excluded. In addition, if a patient’s partner becomes 
pregnant after the patient has been enrolled, the same procedure must be followed. In case of 
pregnancy in a patient’s partner, the partner Pregnancy Informed consent must be completed 
before collecting the Pregnancy Monitoring Form for Clinical Trials. Drug exposure during 
pregnancy has to be reported immediately (within 24 hours or next business day whichever is 
shorter) to the defined unique entry point for SAE forms (specific contact details will be 
provided in the ISF). The outcome of the pregnancy associated with the drug exposure during 
pregnancy must be followed up. In the absence of an (S)AE, only the Pregnancy Monitoring 
Form for Clinical Trials and not the SAE form is to be completed. The ISF will contain the 
Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
Blood and urine samples for determination of serum chemistry, hematology, urinalysis and 
coagulation will be taken at the times indicated in Flow chart 1.1 and Flow chart 1.2. 
Estimated blood volumes are shown in Table 6.1: 1.
The following laboratory parameters will be measured:

Serum chemistry: creatinine, alkaline phosphatase, AST, ALT, gamma glutamyl 
transpeptidase, bilirubin (total and direct), glucose, total cholesterol, total protein, 
albumin, sodium, potassium, chloride, calcium.

Hematology: hemoglobin, hematocrit, platelets, white blood cells, lymphocytes, 
neutrophils.

Urinalysis: protein, glucose, blood.

Coagulation: INR, PT/PTT
In addition, the following parameters will be analyzed at the visits indicated in Flow chart 1.1
and Flow chart 1.2:


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
Infection screen (for hepatitis B, hepatitis C):
o
Active Hepatitis B is defined as positive hepatitis B surface antigen (HBsAg) or 
immunoglobulin (Ig)M hepatitis B core antibody, depending on timing. If any of these 
tests are positive, the result should be confirmed by a positive hepatitis B virus DNA.
o
Active hepatitis C is defined as positive antiHCV and/or a positive antibody. If any of 
these tests are positive, the result should be confirmed by a positive hepatitis virus 
RNA.

Screening for HIV and TB (PPD or QuantiFERON) to be performed according to local 
practice and local regulatory guidance.

Pregnancy testing for females of child-bearing potential only (serum human chorionic 
gonadotropin or urine).
The investigator must assess all laboratory results. The investigator will evaluate any change 
in laboratory values and all clinical laboratory tests will be reviewed for potential clinical 
significance at all time points throughout the trial. The investigator should endeavor to 
provide a reason for all out of range results deemed not clinically significant. If the 
investigator determines a laboratory abnormality to be clinically significant, it will be 
considered an AE/SAE (see Section 5.2.2), however, if the laboratory value abnormality is 
consistent with a current diagnosis, it will be documented accordingly.
Blood samples will be analyzed by a central laboratory, with the exception of HIV and TB, 
and coagulation parameters when assessed for study inclusion. Assessment of coagulation 
parameters for study inclusion will be performed locally unless local analysis is not available, 
in which case central laboratory analysis will be used instead (see Section 3.3.2). The central 
laboratory provider will also provide the materials for blood sampling. Instructions for the 
labeling, storage and shipment of the samples can be found in the Laboratory Manual. Details 
of all blood variable units and reference ranges can be found in the Laboratory Manual.
For laboratory results that are required for decisions on chemotherapy administration, 
laboratory testing should be performed per standard-of-care, based on the site's regular 
practice. Blood samples may be analyzed locally, but this data will not be collected.
5.2.4
Electrocardiogram
Two consecutive resting 12-lead ECGs should be performed prior to administration of trial 
medication at the visits indicated in Flow chart 1.1 and Flow chart 1.2. The first of the 
consecutive ECGs is mandatory. The second of the consecutive ECGs is optional, at the 
discretion of the Investigator in case of clinical significance. Additional ECGs will be 
performed if clinically indicated.
Patients should rest for at least 5 minutes in a supine position before each of the two 
consecutive ECG evaluations.
The original ECG traces and variables must be stored in the patients’ medical records as 
source data. The investigator or designee will evaluate the ECG from a clinical perspective 
and the result (whether the ECG result is normal or abnormal) will be recorded on the 
appropriate section of the eCRF and on the ECG trace signed and dated by Investigator or 
designee.


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5.2.5
Assessment of other safety parameters
Vital signs
Vital signs will be assessed prior to administration of trial medication at the visits indicated in
Flow chart 1.1 and Flow chart 1.2.
Blood pressure, respiratory rate, and pulse rate measurements should be taken following at 
least 5 minutes rest while the patient is in a sitting position. The patient’s body temperature 
will also be recorded. Two or more blood pressure readings should be taken at 2 minute 
intervals and the average of the readings taken. If the first two diastolic readings differ by 
more than 5 mmHg, an additional reading should be obtained and an average taken of the 
three readings.
The investigator must immediately assess all vital signs findings at each visit. If the 
investigator finds any clinically relevant abnormalities, these must be reported as AEs/SAEs 
as appropriate (see Section 5.2.2).
Physical examination
A physical examination will be performed prior to administration of trial medication at the 
visits indicated in Flow chart 1.1 and Flow chart 1.2.
Whenever possible, the same person should perform the physical examination throughout the 
trial (i.e., for all patients at each trial site). The physical examination will include a detailed 
abdominal examination, an assessment of general appearance, skin, head, neck, throat, lymph 
nodes, cardiovascular, neurological, thyroid, musculoskeletal/extremities, respiratory, and 
abdomen. Body weight will also be measured. Height will be measured at screening only. 
Tuberculosis Assessment
Screening for TB will be performed according to local practice and local regulatory guidance. 
There should be no radiographic or clinical evidence of active TB. 
Purified protein derivative skin test
A PPD skin test may be used to assess TB status at Screening.
QuantiFERON®-TB Gold Assay
QuantiFERON Gold assay may be used to assess TB status at Screening.


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5.4
APPROPRIATENESS OF MEASUREMENTS
The RECIST 1.1 guideline (R09-0262) is well established and scientifically accepted and will 
be used for the evaluation of tumor response. The NCI-CTCAE, version 4.0 (R10-4848), a 
standard for assessment of safety in oncology clinical trials, will be used in the assessment of 
AEs in nsNSCLC patients.


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6.
INVESTIGATIONAL PLAN
For all visits, there will be a window of ±3 days unless otherwise specified.
Cycles must not be missed but delays may occur according to Tables 10.3:1 and 10.3:2. The 
maximum timeframe for treatment delay should be assessed based on the investigator´s 
clinical judgement and discussed with the trial medical monitor. However, patients with 
severe hypertension, moderate to severe proteinuria, or severe infusion reactions will not 
receive further treatment with Avastin®/BI 695502 if the event cannot be adequately 
controlled within 14 days.
6.1
VISIT SCHEDULE
A schedule of assessments is provided in Flow chart 1.1 and Flow chart 1.2.
Visits will be scheduled as close as possible to the pre-planned schedule
 
 

Administration of BI 695502/US-licensed Avastin® will occur on Day 1 of each cycle 
(every 21 days).

Administration of chemotherapy will start on Day 1 of each cycle (see Section 4.1.4.1).

Each subsequent cycle will occur 3 weeks (±3 days) after completion of the previous 
cycle, including after the switch visit.

During the switch visit prior to infusion with Avastin®, the assessments as described in 
Flow Chart 1.2 will be performed.

The EOT visit will be performed within 
 after the last BI 695502/Avastin® dose 
on completion of the treatment period.

Non-treatment period: visits will be performed every 
 until initiation of new 
treatment, disease progression, or death for patients who discontinue trial medication for 
reasons other than disease progression but who do not withdraw consent (see 
Section 6.2.3). If a patient remains in the non-treatment period beyond 18 weeks post last 
dose of trial medication, he/she will be treated according to standard of care, and assessed 
for tumor progression every 6 to 9 weeks according to clinical judgment.

A SFU visit will be performed 18 weeks after the last dose of trial medication (IMP 
BI 695502/US-licensed Avastin®). If the patient continues to receive treatment with 
Avastin® beyond the 18 weeks post last IMP dose, then no SFU visit will be performed.
Clinical assessments will be performed within
 before trial medication infusion. 
Laboratory samples must be drawn prior to infusions of premedication and trial medication.
Patients who miss the allocated day for trial medication infusion will be contacted and 
another visit arranged as soon as practically possible in order to administer trial medication. 
Such cases will be considered as CTP deviations (see Section 7.3).
The total volume of blood that will be drawn from each patient during the trial will depend on 
the length of time the patient receives trial medication. The total estimated volume of blood 


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that will be drawn from each patient who receives 10 cycles of treatment during the course of 
the trial, plus the EOT and SFU visits is shown in Table 6.1: 1.
Table 6.1: 1
Estimated blood sample volumes per patient
Parameter
Sample volume (mL)
Number of samples
Total volume (mL)
Laboratory tests (including serum 
chemistry, serum pregnancy test)
3.5
13
45.5
Hematology
2
13
26
INR/PT/PTT
2.7
13
35.1
Infection screen
12
1
12
TB
3
1
3
Approximate total
256.6
 INR = international normalized ratio; PT = prothrombin time; 
PTT = partial thromboplastin time; TB = tuberculosis.
It should also be noted that additional samples may be required if medically indicated, e.g., at 
unscheduled visits to follow up safety findings.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Screening, Visit 0 (Week -4 to -1) 
Once the patient has provided informed consent (before any trial-specific procedures or 
assessments are performed) and the patient meets all inclusion criteria and none of the 
exclusion criteria (see Section 3.3), the trial site will enter the screened patient into the 
system using the IXRS®.
The following assessments will be performed/collected:

EGFR and ALK mutation status.

Demographic information (including sex, date of birth, ethnicity and race), medical and 
surgical history including surgery for lung cancer, and smoking status. 

Hepatitis B and hepatitis C (unless status has previously been confirmed within 6 months 
prior to Screening).

HIV test should be performed only if required per local practice and regulatory guidance.

TB test (PPD skin test or QuantiFERON TB Gold test) according to local practice and 
local regulatory guidance, or no radiographic or clinical evidence of active TB.

Serum pregnancy test for women of childbearing potential.

Physical examination, including height (cm) and weight (kg).


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
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.2.5).

Laboratory testing (serum chemistry, hematology, urinalysis and coagulation; see 
Section 5.2.3).

12-lead ECG (see Section 5.2.4).

Previous and concomitant therapy/medications (see Section 4.2).

Assessment of AEs (see Section 5.2.2). 

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and the 
involved area, if applicable). A PET scan can be performed in addition to the tumor 
assessment CT scan (see Section 5.1.2.1). To be performed within 21 days of 
randomization.

ECOG PS.

Contact IXRS® (see Section 4.1.2)
Subjects are only allowed to be re-screened once and he/she must be re-consented before 
re-screening occurs.
6.2.2
Treatment period
Cycle 1
Eligible patients will be randomized and allocated to treatment as per the IXRS® within 
4 days of Day 1 of Cycle 1 (baseline). The following will also be performed/collected:

Assessment of eligibility.

Urine pregnancy test for women of childbearing potential (serum pregnancy test to be 
performed in case of positive urine pregnancy test).

Physical examination, including weight (kg) (see Section 5.2.5).

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.2.5).

Laboratory testing (serum chemistry, hematology, urinalysis and coagulation; see 
Section 5.2.3).

Previous and concomitant medications (see Section 4.2).

Assessment of AEs (see Section 5.2.2).

ECOG PS.

Survival.

Contact IXRS® (see Section 4.1.2)

Administration of premedication (see Section 4.1.4.1).

Trial medication infusion (see Section 4.1.4).

Administration of chemotherapy (see Section 4.1.4.1). 


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Cycles 2, 3, 4, 5, 6
The following will be performed/collected:

Urine pregnancy test for women of childbearing potential to be performed every 6 weeks
starting at Cycle 3 (serum pregnancy test to be performed in case of positive urine 
pregnancy test).

Physical examination, including weight (kg) (see Section 5.2.5).

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.2.5).

Laboratory testing (serum chemistry, hematology, urinalysis and coagulation; see Section 
5.2.3).

12-lead ECG (to be performed at Cycle 3 and 5 only) see Section 5.2.4).

Previous and concomitant medications (see Section 4.2).

Assessment of AEs (see Section 5.2.2).

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and involved 
area, if applicable). A PET scan can be performed in addition to the tumor assessment CT 
scan (see Section 5.1.2.1) (to be performed at Cycle 3 and 5 only). Tumor assessment 
must be available before administration of trial medication at Cycles 3 and 5. During the 
induction phase, the tumor evaluations must be performed every 2 cycles. Therefore, if a
cycle is delayed, the next tumor evaluation will also be delayed.

ECOG PS (to be performed at Cycle 3 and 5 only).

Survival.

Contact IXRS® (see Section 4.1.2)

Administration of premedication (see Section 4.1.4.1).

Trial medication infusion (see Section 4.1.4).

Administration of chemotherapy (see Section 4.1.4.1). Paclitaxel/carboplatin 
chemotherapy will be administered every 3 weeks.
Cycle 7 to Cycle 10 and onwards
The following will be performed/collected:

Urine pregnancy test for women of childbearing potential (to be performed every 6 weeks
starting at Cycle 7). Serum pregnancy test to be performed in case of positive urine
pregnancy test.

Physical examination, including weight (kg) (see Section 5.2.5).

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.2.5).

Laboratory testing (serum chemistry, hematology, urinalysis and coagulation; see 
Section 5.2.3).


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
12-lead ECG (to be performed at Cycles 7, 10, and every 3 cycles thereafter, see 
Section 5.2.4).

Concomitant medications (see Section 4.2).

Assessment of AEs (see Section 5.2.2).

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and involved 
area, if applicable). A PET scan can be performed in addition to the tumor assessment CT 
scan (see Section 5.1.2.1) (to be performed at Cycles 7, 10, and every 3 cycles thereafter).
In case of a treatment cycle delay (i.e. due to toxicity), imaging assessment (e.g. CT, 
MRI) for the primary endpoint will be performed at Week 18 ±14 days (fixed time point), 
regardless of the number of cycles administered to date and whether or not this 
assessment coincides with Cycle 7. After Week 18, if a cycle is delayed, tumor 
assessment will also be delayed.

ECOG PS (to be performed at Cycles 7, 10, and every 3 cycles thereafter).

Survival

Contact IXRS® (see Section 4.1.2)

Trial medication infusion (see Section 4.1.4).
Switch Visit, prior to Avastin® administration:
Prior to Avastin® administration, all patients on active treatment must undergo the following 
assessments:

Serum pregnancy test.

Physical examination, including weight (kg) (see Section 5.2.5).

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.2.5).

Laboratory testing (serum chemistry, hematology, urinalysis and coagulation; see 
Section 5.2.3).

12-lead ECG (see Section 5.2.4).

Concomitant medications (see Section 4.2).

Assessment of AEs (see Section 5.2.2).

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and involved 
area, if applicable; to be performed only if a tumor assessment was not performed within 
the previous 4 weeks). A PET scan can be performed in addition to the tumor assessment 
CT scan (see Section 5.1.2.1).

ECOG PS.

Survival.

Contact IXRS® (see Section 4.1.2)


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
Trial medication infusion (see Section 4.1.4).
6.2.3
End of trial and follow-up period
End of Treatment Visit
All patients who receive at least one infusion of BI 695502 or US-licensed Avastin® and 
who discontinue the trial at any time after Day 1 (but do not withdraw their consent) will be 
required to have all of the evaluations for the EOT visit as soon as possible and in any case 
within 21 days after the last administration of BI 695502 or Avastin®. 
The following will be performed/collected:

Serum pregnancy test.

Physical examination, including weight (kg) (see Section 5.2.5).

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.2.5).

Laboratory testing (serum chemistry, hematology, urinalysis and coagulation; see 
Section 5.2.3).

12-lead ECG (see Section 5.2.4).

Concomitant medications (see Section 4.2).

Assessment of AEs (see Section 5.2.2).

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and involved 
area, if applicable). A PET scan can be performed in addition to the tumor assessment CT 
scan (see Section 5.1.2.1).

ECOG PS.

Survival.
Non-treatment period
For all patients who discontinue trial medication for reasons other than disease progression,
but do not withdraw consent, the following will be performed/collected every 3 weeks after 
the EOT visit until death, disease progression, or initiation of a new treatment, whichever 
occurs earlier.

Physical examination, including weight (kg) (see Section 5.2.5).

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.2.5).

Laboratory testing (serum chemistry, hematology, urinalysis and coagulation; see 
Section 5.2.3).

12-lead ECG (see Section 5.2.4).

Concomitant medications (see Section 4.2).

Assessment of AEs (see Section 5.2.2).


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
Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and involved 
area, if applicable). A PET scan can be performed in addition to the tumor assessment CT 
scan (see Section 5.1.2.1) (to be performed at the investigator’s discretion, or at a 
minimum of every 3 cycles [approximately every 9 weeks]).

ECOG PS.

Survival.
If a patient remains in the non-treatment period beyond 18 weeks post last dose of trial 
medication, he/she will be treated according to standard of care, and assessed for tumor 
progression every 6-9 weeks according to clinical judgment. The following will be 
performed/collected:

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and involved 
area, if applicable). A PET scan can be performed in addition to the tumor assessment CT 
scan (see Section 5.1.2.1).

Assessment of AEs (see Section 5.2.2).

Date of disease progression (if applicable).
Safety Follow-up Visit
The SFU visit will be performed 18 weeks after the last administration of 
BI 695502/US-licensed Avastin® prior to the switch visit. If the patient continues to receive 
treatment with Avastin® beyond 18 weeks post last IP dose, then no SFU visit will be 
performed. The following will be performed/collected:

Concomitant medications (see Section 4.2).

Assessment of AEs (see Section 5.2.2).

Date of initiation of second-line therapy (if applicable).

Survival.

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.2.5).
Survival monitoring
After the SFU visit or discontinuation of Avastin® (whichever occurs later), all patients who 
remain in the trial will be monitored via telephone call for survival every 3 months.
End of trial definition
The trial will be closed when all randomized and treated patients have either died, are lost to 
follow-up, or have withdrawn consent, or for a maximum of 20 months after the last patient
randomized plus the EOT visit, whichever occurs earlier. 


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The sponsor may also elect to discontinue clinical investigations under this trial for any 
reason, at any time.
Unscheduled visit assessments
Patients may attend the trial site for unscheduled visits at any time for additional safety 
monitoring at the discretion of the investigator. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a randomized, double-blind, active-controlled multicenter trial. The primary objective 
is to show statistical equivalence based on the clinical efficacy endpoint. The primary 
endpoint will be measured as best ORR, defined as the proportion of patients with CR or PR 
(not required to be confirmed by a subsequent assessment) according to RECIST criteria 1.1 
as assessed by central imaging review until 18 weeks after start of treatment. The ORR ratio
between BI 695502 versus US-licensed Avastin® will be used for analysis of the primary 
endpoint.
Patients will be treated with one of the two different compounds (BI 695502 plus 
chemotherapy or US-licensed Avastin® plus chemotherapy).
Secondary objectives are the evaluation of additional efficacy parameters and safety and 
tolerability of BI 695502 versus US-licensed Avastin®. 
 
The analysis of the primary efficacy endpoint is not impacted by the switch from BI 695502 
to Avastin® as all patients had already completed the Week 18 assessment at the time of the 
transition. The main analyses will cover the period up until patients were switched from 
BI 695502 to Avastin® in the BI 695502 group and data will be analyzed to the extent 
available. Adverse events will be presented by underlying treatment and taking the 
corresponding exposure into account.
Additionally, after the transition from BI 695502 to Avastin® in the BI 695502 group, the 
impact of switching will be assessed based on the occurrence of relevant adverse events after 
the transition, i.e. anaphylactic reactions/hypersensitivity reactions/infusion-related reactions 
and the occurrence of anti-drug antibodies by comparing switched patients and patients 
staying continuously on Avastin®. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
The primary test for equivalence will be performed with respect to BI 695502 versus 
US-licensed Avastin®. The primary hypothesis is based on the ratio in best ORR between the 
two treatments:
H0: Ratio in best ORR by Week 18 (BI 695502 versus US-licensed Avastin®) ≤0.736 or 
≥1.359.
H1: Ratio in best ORR by Week 18 (BI 695502 versus US-licensed Avastin®) within the 
interval (0.736, 1.359).
The null hypothesis will be rejected in favor of equivalence if the two-sided 90% CI for the 
ratio in best ORR between the treatments falls completely within the range defined by the 
equivalence margin; i.e., the comparison will be based on two one-sided tests (TOST) with a 


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5% type I error rate. The TOST procedure controls the overall type I error rate at alpha=5% 
(R14-3718).
The equivalence margin (0.736, 1.359) for ORR ratio is based on a meta-analysis that
included the following three studies: Sandler et al 2006 (R07-1161), Niho et al 2012 
(R14-0473), and Johnson et al 2004 (R04-4661). The rationale to include these studies was to 
meet the following criteria:

Studies being representative for efficacy effect of Avastin® and BI 695502 in the 
intended 1302.5 trial population as measured by comparing the ratio of best ORR.

All data used were taken from studies with a backbone chemotherapy control arm.

Only studies using the identical backbone therapy as planned in trial 1302.5 
(paclitaxel 200 mg/m2 followed by carboplatin target AUC 6) were considered to 
ensure homogeneity and representativeness of the reference data to the planned trial 
1302.5. All data used were taken from studies or study arms excluding squamous cell 
type.

All data used were taken from studies or study arms with a dosing regimen of 
15 mg/kg Avastin®.
Table 7.2: 1 summarizes the estimation results of the treatment effect of Avastin® over
control using a fixed effects meta-analysis of the three reference studies based on the ORR 
ratio between Avastin® plus chemotherapy and carboplatin-paclitaxel chemotherapy alone. 
Table 7.2: 1
Meta-analysis of ORR ratio
Avastin®
Control
Source
Events
Total N
ORR
Events
Total N
ORR
Weight
ORR ratio
Sandler (2006)
133
381
34.9%
59
392
15.1%
64.4%
2.319
Niho (2012)
71
117
60.7%
18
58
31.0%
28.6%
1.955
Johnson (2013)
16
32
50.0%
5
25
20.0%
6.5%
2.500
Total 
(weighted)
43.3%
20.0%
2.220
ORR = overall response rate
Calculations based on Metacalc v3.0  
The calculated ORR of Avastin® combined with paclitaxel and carboplatin in nsNSCLC is 
43.3% and the ORR ratio for Avastin® versus chemotherapy alone is 2.220 with a 90% CI of 
(1.847, 2.668) across all studies included in the meta-analysis (Table 7.2: 1).  
The non-inferiority margin is chosen in a conservative way to preserve 50% of the lower 90% 
CI bound on the log-ratio scale. This corresponds to an equivalence margin of (0.736, 1.359) 
on the ORR ratio scale.
In this equivalence trial, the test of the primary hypothesis and the corresponding equivalence 
margin are designed in order to provide evidence of clinical similarity; i.e., absence of a 
clinically meaningful difference between BI 695502 versus US-licensed Avastin® with 


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respect to the primary endpoint best ORR. If, for example, best ORR of BI 695502 is 
estimated at 37.6% and the best ORR of US-licensed Avastin® at 43.3% then the ratio in best 
ORR by Week 18 (BI 695502 versus US-licensed Avastin®) would equal 0.867 with a 90% 
CI of (0.741,1.013), and then the primary null hypothesis could be rejected. This corresponds 
to a difference between the treatments that is clinically not meaningful. Thus the choice of the 
equivalence margin is justified on both clinical and statistical grounds.
For details of the margin calculation and justification refer to Appendix 10.6.
7.3
PLANNED ANALYSES
The primary analysis set will be the full analysis set (FAS) according to the intention-to-treat 
principle. The FAS will consist of all randomized patients who receive at least one dose of 
trial medication and have a baseline tumor assessment. Patients will be assigned to the 
treatment to which they were randomized. 
Additionally a per-protocol set (PPS) of patients following the CTP in all essential criteria 
will be created for sensitivity analyses. Patients included in the FAS who have important CTP 
violations will be excluded from the PPS. A CTP violation will be considered important if it 
can be expected to have a distorting influence on the assessment of the primary endpoint. 
Important CTP violations include but are not limited to:

Randomized trial medication not administered or incorrect trial medication administered.

Major violation of treatment compliance.

Major violation of inclusion criteria.
All patients treated with at least one dose of trial medication (treated set) will be included in 
the safety evaluation.
For the handling of missing values refer to Section 7.4.
The main analyses will cover the period up until patients were switched from BI 695502 to 
Avastin® in the BI 695502 group and data will be analyzed to the extent available; the above 
described definitions for the analysis populations will be applied. Appropriate censoring 
methods will be applied at the time of switching and will be defined in the TSAP.
Exploratory analyses will be performed based on all available data beyond the timepoint of 
switching with side-by-side displays of the BI 695502/Avastin® and Avastin® treatment 
groups. No additional analysis populations will be defined.


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7.3.1
Primary analyses
7.3.1.1
Primary ORR ratio analyses
The primary endpoint of the study is the best ORR, defined as the proportion of patients with 
CR or PR (not required to be confirmed by a subsequent assessment according to 
RECIST 1.1, R09-0262) as assessed by central imaging review until 18 weeks after the start 
of treatment. The best ORR ratio between BI 695502 versus US-licensed Avastin® will be 
used for analysis of the primary endpoint.
The primary analysis will be based on the FAS and will be performed after centrally 
reviewed tumor response assessments have been provided for all patients of the primary 
analysis population for the biosimilarity hypothesis testing. Overall response rate will be 
evaluated from date of randomization until either progression, treatment stop for 
unacceptable toxicity, death or up to 18 weeks, whichever happens earlier. The data of the 
primary analysis population for biosimilarity will be unblinded at the time point of the 
primary analysis only for the team members involved in the analysis (including the sponsor 
and the CRO). For details on unblinding procedures see Section 4.1.5.1. 
The primary analysis is based on a log binomial regression model (R14-3815) with 
subsequent transformation of the estimated parameters to the ratio in best ORR including the 
respective CI.
The statistical model will be:
log (E{ORR}) = treatment + sex + smoking status + NSCLC stage + ethnicity
The difference in log(best ORR) between BI 695502 and US-licensed Avastin® will be 
estimated, with 90% CI, adjusted for sex, smoking status, NSCLC stage, and ethnicity. The 
estimate and CI will be exponentiated to return to the ratio scale.
This model includes the following explanatory variables: treatment, sex (male versus female), 
smoking status (never smoked versus current/past smoker), NSCLC stage (recurrent versus
Stage IV) and ethnicity (East Asian origin versus non East Asian). In case of sparse data in 
one (or more) strata which affects the convergence of the model the respective factors may be 
omitted in the model.
For the handling of missing primary efficacy assessment scores see Section 7.4.1. For the 
assessment of the primary efficacy endpoint best ORR at Week 18 a time window of 
±14 days will be applied. 
Equivalence will be declared if the two-sided 90% CI for the ORR ratio between BI 695502
and US-licensed Avastin® falls completely between the lower margin bound of 0.736 and the 
upper margin bound of 1.359.
For details on the statistical model and the equivalence test refer to Appendix 10.6.2.


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7.3.1.2
Sensitivity analyses for the primary endpoint best ORR 
To assess the robustness of the results, the primary analysis will be repeated using the PPS 
population. The same model will be employed as for the primary analysis. A further 
sensitivity analysis will be based on investigator overall response assessment employing the 
same methods and statistical model as used in the primary analysis.
To further assess the robustness of the results, the primary analysis will be repeated for an 
additional way of calculating the equivalence margin and corresponding hypothesis test. 
An equivalence margin (0.727, 1.376) for the ORR ratio preserves 3/5 of the point estimate of 
the historical treatment effect of Avastin® based on the same meta-analysis that was used for 
the primary hypothesis on the log-ratio scale. If the two-sided 95% CI for the ORR ratio falls 
completely within the range defined by the equivalence margin (0.727, 1.376), equivalence 
would be shown with the TOST procedure following a more strict alpha=2.5% type I error 
rate. 
7.3.2
Secondary analyses
Secondary analyses include:

PFS: A Cox-proportional hazards (PH) model using the same adjustment factors as for 
best ORR ratio will be used to assess PFS. Progression-free survival is defined as the time 
from randomization until disease progression or death. Disease progression is assessed 
according to the RECIST 1.1 response criteria for NSCLC. 

OS: A Cox-PH model using the same adjustment factors as for best ORR ratio will be 
used to assess OS. Overall survival is defined as the time from randomization until death 
from any cause. Overall survival data will be collected every 3 months.

Duration of response: A Cox-PH model using the same adjustment factors as for best
ORR ratio will be used to assess Duration of response. Duration of response is defined as 
the time from first documented CR or PR until time of progression as per investigator 
assessment.
7.3.3
Other analyses
Other analyses will explore the influence of different number of cycles on the primary 
endpoints. For this purpose, number of cycles will be added as an independent, fixed effect 
factor to the primary analysis models, if sufficient data for both groups are available.
In addition, other analyses will explore the influence of country/region on the primary 
endpoint. For this purpose the primary analysis model will additionally include 
country/region as a fixed effect; small countries/regions may be combined.
A further analysis will assess the best ORR until progression or death (instead of until 
18 weeks) based on investigator assessment employing descriptive statistical methods.


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7.3.4
Safety analyses
All safety data, including secondary safety parameters, will be displayed and analyzed using 
descriptive statistical methods. No formal inferential analysis is planned for safety 
comparisons. For AEs selected for comparability assessment, separate tables will be 
displayed including descriptive CIs comparing the proportion of patients with AEs selected 
for comparability assessment.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA). Adverse events will be assigned to the screening phase, as appropriate. All AEs 
with an onset after the first dose of trial medication up to a period of 16 weeks after the last 
dose of the trial medication will be assigned to the treatment phase for evaluation and will be 
considered as treatment-emergent AEs. Severity of AEs will be reported using the 
NCI-CTCAE version 4.0 criteria (see Section 5.2.2). Frequencies of AEs will be derived and 
compared for the treatment groups BI 695502 and US-licensed Avastin®. Adverse events 
potentially related to immunogenicity will also be evaluated.
Laboratory values taken after the first dose of trial medication up to a period of 16 weeks 
after the last dose of the trial medication will be assigned to the treatment phase for 
evaluation. Laboratory values will be graded according to the NCI-CTCAE version 4.0 and 
reported by frequency for each treatment group. Non-graded laboratory parameters will be 
compared to their reference ranges and frequency tables will be provided for the number of 
patients within and outside the reference range.
Changes in blood pressure, pulse rate and ECG parameters will be summarized by treatment 
group.
7.3.5
Interim analyses
No interim analysis will be performed in this trial.
7.3.5.1
DSMB analyses
The DSMB analyses will be performed as specified in the DSMB charter.
An early safety analysis will be reviewed after approximately 20 patients per arm have been 
treated for 3 cycles (40 evaluable patients). To keep the trial blinded, the safety analysis will 
be reviewed by the DSMB using descriptive statistics of AEs. If no unexpected changes in 
the known safety profile for Avastin® are observed for BI 695502, the DSMB will 
recommend continuing the trial. An indirect comparison with historical safety data for 
Avastin® might also be considered by the DSMB.
The DSMB will review patient safety on an ongoing basis. For the DSMB analyses, no 
interim reports will be provided to the sponsor. Since May 2016, there have been 5 regularly 
spaced DSMB meetings, all of which recommended continuation of the trial without 
modification.


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7.3.5.2
Blinded review of sample size assumption
The fully blinded, pooled ORR will be closely monitored to verify the sample size 
assumptions. After approximately 200 patients (100 patients per arm) have had tumor 
response assessments performed until Week 18, an independent blinded statistician will 
perform a blinded evaluation to confirm the initially calculated sample size.
The blinded sample size assumption review will take into consideration whether blinded 
results observed so far allow for sufficient precision and power of the primary analysis. In 
case that the pooled ORR is substantially below 40%, the sample size and the primary 
analysis model will be revisited.
No formal statistical testing for efficacy will be performed.
7.3.5.3
Primary analysis time point and follow-up analysis time point
As described in Section 7.3.1 the primary analysis will take place when all primary efficacy 
endpoint data are available, i.e., after all patients have had tumor response assessments 
performed after Week 18, or earlier if no more patients are expected to complete the Week 18 
visit. At this point all data including safety data will be evaluated. The data will be unblinded 
at the time point of the primary analysis for the team members involved in the analysis 
(including the sponsor and its designees). All other team members will remain blinded until 
the final unblinding. The results will be summarized in a CTR (primary analysis of efficacy 
and safety).
A follow-up analysis will be conducted at a later time point, as required by the regulatory 
authorities. In this follow-up analysis, all analyses performed at the primary analysis time 
point will be repeated with the (partially) updated data, in particular with respect to safety and 
the endpoints collected. The results of this analysis will be summarized in a follow-up CTR. 
For details on unblinding procedures, see Section 4.1.5.1.


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7.4
HANDLING OF MISSING DATA
7.4.1
Efficacy endpoints
The central imaging unit will work with the clinical sites towards a standard implementation 
of the RECIST 1.1 criteria. An imaging charter will detail all procedures, including quality 
control and the criteria needed to handle missing assessments. 
For response assessment, drop out due to disease progression or death will be classified to 
“disease progression” response category. For the primary endpoint, in order to preserve any 
observed difference between treatment groups, best ORR will be assumed to be missing at 
random. Robustness of the primary conclusion to the missing at random assumption will be 
evaluated by sensitivity analyses that will take account of the reason for discontinuation.  
7.4.3
Safety and other endpoints
For safety and other endpoints rules for handling of missing data will be specified in the 
TSAP.
7.5
RANDOMIZATION
Patients may be pre-randomized in a blinded fashion to either BI 695502 or US-licensed 
Avastin® at screening (see Section 4.1.2 for details). At Day 1 patients will be randomized to 
double-blind treatment according to their pre-randomization, if applicable. Patients who do 


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not meet all the inclusion criteria or meet one or more of the exclusion criteria will not be 
randomized and will be considered screen failures.
For biosimilarity evaluation, patients in the trial will be randomly assigned in a blinded 
fashion to either BI 695502 or US-licensed Avastin® with a 1:1 allocation ratio. The 
randomization will be stratified by the following variables:

Sex (male versus female)

Smoking status (never smoked versus current/past smoker)

NSCLC stage (recurrent versus Stage IV).

Ethnicity (East Asian origin versus non East Asian)
Randomization will be performed by IXRS®. Boehringer Ingelheim Pharma GmbH & Co. 
KG, Clinical Trial Support Group or a CRO appointed by the sponsor will provide the 
randomization list using a validated randomization number generating system. Access to the 
randomization code will be controlled and documented. Boehringer Ingelheim/Quintiles will 
not have access to the randomization assignments generated by the IXRS®. All persons 
directly involved in the conduct and analysis of the trial will have no access to the treatment 
allocation prior to final database lock. The data of the primary analysis population for 
biosimilarity evaluation will be unblinded at the time point of the primary analysis only for 
the team members involved in the analysis (including the sponsor and CRO) (see 
Section 4.1.2 and Section 4.1.5). On an individual patient basis, the drug administered may be 
revealed during pharmacovigilance activities. The block size(s) of the randomization will be 
documented in the CTR.


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7.6
DETERMINATION OF SAMPLE SIZE
The sample size is approximately N = 660 patients (n = 330 per treatment arm) based on an 
ORR ratio of 1.000, an equivalence margin of (0.736, 1.359) on the ORR ratio scale and a 
power of 92%. The equivalence margin is based on meta-analysis (see Section 7.2).
Using the above equivalence margin, the total sample size (N = 660) is robust with respect to 
the assumed ORR effect size in both arms and the assumed ORR ratio. A high power is 
ensured even if the observed ORR effect size is slightly lower than calculated from the trials 
included in the meta-analysis (Table 7.6: 1). 
Table 7.6: 1
Robustness of trial design with respect to power (primary hypothesis)
ORR
36%
38%
40%
43.3%
Power
80%
84%
88%
92%
ORR = overall response rate
Calculations based on Addplan v6.0.4
Based on this sample size of N = 660, if the sensitivity analysis margin (0.727, 1.376) for the 
ORR ratio would be tested with the TOST procedure following a more strict alpha=2.5% 
type I error rate, a similarly high power would be achieved (Table 7.6: 2). 
Table 7.6: 2
Robustness of trial design with respect to power (sensitivity analysis)
ORR
36%
38%
40%
43.3%
Power
72%
78%
82%
88%
ORR = overall response rate
Calculations based on Addplan v6.0.4
For details of the sample size calculation refer to Appendix 10.6.3.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
GCP and relevant BI Standard Operating Procedures (SOPs). Standard medical care 
(prophylactic, diagnostic and therapeutic procedures) remains in the responsibility of the 
treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the trial patients against any immediate hazard, and also of any serious breaches of 
the protocol/ICH GCP and the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997).
The rights of the investigator (trial site – Japan only) and of the sponsor with regard to 
publication of the results of this trial are described in the investigator contract (trial site’s 
contract – Japan only). As a general rule, no trial results should be published prior to 
finalisation of the CTR.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/IEC and CA according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional 
patient-information form retained by the investigator as part of the trial records. A signed 
copy of the informed consent and any additional patient information must be given to each 
patient or the patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his/her medical records may be examined by authorized 
monitors (Local Clinical Monitor/Clinical Research Associate [CRA]) or Clinical Quality 
Assurance auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities.


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Starting as of 21 Dec 2017, all patients will be informed verbally by the investigator about 
the switch from BI 695502 to Avastin®. Once the updated ICF is available, written informed 
consent must be obtained from each patient (or the patient’s legally accepted representative) 
according to ICH GCP and to the regulatory and legal requirements of the participating 
country.  
Japan only: The investigator must give a full explanation to trial patients by using the patient 
information form, which is prepared avoiding the use of technical terms and expressions. The 
patient is given sufficient time to consider participation in the trial. The investigator obtains 
written consent of the patient’s own free will with the informed consent form after 
confirming that the patient understands the contents. The investigator must sign (or place a 
seal on) and date the informed consent form. If a trial collaborator has given a supplementary 
explanation, the trial collaborator also signs (or places a seal on) and dates the informed 
consent.
The following items need to be included:
1. That the clinical trial is aimed at testing.
2. Objectives of the trial.
3. The name, title, and address of the investigator to contact.
4. Trial procedures.
5. Anticipated benefits of the investigational products and anticipated disadvantages to the 
patient.
6. Matters concerning other therapeutic measures.
7. Duration of participation in the clinical trial.
8. That the patient may withdraw from the trial at any time.
9. That patient’s refusal of or withdrawal from participation in the trial does not cause any 
disadvantage to him or her.
10. That the monitors, the auditors, and the IRB are given access to the relevant source 
documents on condition that confidentiality of the patient is fully secured.
11. That privacy of the patient is kept.
12. The office of the medical institution to contact in the event of trial-related injury.
13. That necessary treatment is available to the patient in the event of trial-related injury.
14. Matters concerning compensation in the event of any trial-related injury.
15. The type of the IRB which is used for the reviews and deliberations on the matters such 
as appropriateness of conducting the clinical trial, the matters to be reviewed and deliberated 
by each IRB, and other matters concerning the IRBs involved in the clinical trial.
16. Other necessary matters concerning the clinical trial.


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In case of partner’s pregnancy, written consent for pregnancy follow-up will be requested. 
Follow-up on the pregnancy and its outcome will be performed to evaluate whether there are 
risks to the pregnant woman or the unborn fetus.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case report forms for individual patients will be provided by the sponsor, either on paper or 
via remote data capture. See Section 4.1.5.2 for rules about emergency code breaks. For drug 
accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. All 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g., FDA). The CRA/on-site monitor 
and auditor may review all CRFs/eCRFs, and written informed consents. The accuracy of the 
data will be verified by reviewing the documents described in Section 8.3.1.


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8.3.3
Storage of records
Japan only: 
Storage period of records
Trial sites: The trial sites must retain the source documents and essential documents for a 
period defined by the Japanese GCP regulation and the sponsor’s SOP.
Sponsor: The sponsor must retain the essential documents according to the sponsor’s SOPs.
When it is no longer necessary for the trial site to retain the source documents and essential 
documents, the sponsor must notify the head of trial site.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfill the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular AE is "listed", i.e., is a known side effect of the drug or not. Therefore a 
unique reference document for the evaluation of listedness needs to be provided. For 
BI 695502 this is the current version of the Investigator’s Brochure. The current version of 
this reference document is to be provided in the ISF. Expected AEs are listed in the most 
current version of the EU Summary of Product Characteristics (SPC) and the US Prescribing 
Information for Avastin® (R15-1223, R18-0043). For the non-investigational medicinal 
products, the reference document for paclitaxel is the UK SPC and for carboplatin the UK 
SPC. The current versions of these reference documents are to be provided in the ISF.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of SAEs, e.g., suspected unexpected serious adverse reactions (known as 
SUSARs) to health authorities and IECs/IRBs, will be done according to local regulatory 
requirements. Progression of underlying disease and death due to progression of underlying 
disease are considered as outcome events and are not to be reported as SAEs. Further details 
regarding this reporting procedure are provided in the ISF. 
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities.


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8.6
COMPLETION OF TRIAL
Additional information for EU member states:
The ethics committee/CA in each participating EU member state needs to be notified about 
the end of the trial (last patient out, unless specified differently in Section 6.2.3 of the CTP) 
or early termination of the trial.
Japan only:
When the trial is completed, the investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
sponsor of the completion in writing.
8.7
PROTOCOL VIOLATIONS
Japan only:
The investigator or sub-investigator should record all CTP violations regardless of their 
reasons. Only when the protocol is not followed in order to avoid an immediate hazard to trial 
patients or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
Japan only:
In the event of health injury associated with this trial, the sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R13-1113
Ferlay J, Shin HR, Bray F et al. Estimates of worldwide burden of cancer in 
2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.  
R18-0043
Avastin (bevacizumab) solution for intravenous infusion (Genentech) (U.S. 
prescribing information, revised: 12/2017). 2017
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125085s319lbl.p
df  (access date 10 January 2018)
R15-1223
Avastin®: European Public Assessment Report – Summary of Product 
Characteristics, 21/07/2017. 
02/06/2017  Avastin -EMEA/H/C/000582 –II/0092
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000582/WC500029271.pdf (access date 
17 October 2017)
P14-01224
Lu C; Onn A, Vaporciyan AA et al. "78: Cancer of the Lung". Holland-Frei 
Cancer Medicine (8th ed.). Sheldon, Connecticut. People's Medical 
Publishing House. 2010.  
R11-0052
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging 
Project: proposals for the revision of the TNM stage groupings in the 
forthcoming (seventh) edition of the TNM Classification of malignant 
tumours. J Thorac Oncol. 2007;2(8):706-14.  
R09-5804
Clegg A; Scott DA, Hewitson P, et al. Clinical and cost effectiveness of 
paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung 
cancer: a systematic review. Thorax (BMJ Publishing Group). 
2002;57(1):20–28.  
R08-4164
Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing 
cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-
naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 
2008;26(21):3543-51.
R13-5402
D'Addario G, Pintilie M, Leighl NB, et al. Platinum-based versus non-
platinum-based chemotherapy in advanced non-small-cell lung cancer: a 
meta-analysis of the published literature. J Clin Oncol. 2005;23(13):2926-36.


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R04-1314
Schiller JH, Harrington D, Belani CP, et al. Comparison of four 
chemotherapy regimens for advanced non–small-cell lung cancer. N Engl J 
Med. 2002;346:92-8.
R05-1052
Sandler AB, Johnson DH, Herbst RS. Anti-vascular endothelial growth factor 
monoclonals in non-small cell lung cancer. Clin Cancer Res. 2004;10:4258s-
4262s.
R07-1161
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;355:2542-50.
R10-4848
National Cancer Institute Common Terminology Criteria Adverse Events 
(NCI-CTCAE); Version 4.0. website: ctep.cancer.gov/reporting/ctc.html.
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation 
criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45:228-47.
R12-3779
Azzoli CG, Temin S, Aliff T, et al. 2011 Focused Update of 2009 American 
Society of Clinical Oncology Clinical Practice Guideline Update on 
Chemotherapy for Stage IV Non–Small-Cell Lung Cancer. J Clin Oncol.
2011;29:3825-31.
R14-0472
Soria JC, Mauguen A, Reck M, et al. Systematic review and meta-analysis of 
randomised, phase II/III trials adding bevacizumab to platinum-based 
chemotherapy as first-line treatment in patients with advanced non-small-cell 
lung cancer. Ann Oncol. 2013;24:20-30.
R14-0473
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;76:362-7.
R04-4661
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.
R11-0050
Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-
gemcitabine and bevacizumab or placebo as first-line therapy for 
nonsquamous non-small-cell lung cancer: results from a randomised phase III 
trial (AVAiL). Ann Oncol. 2010;21:1804-9.


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R13-5425
Patel JD, Socinski MA, Garon EB. PointBreak: A Randomized Phase III 
Study of Pemetrexed Plus Carboplatin and Bevacizumab Followed by 
Maintenance Pemetrexed and Bevacizumab Versus Paclitaxel Plus 
Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in 
Patients With Stage IIIB or IV Nonsquamous Non-Small-Cell Lung Cancer. J 
Clin Oncol 2013;31:4349-57.
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Socinski MA, Schell MJ, Peterman A. Phase III trial comparing a defined 
duration of therapy versus continuous therapy followed by second-line 
therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 
2002;20:1335-43.
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Johnson BE, Kabbinavar F, Fehrenbacher L. ATLAS: Randomized, Double-
Blind, Placebo-Controlled, Phase IIIB Trial Comparing Bevacizumab 
Therapy With or Without Erlotinib, After Completion of Chemotherapy, 
With Bevacizumab for First-Line Treatment of Advanced Non-Small-Cell 
Lung Cancer. J Clin Oncol 2013;31:3926-34.
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Giaccone G. Epidermal growth factor receptor inhibitors in the treatment of 
non-small-cell lung cáncer. J Clin Oncol. 2005;23(14):3235-42.
R12-1015
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard 
chemotherapy as first-line treatment for European patients with advanced 
EGFR mutation-positive non-small-cell lung cancer (EURTAC): a 
multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 
2012;13:239–46. 
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Camidge DR, Bang YJ, Kwak EL et al. Activity and safety of crizotinib in 
patients with ALK-positive non-small-cell lung cancer: updated results from 
a phase 1 study. Lancet Oncol. 2012 Oct;13(10):1011-9.
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Wu Y-L, Zhong W-Z, Li L-Y, et al. Epidermal growth factor receptor 
mutations and their correlation with gefitinib therapy in patients with non-
small cell lung cancer: a meta-analysis based on updated individual patient 
data from six medical centers in mainland China. J Thoracic Oncol. 
2007;2(5):430-439.  
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Berger RL and Hsu JC. Bioequivalence trials, intersection-union tests and 
equivalence confidence sets. Statistical Science. 1996;11:283-319.
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Spiegelman D and Hertzmark E. Easy SAS Calculations for Risk or 
Prevalence Ratios and Differences. Am J Epidemiol. 2005;162:199–200.


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9.2
UNPUBLISHED REFERENCES
Not applicable.


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10.
APPENDICES
10.1
GUIDELINES FOR EVALUATION OF OBJECTIVE TUMOR RESPONSE 
USING RECIST 1.1 CRITERIA (RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS)
INTRODUCTION
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 Guidelines (R09-0262) for the 1302.5 trial with regards to Investigator 
assessment of tumor burden including protocol-specific requirements for this trial.
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET AND 
NON-TARGET LESIONS
Only patients with measurable disease at baseline should be included in the study. 
Measurable disease is defined by the presence of at least one measurable lesion which has not 
been irradiated within 12 weeks prior to the date of randomization.
Measurable:

For tumor lesions: the longest diameter in the plane of measurement has to be 
recorded with a minimum size of 10 mm by computed tomography (CT) scan when 
CT scan slice thickness is no greater than 5 mm or by magnetic resonance imaging 
(MRI) and which is suitable for accurate repeated measurements.

For nodal lesions: at baseline and in the follow-up, only the short axis of lymph node 
will be measured and followed. To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed at baseline.
Non-measurable:

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15 mm short axis at baseline). Nodes with <10 mm short 
axis are considered non-pathological and should not be recorded or followed as 
non-target lesions (NTL).

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural / pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI.

Measurable previously irradiated lesions where other measurable lesions are available 
for assessment as target lesions and lesions irradiated within 12 weeks of 
randomization.

Skin lesions assessed by clinical examination,


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Special Cases:

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. Blastic lesions are considered non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient, these should be selected as target lesions.
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as 
target lesions (TL) at baseline.
Non-Target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.
METHODS OF ASSESSMENT
The same method of assessment and the same technique should be used to characterize each 
identified and recorded lesion at baseline and during follow-up visits.
CT and MRI
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and 
identification of any new lesions.
In the 1302.5 trial, CT or MRI examinations of the chest and abdomen, including adrenals, 
will be used to assess tumor burden at baseline and follow-up visits. CT examination with i.v. 
contrast media administration is the preferred method. MRI with contrast (Gadolinium) 
should be used where CT is not feasible or it is medically contra-indicated. For brain lesion 
assessment, MRI is the preferred method.


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Clinical examination
In the 1302.5 trial, clinical examination will not be used for assessment of TL. Clinically 
detected lesions can be selected as target lesions if they are assessed by CT or MRI scans. 
Clinical examination can be used to assess NTL and to identify the presence of new lesions.
X-ray
Chest X-ray
In the 1302.5 trial, chest X-ray assessment will not be used for assessment of TL as they will 
be assessed by CT examination or MRI examination. Chest X-ray can, however, be used to 
assess NTL and to identify the presence of new lesions.
Plain X-ray
In the 1302.5 trial, plain X-ray may be used as a method of assessment for bone NTL and to 
identify the presence of new bone lesions.
Ultrasound
In the 1302.5 trial, ultrasound examination will not be used for assessment of TL and NTL as 
it is not a reproducible method, does not provide an accurate assessment of tumor size and it 
is subjective and operator dependent. Ultrasound examination can, however, be used to 
identify the presence of new lesions. If new clinical symptoms occur and an ultrasound is 
performed then new lesions should be confirmed by CT or MRI examination.
Endoscopy and laparoscopy
In the 1302.5 trial, endoscopy and laparoscopy will not be used for tumor assessments as they 
are not validated in the context of tumor assessment.
Tumor markers
In the 1302.5 trial, tumor markers will not be used for tumor response assessments as per 
RECIST 1.1.
Cytology and histology
In the 1302.5 trial, histology will not be used as part of the tumor response assessment as per 
RECIST 1.1.
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumor has met criteria for response or 
stable disease. In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (PD) (if the neoplastic origin of the fluid is confirmed). Where cytology findings are 
not available, any effusion that significantly worsens (from trace to large) or appearance of 


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clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTL, or disease progression due to new lesions.
Isotopic bone scan
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or 
X-ray at baseline should be recorded as NTL and followed by the same method as per 
baseline assessment.
In the 1302.5 trial, isotopic bone scans may be used as a method of assessment to identify the 
presence of new bone lesions at follow-up visits. New lesions will be recorded where a 
positive hot-spot that was not present on the baseline bone scan assessment is identified on a 
bone scan performed at any time during the study. The investigator should consider the 
positive hot-spot to be a significant new site of malignant disease and represent true disease 
progression in order to record the new lesion. Confirmation by CT, MRI and X-ray is 
recommended where bone scan findings are equivocal.
Fludeoxyglucose-Positron emission tomography scan
In the 1302.5 trial, fludeoxyglucose (FDG)-positron emission tomography (PET) scans may 
be used as a method for identifying new lesions if a baseline FDG-PET scan is done, 
according with the following algorithm: New lesions will be recorded where there is positive 
FDG uptake not present on baseline FDG-PET scan or in a location corresponding to a new 
lesion on CT/MRI at the same follow-up visit. A positive FDG-PET scan lesion should be 
reported only when an uptake greater than twice that of the surrounding tissue is observed. If 
there is no baseline FDG-PET scan available, and no evidence of new lesions on CT/MRI 
scans then follow-up CT/MRI assessments should be continued, scheduled as per protocol or 
clinical indicated, in order to confirm new lesions.
TUMOR RESPONSE EVALUATION
Schedule of evaluation
Baseline assessments should encompass the chest and abdomen, including adrenals, and 
should additionally investigate areas that may be involved based on signs and symptoms of 
individual patients. Baseline assessments should be performed no more than 21 days (see 
Flow chart 1.1 and Flow chart 1.2) before the start of study treatment. Follow-up assessments 
will be performed every 6 weeks (± 3 days) after randomization until Week 18, then every 
9 weeks (± 3 days) (see Flow chart 1.1 and Flow chart 1.2) until objective disease progression 
as defined by RECIST 1.1. Any other sites at which new disease is suspected should also be 
adequately imaged at follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every 
attempt should be made to perform the subsequent assessments at their scheduled visits. This 
schedule is to be followed in order to minimize any unintentional bias caused by some 
patients being assessed at a different frequency than other patients.


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Target lesions (TL)
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as TL at baseline. 
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters. At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters. At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters.
Special cases:

For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis.

If the CT/MRI slice thickness used is >5mm, the minimum size of measurable disease 
at baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm.

If a TL splits into two or more parts, then the sum of the diameters of those parts
should be recorded.

If two or more TL merge then the sum of the diameters of the combined lesion should 
be recorded for one of the lesions and 0 mm recorded for the other lesion(s).

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, an estimate of the size 
of the lesion should be provided.

When a TL has had any intervention e.g., radiotherapy, embolization, surgery etc., 
during the study, the size of the TL should still be provided where possible.


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Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL.
Complete Response (CR) Disappearance of all target lesions since baseline. Any 
pathological lymph nodes selected as target lesions must have a reduction in short axis to 
<10 mm.
Partial Response (PR) At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters.
Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD.
Progressive Disease (PD) At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
Not Evaluable (NE) Only relevant if any of the target lesions were not assessed or not 
evaluable or had a lesion intervention at this visit. Note: If the sum of diameters meets the 
progressive disease criteria, progressive disease overrides not evaluable as a target lesion 
response.
Non-Target lesions 
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit an overall assessment of the NTL response should be 
recorded by the Investigator. This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit. 
Complete Response (CR) Disappearance of all non-target lesions since baseline. All lymph 
nodes must be non-pathological in size (<10 mm short axis).
Non CR/Non PD Persistence of one or more NTL.
Progression (PD) Unequivocal progression of existing NTL. Unequivocal progression may
be due to an important progression in one lesion only or in several lesions. In all cases the 
progression MUST be clinically significant for the physician to consider changing (or 
stopping) therapy.
Not Evaluable (NE) Only relevant when one or some of the non-target lesions were not 
assessed and, in the Investigator's opinion, they are not able to provide an evaluable overall 
non-target lesion assessment at this visit.


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To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status.
New Lesions
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor.
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the new lesion has been confirmed. If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor 
assessments where possible until objective disease progression is observed.
Evaluation of Overall Visit Response
The overall visit response will be derived using the algorithm shown in Table 10.1: 1.


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Table 10.1: 1
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non CR/Non PD
No
PR
CR
NE
No
PR
PR
Non PD or NE
No
PR
SD
Non PD or NE
No
SD
NA
Non CR/Non PD
No
SD (Non CR/Non PD)
NE
Non PD or NE
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable; 
NA = not applicable (only relevant if there were no target lesions/non-target lesions at baseline).
CENTRAL REVIEW
Radiological examinations performed in the conduct of this study for RECIST response 
assessments must be retained at the trial site as source data and a copy anonymized for 
personal identifiers e.g., name, initials, be available for collection by the sponsor for 
centralized review if required.


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10.2
GUIDELINES FOR BI 695502/ AVASTIN® PREPARATION AND 
ADMINISTRATION
Supply
BI 695502 will be provided as a concentrate for solution for infusion in 4 mL vials 
(containing 100 mg of BI 695502 per 4 mL) and in 16 mL vials (containing 400 mg of 
BI 695502 per 16 mL) at a concentration of 25 mg/mL. 
Avastin® will be provided as a concentrate for solution for infusion in 4 mL vials (containing 
100 mg of bevacizumab per 4 mL) and 16 mL vials (containing 400 mg of bevacizumab per 
16 mL) at a concentration of 25 mg/mL. 
Stability and Storage
No preservative is used in BI 695502/US-licensed Avastin®; therefore, the vials are intended 
for single use only. BI 695502/US-licensed Avastin® is biologically and chemically stable at 
2 to 8°C (36 to 46°F). Once reconstituted into i.v. bags, the solution is chemically stable for 
up to 8 hours at 2 to 8°C (36 to 46°F). However, since no preservative is included, diluted 
solutions must be stored refrigerated (2 to 8°C). As no incompatibilities between 
polyvinylchloride or polyolefin bags/lines have been observed for BI 695502/US-licensed 
Avastin®, only bags/lines made of these materials are to be used for US-licensed Avastin®
and BI 695502 infusion administration in this trial. The following special infusion sets must
be used:
Infusion sets
BI 695502
PVC bag
X
PE bag, as a polymer of polyolefin
X
PP bag
X
DEHP free bag and PVC-free bag
X
PVC tubing
X
PE tubing
X
PUR tubing
X
BR
X
Filters tested: for B.Braun Spaceline standard tubing, an additional infusion filter (PALL 0.2 µm Posidyne 
ELD-Filter) was used, all other tested tubings include a 0.2 µm infusion filter
BR = Polybutadiene; PVC = Polyvinyl chloride; PP = Polypropylene; PE = Polyethylene; DEHP = di-
(2-ethylhexyl)phthalate; PUR = Polyurethane; X = tested and passed.
Do not use beyond the expiration date stamped on the vial.
Once switched from BI 695502 to Avastin®, the use of bags and lines should be as per 
Avastin® label. The use of filters as for BI 695502 administration will also be mandatory for 
Avastin® administration.


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Preparation of BI 695502/US-licensed Avastin® for Intravenous Administration
The recommended dose is 15 mg/kg every 3 weeks when used in combination with 
carboplatin/paclitaxel chemotherapy. The dose of BI 695502/Avastin® should be 
recalculated prior to each infusion.
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container 
permit. It is recommended that the necessary amount of BI 695502/US-licensed Avastin®
will be withdrawn and diluted in 0.9% sodium chloride. The mandatory concentration is 
16.5 mg/mL. The volume to be administered for each patient will be calculated based on the 
patient’s weight. Discard any unused portion left in the vial, as the product contains no 
preservatives. If appropriate infusion materials are not available, a smaller investigational
product concentration of 1.4 mg/mL up to 16.5 mg/mL can be temporarily used until the 
required materials are available.
The packaging for BI 695502 and US-licensed Avastin® are different, so to ensure the 
investigator and patient stay blinded, the infusion solutions will be prepared by an unblinded
pharmacist or suitably qualified designee at each trial site.
After the switch from BI 695502 to Avastin®, the recommended concentration for Avastin® 
is from 1.4 mg/mL to 16.5 mg/mL.


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10.3
CHEMOTHERAPY REGIMENS AND RECOMMENDATIONS FOR DOSE 
MODIFICATIONS IN CASES OF TOXICITY
Patients will receive carboplatin/paclitaxel as outlined in earlier sections of the protocol. 
Cycles of carboplatin/paclitaxel plus BI 695502/US-licensed Avastin® should be repeated 
every 3 weeks for up to 6 cycles.
Cycles are not skipped but delay may occur according to the Clinical Trial Protocol, Tables
10.3:1 and 10.3:2. Maximum timeframe treatment delay should be assessed based on the 
investigator´s clinical judgment and should be discussed with the study Medical Monitor. 
However, patients with severe hypertension, moderate to severe proteinuria, or severe 
infusion reactions will not receive further treatment with Avastin®/BI 695502 if the event 
cannot be adequately controlled within 14 days.
During the induction phase, any chemotherapy delay mandates a bevacizumab/BI 695502
infusion delay. All three drugs of this regimen (paclitaxel + carboplatin + 
bevacizumab/ BI 695502) should always be administered together during the induction phase, 
if the patients fulfills the criteria for receiving the next treatment cycle.
Administration of carboplatin/paclitaxel will be according to the standard preparation and 
infusion procedures of each investigational site. The doses should be administered as shown 
below. For the purpose of this Clinical Trial Protocol (CTP), Day 1 is the day when the cycle 
of carboplatin/paclitaxel is initiated. All patients should receive premedication prior to 
carboplatin/paclitaxel administration in order to prevent severe hypersensitivity reactions. 
Such premedication may consist of dexamethasone 16 mg orally administered approximately 
12 and 6 hours before paclitaxel diphenhydramine (or its equivalent) 50 mg intravenously 
(i.v.) (infusion should be completed 30 to 60 minutes prior to paclitaxel), cimetidine (300 
mg) or ranitidine (50 mg) i.v. (infusion should be completed 30 to 60 minutes before 
paclitaxel) (see Section 4.1.4.1).
Paclitaxel will be administered first, followed by carboplatin. All patients will be treated with 
standard combination chemotherapy consisting of paclitaxel 200 mg/m2 followed by 
carboplatin target area under the curve (AUC) 6 mg/mL/min (30- to 60-minute infusion) 
every 3 weeks for up to 6 cycles with adequate pre- and concomitant medication. The initial 
dose of paclitaxel (day 1, cycle 1) must be fixed to 200 mg/m² for all study patients, as well 
as a dose of carboplatin to AUC: 6 mg/mL/min. In case of toxicity after this initial dose, the
dose can be reduced in the event of toxicity according to the protocol guideline 
Table 4.1.4.1:1 and 10.3.1.
Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or 
devices used to prepare paclitaxel solutions for infusion is not recommended. In order to 
minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may 
be leached from PVC infusion bags or sets, paclitaxel solutions should be stored in bottles 
(glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through 
polyethylene-lined administration sets.


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Aluminum reacts with carboplatin causing precipitate formation and loss of potency. 
Therefore, needles or intravenous sets containing aluminum parts that may come in contact 
with the drug must not be used for the preparation or administration of carboplatin.
Preparation of carboplatin intravenous solutions
Carboplatin Injection is supplied either as a ready-to-use solution or as lyophilized powder.
In the first case, 10 mg/mL is supplied as a Ready To Use (RTU) sterile solution in 5 mL, 15 
mL, 45 mL or 60 mL vials. Total content of carboplatin per vial is described in following 
table:
Vial Strength
Diluent Volume
50 mg
5 mL
150 mg
15 mL
450 mg
45 mL
600 mg
60 mL
If supplied as a lyophilized powder, immediately before use, the content of each vial must 
be reconstituted with either Sterile Water for Injection, USP, 5% Dextrose in Water 
(D5W), or 0.9% Sodium Chloride Injection, USP, according to the following schedule:
Vial Strength
Diluent Volume
50 mg
5 mL
150 mg
15 mL
450 mg
45 mL
These dilutions all produce a carboplatin concentration of 10 mg/mL.
Carboplatin for injection can be further diluted to concentrations as low as 0.5 mg/mL with 
5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP.
When prepared as directed, Carboplatin for injection solutions are stable for 8 hours at room 
temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is 
recommended that Carboplatin solutions be discarded 8 hours after dilution. Parenteral drug 
products should be inspected visually for particulate matter and discoloration prior to 
administration.
Storage
Unopened vials of Carboplatin for injection are stable for the life indicated on the package 
when stored at 25°C (77°F) [excursions permitted to 15°- 30°C (59°- 86°F) [see USP 
Controlled Room Temperature] and protected from light. Carboplatin injection multidose 
vials maintain microbial, chemical, and physical stability for up to 15 days at 25°C following 
multiple needle entries.


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Recommended dose modifications: 
Please refer to the Prescribing Information for paclitaxel and carboplatin for details.
Table 10.3: 1
Dose Modifications for Hematologic Toxicities (Regardless of 
Causality)
Toxicity
Paclitaxel/Carboplatin
Grade 3 Neutropenia 
of any duration or 
Grade 4 < 7 days
1st event
Interrupt until recovery to >1500/mm3
Preferably reinitiate at original dose, unless investigator 
deems dose reduction by one level is necessary based 
on individual patient status. Discuss with Medical 
Monitor Sponsor
2nd event
Interrupt until recovery to >1500/mm3
Consider dose reduction by one level at investigators 
discretion, discuss with Medical Monitor Sponsor
3rd event despite dose 
reduction
Interrupt until recovery to >1500/mm3
Consider dose reduction by one level at investigators 
discretion, discuss with Medical Monitor Sponsor
4th event despite dose 
reduction
Off Treatment
Grade 4
Neutropenia
≥ 7 days
1st event
Interrupt until recovery to >1500/mm3
Reinitiate at next lower dose level.
2nd event despite dose 
reduction
Interrupt until recovery to >1500/mm3
Reinitiate at previous lower dose level.
3rd event despite dose 
reduction
Off Treatment
Febrile Neutropenia 
with Absolute 
Neutrophil Count 
(ANC) <3
1000/mm
1st event
Hold dose until ANC >1500/mm3 and T <38ºC
Reinitiate at next lower dose level
2nd event despite dose 
reduction
Hold dose until ANC >1500/mm3 and T <38ºC
Reinitiate at next lower dose level
3rd event despite dose 
reduction
Off Treatment
Thrombocytopenia ≥ 50,000 to <100,000/mm3, all 
events
Hold dose until recovery to ≥100,000/mm3
No change in dose


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Table 10.3: 1
Dose Modifications for Hematologic Toxicities (Regardless of Causality) 
(continued)
Toxicity
Paclitaxel/Carboplatin
Grade ≥3 Thrombocytopenia
≥25,000/mm3
to 
<50,000/mm3,
1st event
Hold dose until recovery to >100,000/mm3
Reinitiate at original dose level
≥25,000/mm3 
to 
<50,000/mm3,
2nd event
Hold dose until recovery to >100,000/mm3
Reinitiate at next lower dose level
<50,000/mm3, 
despite 
previous dose 
reduction
Off Treatment
Grade 4
Thrombocytopenia
Or
Grade 3 with Bleeding Requiring 
Platelet Transfusion
<25,000/mm3,
1st event
Hold dose until recovery to >100,000/mm3
Reinitiate at next lower dose level
<25,000/mm3 
despite 
previous dose 
reduction
Off Treatment
Any Grade Non-hemolytic Anemia
Manage by transfusions 
No change in dose.
If protocol treatment is held for >1 week for granulocyte recovery, then prophylactic 
filgrastim (Neupogen®) or pegfilgrastim (Neulasta®) will be administered (according to the 
package insert) with all subsequent cycles. If a febrile neutropenic episode (≥38.5ºC) occurs 
at any time during therapy accompanied by a granulocyte count of <1000/mm3, prophylactic 
granulocyte-colony stimulating factor (G-CSF) will be used for all subsequent cycles. Other 
additional uses of G-CSF are allowed, according to regular institutional practice and the PI´s 
judgment.
Criteria for dose reductions and discontinuation of therapy for some specific non-hematologic 
toxicities are summarized in Table 10.3: 2:
Table 10.3: 2
Dose Modifications for Selected Non-Hematologic Toxicity 
(Regardless of Causality)
Toxicity
Paclitaxel/Carboplatin
Metabolic
Hyperglycemia
No Change
Hypoglycemia
No Change
Gastrointestinal-related
≥ Grade 3 Nausea/Vomiting 
(1st Event)
No change
≥ Grade 3 Nausea/Vomiting
(2nd Event)
Decrease both by one dose level


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Table 10.3: 2
Dose Modifications for Selected Non-Hematologic Toxicity (Regardless of 
Causality) (continued)
Toxicity
Paclitaxel/Carboplatin
Grade 1 - 2 Diarrhea
No change
≥ Grade 3 Diarrhea lasting >24 hours 
despite maximum anti-diarrheal 
management 
(1st event)
Hold study drug treatment until decreased to ≤ Grade 1 or to 
baseline 
Reinitiate at original dose level
≥ Grade 3 Diarrhea lasting >24 hours 
despite maximum anti-diarrheal 
management 
(2nd Event)
Hold study drug treatment until decreased to ≤ Grade 1 or to 
baseline 
Reinitiate at original dose level
Grade 1 - 2 Mucositis
Hold study drug treatment until decreased to ≤ Grade 1 or to 
baseline 
Reinitiate at original dose level
≥ Grade 3 Mucositis
(1st event)
Hold study drug treatment until decreased to ≤ Grade 1 or to 
baseline 
Reinitiate at original dose level
≥ Grade 3 Mucositis
(2nd Event)
Hold study drug treatment until decreased to ≤ Grade 1 or to 
baseline 
Decrease current dose by one dose level
Hepatobiliary
≥ Grade 2 Aspartate aminotransferase 
(AST) or Alanine aminotransferase 
(ALT) and ≤ Grade 1 Total Bilirubin
Hold until liver function tests (LFTs) ≤ Grade 1. Restart 
paclitaxel at same dose when bilirubin is within normal 
limit. Lower paclitaxel one dose level when bilirubin = 
Grade 1
No dose adjustment for carboplatin
≥ Grade 3 AST or ALT or ≥ Grade 2 
Total Bilirubin
Hold until LFTs ≤ Grade 1. Restart paclitaxel at same dose 
when bilirubin is within normal limit. Lower paclitaxel one 
dose level when bilirubin = Grade 1 
No dose adjustment for carboplatin
Allergic/Hypersensitivity to Paclitaxel
≥ Grade 3 allergic/ hypersensitivity 
despite adequate premedications
Off treatment
Neuropathy
Neuropathy
Grade 2
Hold study drug treatment until decreased to ≤ Grade 1 or to 
baseline 
Decrease paclitaxel by one dose level. No dose adjustment 
for carboplatin
Neuropathy
≥ Grade 3
Hold study drug treatment until decreased to ≤ Grade 1 or to 
baseline 
Decrease paclitaxel by two dose levels. No dose adjustment 
for carboplatin
Since there are no commonly accepted recommendations for dose modifications it is 
suggested to follow the hospital standards and carefully capture any modification in the 
respective electronic case report form page.


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10.4
CLINICAL EVALUATION OF LIVER INJURY
10.4.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (Protocol-Specified 
adverse events of special interest [AESI]), are to be further evaluated using the following 
procedures: 
10.4.2
Procedures
Repeat the following laboratory tests according to the following criteria: 
Patients with liver function test (LFT) value(s) within normal limits at baseline: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin (total and direct) 
within 48 to 72 hours. If ALT and/or AST ≥ 3 times upper limit of normal (ULN) combined 
with an elevation of total bilirubin ≥ 2 times ULN are confirmed, results of the laboratory 
parameters described below must be made available to the investigator and to Boehringer 
Ingelheim as soon as possible.
Patients with elevated LFT value(s) at baseline: Repeat the following laboratory tests: ALT, 
AST, and bilirubin (total and direct) within 48 to 72 hours. If ALT and/or AST ≥ 5 times 
ULN combined with an elevation of total bilirubin ≥ 2 times ULN are confirmed, results of 
the laboratory parameters described below must be made available to the investigator and to 
Boehringer Ingelheim as soon as possible.
Patients with elevated total bilirubin at baseline: The threshold to qualify for repeat 
laboratory tests is defined as elevation of hepatic enzymes based on the above criteria, 
combined with concurrent elevation of total bilirubin above baseline.
In addition:

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “Drug Induced Liver Injury (DILI) checklist” provided in the 
ISF;

obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
according to the “DILI checklist” provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the “DILI checklist” provided in the Investigator Site File 
(ISF); 
and report these via the electronic case report form. A copy of the DILI checklist should also 
be provided along with the SAE form.
The investigator is to follow the laboratory testing and assessments as noted in the DILI 
checklist in the ISF. These assessments include but are not limited to:


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Clinical chemistry including coagulation

alkaline phosphatase, albumin, prothrombin time or International Normalized Ratio, 
creatine kinase, creatine kinase muscle-brain, coeruloplasmin, α-1 antitrypsin, transferin, 
amylase, lipase, fasting glucose, cholesterol, triglycerides, cholinesterase.
Serology

Hepatitis A (Anti-immunoglobulin [Ig]M, total Anti-Ig), Hepatitis B (HbsAg, Anti-HBs, 
DNA), Hepatitis C (Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, total 
Anti-Ig), Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-
Smooth Muscle antibody (titer), Antinuclear antibody (titer), Anti-LKM (liver-kidney 
microsomes) antibody, Antimitochondrial antibody, Epstein Barr Virus (VCA IgG, VCA 
IgM), cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM), varicella (IgG, 
IgM), parvovirus (IgG, IgM), toxoplasmosis (IgG, IgM)
Hormones, tumor marker

Thyroid stimulating hormone.
Hematology

Complete blood count (including differential counts)
Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic pathology, 
e.g., bile duct stones or neoplasm.
Initiate close observation of patients by repeat testing of ALT, AST, and total bilirubin (with 
fractionation by total and direct) at least weekly until the laboratory ALT and/or AST 
abnormalities stabilize or return to normal, then according to the protocol. Depending on 
further laboratory changes, additional parameters identified e.g., by reflex testing will be 
followed up based on medical judgement and Good Clinical Practice (GCP).


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10.5
TUMOR, NODE, METASTASIS (TNM) STAGING


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Website://cancerstaging.org/references-tools/quickreferences/documents/lungmedium.pdf 
(accessed on 24 Mar 2015)


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10.6
DETAILS OF THE STATISTICAL CONCEPT FOR CLINICAL 
SIMILARITY ASSESSMENT
10.6.1
Equivalence Margin
The historical treatment effect of Avastin® is estimated based on a meta-analysis of studies 
being representative for the treatment effect of Avastin® and BI 695502 in the intended 
1302.5 trial population: 

All data used were taken from studies with a backbone chemotherapy control arm.

All data used were taken from studies or study arms excluding squamous cell type lung 
cancer.

All data used were taken from studies or study arms with a dosing regimen of 15 mg/kg 
bevacizumab.

Only studies using the identical backbone therapy as planned in trial 1302.5 (paclitaxel 
200 mg/m2 followed by carboplatin target area under the curve (AUC) 6 mg/mL•minute) 
were considered to ensure homogeneity and representativeness of the reference data to the 
planned trial 1302.5. 
Thus in the meta-analysis the following three studies, which are part of the Soria 2013
(R14-0472) review, were included: Sandler et al 2006 (R07-1161), Niho et al 2012 (R14-
0473), and the non-squamous cell histology subgroup (15 mg/kg bevacizumab versus control) 
of Johnson et al 2004 (R04-4661). 
While the treatment effect of Avastin® by meta-analysis was not significantly heterogeneous 
on the overall response rate (ORR) difference scale (Table 10.6.1: 1), the treatment effect of 
Avastin was even more homogenous on the ORR ratio scale (Table 10.6.1: 2). Therefore the 
best ORR ratio is chosen as the primary measure for treatment differences in this trial. 
Table 10.6.1: 1
Fixed-effects meta-analysis of ORR difference
Avastin®
Control
Source
Events
Total N
Events
Total N
Weight
ORR 
difference
(90% 
CI)
Sandler 
(2006)
133
381
59
392
81.6%
19.9%
(14.9%, 
24.9%)
Niho 
(2012)
71
117
18
58
13.1%
29.6%
(17.2%, 
42.1%)
Johnson 
(2004)
16
32
5
25
5.3%
30.0%
(10.4%, 
49.6%)
Total 
(weighted)
21.7%
(17.2%, 
26.2%)
Test for heterogeneity: p=0.3761.
CI = confidence interval; ORR = overall response rate
Calculations based on Metacalc v3.0  


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Table 10.6.1: 2
Fixed-effects meta-analysis of ORR ratio
Avastin®
Control
Source
Events
Total N
Events
Total N
Weight
ORR 
ratio
(90% 
CI)
Sandler 
(2006)
133
381
59
392
64.4%
2.319
(1.846, 
2.914) 
Niho 
(2012)
71
117
18
58
28.6%
1.955
(1.386, 
2.759)
Johnson 
(2004)
16
32
5
25
6.5%
2.500
(1.218, 
5.132)
Total 
(weighted)
2.220
(1.847, 
2.668)
Test for heterogeneity: p=0.7632.
CI = confidence interval; ORR = overall response rate
Calculations based on Metacalc v3.0  
To account for variability in the treatment effect estimate, a conservative estimate of the 
historical ORR ratio between Avastin® plus chemotherapy and chemotherapy alone is given 
by the lower limit of the 90% confidence interval (CI) of the ORR ratio, M1 = 1.847. The 
non-inferiority margin M2 that preserves ½ (50%) of M1 is calculated on the log ORR ratio 
scale for symmetry reasons. It follows that M2 = exp(log(M1)/2) = 1.359 and therefore the 
equivalence margin for best ORR ratio is given by the interval (1/1.359, 1.359) = (0.736, 
1.359). This margin will be used for the test of the primary hypothesis.
An alternative method to obtain assay-sensitivity with respect to the control therapy of 
carboplatin and paclitaxel alone is to base the margin calculation on preserving more than 
half of the point estimate of the historical treatment effect of Avastin®. The non-inferiority 
margin M2 = 1.376 preserves 3/5 (60%) of the point estimate of the treatment effect measured 
on the log ORR ratio scale, i.e., it preserves 82.4 percentage points or more than 2/3 of the 
122 percentage points relative increase in ORR. The corresponding equivalence margin for 
best ORR ratio is given by the interval (1/1.376, 1.376) = (0.727, 1.376). This margin will be 
used in a sensitivity analysis to the primary analysis to assess the robustness of the results 
with respect to the margin calculation.
10.6.2
Statistical model and equivalence test
The primary analysis is based on a log binomial regression model with subsequent 
transformation of the estimated parameters to the ratio in best ORR including the respective 
CI. The log binomial regression model is a generalized linear model for the binomial 
distribution with log link. It is suited for estimating relative risks (Spiegelman and Hertzmark 
2005; R14-3815). The ratio of best ORR is a relative risk.   
The statistical model will be:
log (E{ORR}) = treatment + sex + smoking status + NSCLC stage + ethnicity


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The difference in log(best ORR) between BI 695502 and US-licensed Avastin® will be 
estimated, with 90% CI, adjusted for sex, smoking status, nonsmall cell lung cancer 
(NSCLC) stage, and ethnicity. The estimate and CI will be exponentiated to return to the ratio 
scale.
This model includes the following explanatory variables: treatment, sex (male versus female), 
smoking status (never smoked versus current/past smoker), NSCLC stage (recurrent versus
Stage IV) and ethnicity (East Asian origin versus non East Asian). In case of sparse data in 
one (or more) strata which affects the convergence of the model the respective factors may be 
omitted in the model.
The primary test for equivalence will be performed with respect to BI 695502 versus 
US-licensed Avastin®. The primary hypothesis is based on the ratio in best ORR between the 
two treatments:
H0: Ratio in best ORR by Week 18 (BI 695502 versus US-licensed Avastin®) ≤0.736 or 
≥1.359.
H1: Ratio in best ORR by Week 18 (BI 695502 versus US-licensed Avastin®) within the 
interval (0.736, 1.359).
The primary hypothesis will be tested using a union-intersection test based on two one-sided 
tests (TOST) with a 5% type I error rate. This test, also called equivalence test or similarity 
test preserves the overall type I error rate at alpha = 5% (R14-3718). 
To implement this, a decision rule based on the 90% two-sided confidence interval of the 
ORR ratio between BI 695502 and US-licensed Avastin® will be used. The null hypothesis 
will be rejected in favor of the alternative hypothesis of clinical equivalence if the 90% CI for 
the ORR ratio falls completely between the lower bound of 0.736 and the upper bound of 
1.359 of the similarity margin.
The test of the primary hypothesis is designed in a way to provide evidence of no clinically 
meaningful difference between BI 695502 versus US-licensed Avastin® with respect to the 
primary endpoint best ORR. 
If, for example, the best ORR of BI 695502 would be estimated at 37.3% and the best ORR 
of US-licensed Avastin® at 43.3% and the ratio in best ORR by Week 18 (BI 695502 versus 
US-licensed Avastin®) would equal 0.860, with a 90% CI of (0.735, 1.005), then the primary 
null hypothesis could not be rejected.
However, if best ORR of BI 695502 would be estimated at 37.6% and the best ORR of 
US-licensed Avastin® still at 43.3% and the ratio in best ORR by Week 18 (BI 695502
versus US-licensed Avastin®) would equal 0.867 with a 90% CI of (0.741,1.013), then in this 
case the primary null hypothesis could be rejected. The difference between the treatments 
would not be clinically meaningful. Thus the choice of the equality margin is justified on 
both clinical and statistical grounds.


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If BI 695502 and US-licensed Avastin® are clinically equal, a high power is obtained 
(Appendix 10.6.3).
10.6.3
Sample Size
The sample size is approximately N = 660 patients (n = 330 per treatment arm). It is based on 
an ORR ratio of 1.000, an equivalence margin of (0.736, 1.359) on the ORR ratio scale and a 
power of 92% in the test of the primary hypothesis for an ORR of 43.3% in both treatment 
arms. 
The ORR of 43.3% is the weighted average of the ORR of Avastin® in the meta-analysis for 
ORR ratio, using the weights resulting from this meta-analysis. Since the meta-analysis is 
based on the ORR ratio and not designed to provide an estimate of ORR, other ways of 
computing the ORR for Avastin® are possible and would lead to similar results. 
The total sample size (N = 660) is chosen to be robust with respect to the assumed ORR 
effect size in the BI 695502 and US-licensed Avastin® treatment arms. A high power for the 
test of the primary hypothesis is ensured even if the observed ORR effect size is slightly 
lower than calculated from the trials included in the meta-analysis (Table 7.6: 1). 
For an ORR >30%, the power for the test based on the ratio of best ORR is also higher than 
the power of a test based on the best ORR difference scale. For example a margin of (-8.6%, 
8.6%) preserving 50% of the lower bound of the 90% CI for the treatment difference on the 
ORR difference scale tested using a 90% CI results in a power of only 44% (assuming an 
ORR of 43.3%). This further justifies the use of the best ORR ratio as compared to the best 
ORR difference in the primary analysis.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
01 April 2015
EudraCT number
2014-002161-30
BI Trial number
1302.5
BI Investigational Product(s)
BI 695502
Title of protocol
A multicenter, randomized, double-blind Phase 
III trial to evaluate efficacy and safety of BI 
695502 plus chemotherapy versus Avastin® plus 
chemotherapy in patients with advanced 
nonsquamous Non-Small Cell Lung Cancer
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Throughout protocol
Description of change
1. US-sourced Avastin® has been updated to 
US-licensed Avastin®.
2. EU-sourced Avastin® has been updated to 
EU-approved Avastin®.
3. References to Avastin® or bevacizumab have 
been updated to US-licensed Avastin®, as 
applicable.
Rationale for change
As a result of FDA feedback the use of the term
US-licensed Avastin® has been specified, as 
applicable, to indicate clearly which product will 
be used in the trial. Since the source of Avastin®
is not specified in originator publications, the 
general term “Avastin®” has been used when 
referencing such documents. For general mode-


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of-action description of the molecule, the term 
“bevacizumab” has been used.
Section to be changed
Synopsis, Main Criteria for Inclusion
Description of change
The statement “Patients must have no 
contraindication to Avastin®” has been revised to 
state patients must have no known sensitivity to 
any of the trial drugs or their excipients.
Rationale for change
To ensure consistency with Section 3.3.3, 
Exclusion Criterion 27.
Section to be changed
1.2
Description of change
1. In the first sentence, “reference bevacizumab 
product” has been revised to “bevacizumab 
product”.
2. In the last paragraph, text has been revised to 
state that bevacizumab is approved for 
primary peritoneal cancer in the US as well 
as in the EU.
3. In the last paragraph (and throughout the 
protocol), references to R14-3588 and R14-
3589 have been updated to R15-1223 and 
R15-1222
Rationale for change
To improve clarity and update references
Section to be changed
3.1
Description of change
The description of the requirements for the SFU 
Visit has been clarified.
Rationale for change
To clarify that all patients will be required to 
attend the SFU visit once they have completed 
trial therapy.
Section to be changed
3.3.2
Description of change
Inclusion criterion 10 has been revised to specify 
that all patients (males and females of 
childbearing potential) must continue to use an 
acceptable form of contraception for 6 months 
following completion or discontinuation of trial 
medication, and to add text defining child-
bearing potential.
Rationale for change
To ensure the protocol and Informed Consent 
Form are consistent.
Section to be changed
3.3.4.1
Description of change
The criteria for withdrawal from the trial, 
discontinuation from trial medication and the 


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requirements for follow-up of patients who 
discontinue treatment have been clarified.
Rationale for change
FDA requirement to state clearly the difference 
between criteria that lead to withdrawal from 
trial and those that lead to discontinuation from 
treatment.
Section to be changed
4.1.4
Description of change
The reference to the table for chemotherapy dose 
modification has been corrected.
Rationale for change
To correct an error.
Section to be changed
4.1.4.1
Description of change
To clarify that patients who are unable to tolerate 
at least 3 cycles of chemotherapy or those that 
start a new backbone chemotherapy will not be 
withdrawn from the trial, but will be 
discontinued from trial medication.
Rationale for change
For consistency with the changes made in 
Section 3.3.4.1.
Section to be changed
4.2.2.1
Description of change
Text stating that for elective surgery during the 
trial the interval between termination of the 
BI 695502/ US-licensed Avastin® infusion and 
subsequent elective surgery should be at least 
28 days to comply with the black box warning of 
the Avastin® US prescribing information has 
been revised to remove the reference to the US 
prescribing information.
Rationale for change
Text removed as the warning is not specific to 
the US.
Section to be changed
8.6
Description of change
The text “last patient/patient out” has been 
revised to “last patient out”
Rationale for change
To improve clarity
Section to be changed
9.1
Description of change
The reference for the US prescribing information 
and EU SPC for Avastin® have been updated
and minor formatting changes have been made.
Rationale for change
To reflect the most recent version of the labels 
for Avastin® and to ensure correct and consistent 
formatting of references.


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Number of global amendment
2
Date of CTP revision
10 July 2015
EudraCT number
2014-002161-30
BI Trial number
1302.5
BI Investigational Product(s)
BI 695502
Title of protocol
A multicenter, randomized, double-blind Phase 
III trial to evaluate efficacy and safety of BI 
695502 plus chemotherapy versus Avastin® plus 
chemotherapy in patients with advanced 
nonsquamous Non-Small Cell Lung Cancer
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
4.1.4.1
Description of change
Second paragraph last sentence “In case of 
anticipated toxicity, the investigator may start 
paclitaxel at a dose of 175 mg/m2 and/or 
carboplatin target AUC 5 mg/mL•min.” has been 
changed to “The dose can be reduced in the event 
of toxicity according to the protocol guideline 
Table 4.1.4.1:1 and 10.3.1.”
Rationale for change
As a result of FDA feedback to ensure 
consistency with prior clinical trials, all patients 
should start treatment at the proposed dose of 
paclitaxel 200 mg/m2 and/or carboplatin AUC 6 
mg/mL/min; the dose can be reduced in the event 
of toxicity following the protocol guideline.
Section to be changed
4.2.1
Description of change
Second paragraph “Administration of BI 
695502/US-licensed Avastin® should be 


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temporarily suspended for at least 28 days 
following severe hypertension not controlled 
with medical management; moderate to severe 
proteinuria pending further evaluation; or severe 
infusion reactions. “ was deleted and replaced by 
“Patients with severe hypertension, moderate to 
severe proteinuria, or severe infusion reactions 
will not receive further treatment with US-
licensed Avastin® or BI695502 if the event 
cannot be adequately controlled within 14 days.” 
Rationale for change
As a result of FDA feedback that a patient who 
experienced an event of such severity that 
required a 28 day treatment interruption for 
recovery would not benefit from further 
treatment with bevacizumab or BI695502. 
Section to be changed
Appendix 10.3
Description of change
Paragraph 4 last sentence: “In case of anticipated 
toxicity, the investigator may start paclitaxel at a 
dose of 175 mg/m2 and/or carboplatin target 
AUC 5 mg/mL min.” was cancelled and replaced 
by “The dose can be reduced in the event of 
toxicity according to the protocol guideline Table 
4.1.4.1:1 and 10.3.1.”
Rationale for change
As a result of FDA feedback to ensure 
consistency with prior clinical trials, all patients 
should start treatment at the proposed dose of 
paclitaxel 200 mg/m2 and/or carboplatin AUC 6 
mg/mL/min; the dose can be reduced in the event 
of toxicity following the protocol guideline.


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Number of global amendment
3
Date of CTP revision
19 February 2016
EudraCT number
2014-002161-30
BI Trial number
1302.5
BI Investigational Product(s)
BI 695502
Title of protocol
A multicenter, randomized, double-blind Phase 
III trial to evaluate efficacy and safety of BI 
695502 plus chemotherapy versus Avastin® plus 
chemotherapy in patients with advanced 
nonsquamous Non-Small Cell Lung Cancer
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Throughout protocol
Description of change
Minor editorial modifications
Rationale for change
To improve understanding, correct spelling and 
update study personnel qualifications. 
Section to be changed
Synopsis (Main criteria for inclusion)
Description of change
The Japan age requirement was changed from 
“Age ≥20 years at Visit 1” to Age ≥20 years at 
Screening”
Rationale for change
To clarify the requirement that patients from 
Japan be ≥20 years when informed consent is 
taken. 


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Section to be changed
Throughout protocol
Description of change
Throughout the protocol text has been added to 
specify that coagulation parameters will be 
assessed more frequently, updated so that 
coagulation assessments follow the same 
schedule as laboratory tests. This includes update 
to Flow Charts 1.1 and 1.2. 
Rationale for change
To provide further clarity on when coagulation 
parameters should be assessed. 
Section to be changed
Flow chart 1.1 – cycle 1 up to cycle 6
Description of change
The second sentence of the third footnote 
“Screening for HIV and TB will be performed 
according to local practice and local regulatory 
guidance.” Has been revised to “Screening for 
HIV and TB (purified protein derivative or 
QuantiFERON) to be performed according to 
local practice and local regulatory guidance.”
Rationale for change
To further clarify the methods for HIV and TB 
screening.
Section to be changed
Flow chart 1.1 – cycle 1 up to cycle 6
Description of change
Footnote 9, after first sentence “Two consecutive 
recordings will be made” was added and “ECGs 
will be performed” deleted so that Footnote 9 
reads “Patients should rest for at least 5 minutes 
in a supine position before ECG evaluations. 
Two consecutive recordings will be made at 
Screening, and before starting Cycle 3 and Cycle 
5. Additional ECGs will be performed if 
clinically indicated.”
Rationale for change
To clarify ECG procedures and ensure 
consistency with Flow Chart 1.2. 
Section to be changed
Flow chart 1.1 – cycle 1 up to cycle 6
Description of change
Footnote 11. Text was added to specify that 
abdominal MRIs will be performed with contrast 
using gadolinium.
Rationale for change
To be aligned with the Investigator Site Image 
Manual from Parexel
Section to be changed
Flow chart 1.1 – cycle 1 up to cycle 6


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Description of change
Footnote 14. The following text was added to the 
end of the footnote: “During the induction phase, 
tumor assessments should be performed before 
treatment administration of Cycles 3 and 5. If an 
induction therapy cycle is delayed, the tumor 
assessment will also be delayed.”
Rationale for change
To further clarify the timing of tumor 
assessments. 
Section to be changed
Flow chart 1.2
Description of change
An assessment of vital signs was added to the 
safety follow-up visit.
Rationale for change
To clarify that vital signs should be assessed at 
safety follow-up. 
Section to be changed
Flow chart 1.2 – cycle 7 onwards
Description of change
Footnote 9. Text was added to specify that 
abdominal MRIs will be performed with contrast 
using gadolinium, and to specify that a delay in a 
maintenance therapy cycle will result in a delay 
in tumor assessment.
Rationale for change
To be aligned with the Investigator Site Image 
Manual from Parexel, and to align with induction 
phase procedures.
Section to be changed
Flow chart 1.2 – cycle 7 onwards
Description of change
Footnote 11. The following text was added to the 
end of the footnote: “In case of a treatment cycle 
delay (i.e. due to toxicity), imaging assessment 
(e.g. CT, MRI) for the primary endpoint will be 
performed at Week 18 ±14 days (fixed time 
point), regardless of the number of cycles 
administered to date.”
Rationale for change
To further clarify the procedure for tumor 
assessments where a treatment cycle delay 
occurs.
Section to be changed
1.2
Description of change
The list of indications and territories in which 
Avastin® is approved for use was updated to 
reflect the approval of Avastin® for metastatic 
cervical cancer in the European Union as well as 
the US. 
Rationale for change
To update the current status of Avastin®
licensing. 


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Section to be changed
3.3.1
Description of change
The Japan age requirement was changed from 
“Age ≥20 years at Visit 1” to Age ≥20 years at 
Screening”. It was also specified that for patients 
with recurrent disease, radiotherapy for locally 
advanced tumor must have been stopped for at 
least 12 months prior to Screening
Rationale for change
To clarify the requirement that patients from 
Japan be ≥20 years when informed consent is 
taken, and to ensure consistency with exclusion 
criterion 3
Section to be changed
3.3.1
Description of change
Second sentence: the following text was added: 
“or radiotherapy for locally advanced tumor” to 
add treatment of locally advanced tumors by 
radiotherapy to the list of treatments not 
permitted within 12 months prior to screening. 
Rationale for change
To ensure consistency with exclusion criterion 3. 
Section to be changed
3.3.2
Description of change
Criterion 1. The Japan age requirement was 
changed from “Age ≥20 years at Visit 1” to Age 
≥20 years at Screening”
Rationale for change
To clarify the requirement that patients from 
Japan be ≥20 years when informed consent is 
taken.
Section to be changed
3.3.2
Description of change
Criterion 4. The following text was added to the 
end of the criterion: “Despite EGFR mutational 
status, patients may enter the trial if the site's best 
standard of care would be to administer such a 
chemotherapy regimen for that specific patient. 
However, if an EGFR test result is pending, and 


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chemotherapy treatment would be switched in 
case of a mutational positive result, patients may 
not be included in this trial.”
Rationale for change
The text was added to anticipate investigator’s 
questions regarding the eligibility criterion. 
Section to be changed
3.3.2
Description of change
Criterion 5. The following text was added to the 
end of the criterion: “Despite ALK mutational 
status, patients may enter the trial if the site's best 
standard of care would be to administer such a 
chemotherapy regimen for that specific patient. 
However, if an ALK test result is pending, and 
chemotherapy treatment would be switched in 
case of a mutational positive result, patients may 
not be included in this trial”
Rationale for change
The text was added to anticipate investigator’s 
questions regarding the eligibility criterion.
Section to be changed
3.3.2
Description of change
Criterion 8. Bullets a to i were reordered. 
Additionally, bullet h (international normalized 
ratio) was deleted and added as criterion 9. The 
mg/mmol protein/creatinine ratio was updated 
from 226 to 22.6 mg/mmol. 
Rationale for change
To remove the International normalized ratio 
criterion from this list, to reorder the bullet points 
to a more logical order, and to correct an error in 
the mg/mmol protein/creatinine ratio. 
Section to be changed
3.3.2
Description of change
A new criterion 9 was inserted as follows: 
“International normalized ratio ≤1.4 as analyzed 
locally. Partial thromboplastin time within 
normal limits according to local practice. Central 
laboratory analysis will be used for coagulation 
parameters where local analysis is not available.” 
Subsequent inclusion criteria were renumbered to 
account for new criterion 9. 
Rationale for change
To clarify the order of the inclusion criteria and 
align the study population with that in the 
original approval dossier for Avastin, and to 
permit coagulation parameters for inclusion 
criteria to be assessed locally where possible.
Coagulation is a test which is susceptible to 


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sample deterioration artefacts. Therefore the 
shipping process and time to a central laboratory 
for analysis can impact the result obtained.
values.
Section to be changed
3.3.2
Description of change
Criterion 11 (previously 10). Text was added to 
highlight that a list of acceptable contraception 
methods is provided in patient information.
Rationale for change
To clarify where information on acceptable 
methods of contraception can be found. 
Section to be changed
3.3.3
Description of change
Criterion 6 was deleted and replaced with “6.
Patients with known symptomatic brain 
metastasis:
a.
Brain metastasis which is symptomatic at 
screening or randomization visits, or
b.
Patients who have previously irradiated 
brain metastasis that has not been shown to be 
stable at least 1 month after completion of the 
radiation therapy (either by CT scan or MRI) at 
screening visit.
Rationale for change
To further clarify the exclusion of patients with 
brain metastasis
Section to be changed
3.3.3
Description of change
Criterion 23. The following text was added to the 
end of the criterion: “There should be no 
radiographic or clinical evidence of active TB.” 
Additionally the HIV and TB screening methods 
QuantiFERON and purified protein derivative 
were added as appropriate tests.
Rationale for change
To provide further clarity regarding testing for
HIV and TB. 
Section to be changed
3.3.4.1
Description of change
The following text was added to the end of the 
first paragraph: “Patients may be re-screened 
once in order to fulfill all the inclusion criteria, 
provided the patient would receive the 
bevacizumab + paclitaxel/carboplatin regimen in 
regular practice at the Investigator’s discretion.”
Rationale for change
To provide further clarification on re-screening 
process.


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Section to be changed
3.3.4.1
Description of change
The following items were added to the list of 
reasons patients can be discontinued from trial 
treatment:
•
Progressive disease
•
GI perforations (including fistula 
formation in the GI tract, intra-abdominal 
abscess)
•
Fistula formation involving an internal 
organ
•
Wound dehiscence and wound healing 
complications requiring medical intervention
•
Serious hemorrhage (i.e., requiring 
medical intervention)
•
Severe arterial thromboembolic events
•
Hypertensive crisis or hypertensive 
encephalopathy
•
RPLS
•
Nephrotic syndrome.
•
Severe hypertension, moderate to severe 
proteinuria, or severe infusion reactions if the 
event cannot be adequately controlled within 
14 days.
The list was also reordered to a more logical 
order. 
Rationale for change
To ensure consistency with the discontinuation 
reasons listed in Section 4.1.4, and to clarify that 
progressive disease requires discontinuation.
Section to be changed
3.3.4.1
Description of change
Prior to the paragraph “It is understood by all 
concerned that an excessive rate of withdrawals 
can render the trial uninterpretable; therefore, 
unnecessary withdrawal of patients from the trial 
should be avoided.” the following text was 
added: “Patients discontinued from trial 
treatment or withdrawn from the trial will not be 
replaced, regardless of the reason for 
discontinuation/withdrawal.”
Rationale for change
To clarify whether discontinued/withdrawn 
patients will be replaced. 
Section to be changed
3.3.4.2
Description of change
Text was added in the first sentence to specify 
that the trial may be discontinued overall or at a 
particular trial site for reasons including but not 


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restricted to those listed in Section 3.3.4.2
Rationale for change
To clarify that circumstances outside those listed 
in Section 3.3.4.2 may result in trial 
discontinuation locally or overall. 
Section to be changed
4.1.3
Description of change
Text was added to state that the dose of Avastin/
BI 695502 should be recalculated prior to each 
infusion. 
Rationale for change
To clarify that the correct dose needs to be 
calculated at each infusion. 
Section to be changed
4.1.4.1
Description of change
In the second paragraph. “(according to regular 
institutional practice)” was deleted, as was the 
final sentence. The following text was added to 
the end of the paragraph: “The initial dose of 
paclitaxel (day 1, cycle 1) must be fixed to 
200 mg/m² for all study patients, as well as a 
dose of carboplatin to AUC: 6 mg/mL/min. In 
case of toxicity after this initial dose, the dose 
can be reduced according to the protocol 
guideline Table 4.1.4.1:1 and 10.3.1.”
Rationale for change
This change was made at the request of the 
regulatory authority, and to obtain a more 
homogeneous trial treatment population. The 
change was also made in anticipation of requests 
for initial dose at 175 mg. 
Section to be changed
4.1.4.1
Description of change
The following text was added after the 
description of the Cockroft-Gault formula 
equation: “The Cockcroft–Gault formula will be 
used to calculate the creatinine 
clearance/glomerular filtration rate (GFR) 
(required for the Calvert´s formula). As clinically 
recommended, GFR will be capped at 125 
mL/min (even if the result obtained is higher) so 
as to avoid potential overdosing. Accordingly, 
the maximum total dose of carboplatin would be 
900 mg per cycle.”
Rationale for change
To further clarify the dosing calculation. 
Section to be changed
4.1.8
Description of change
Text indicating that investigational drugs can be 
received by a site if signing of the CTP is 


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imminent was deleted.
Rationale for change
To clarify that a signed and dated CTP is 
required prior to sites receiving investigational 
drugs.
Section to be changed
Table 4.2.2.1: 1 Prior and concomitant treatments
Description of change
The radiotherapy restriction text “Patients should 
not have received radiotherapy for locally 
advanced nsNSCLC within 12 months prior to 
screening. Palliative radiotherapy is permitted 
during treatment for local/non-target lesions, but 
this must not include radiotherapy to the chest.” 
was deleted and replaced with “Palliative local 
radiation therapy (outside the only measurable 
lesion used for RECIST assessment) is 
acceptable, both previously and during the trial, 
at the Investigator´s discretion. However, any 
radiotherapy to the chest must have finished >12 
months prior to screening. Previously irradiated 
brain metastasis must be shown to be stable at 1 
month after completion of radiation therapy (by 
CT or MRI) and before screening, the patient 
must be asymptomatic from brain metastasis, 
with a stable dose of oral corticosteroids 
≤10 mg/day of prednisolone (or equivalent) 
during the last 4 weeks, no parenteral 
corticosteroids in the last 6 weeks prior to Day 1 
(see below item in this table), and with an 
indication of treatment with the study regimen 
(inclusion criterion #2). Patients must be 
recovered at screening from any adverse event 
(>grade 1, except alopecia) related to previous 
radiotherapy (exclusion criterion #10).”
Rationale for change
To ensure consistency with inclusion criterion 2 
and exclusion criterion 10, and to provide greater 
specificity regarding radiotherapy restrictions. 
Section to be changed
Table 4.2.2.1: 1 Prior and concomitant treatments
Description of change
The following text was added to the restrictions 
on drugs/therapies that have not received 
regulatory approval for any indication: 
“Simultaneous participation in non-interventional 
studies (e.g. observational studies) is allowed.”
Rationale for change
To ensure consistency with new exclusion 
criterion 28


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Section to be changed
Table 4.2.2.1: 1 Prior and concomitant treatments
Description of change
The following text was added to the end of the 
NSAID restrictions: “Acetaminophen 
(paracetamol) as well as natural and synthetic 
opioids could be used as pain relievers”
Rationale for change
To provide further clarification on permitted 
medication form pain management
Section to be changed
Table 4.2.2.1: 1 Surgical procedures
Description of change
The timeframe for permitted invasive procedures 
was changed from “within 28 days prior to the 
first dose of BI 695502/US licensed Avastin®” to 
“≥28 days prior to the first dose of BI 695502/US 
licensed Avastin®”
Rationale for change
To clarify the timeframe in which invasive 
procedures are permitted. 
Section to be changed
Table 4.2.2.1: 1 Prior and concomitant treatments
Description of change
The following text was added to the end of the 
All supportive therapies restrictions: 
“Prophylactic use of growing factors is permitted 
according to regular institutional practice and the 
PI´s judgment.”
Rationale for change
To provide further guidance to investigators on 
the use of growing factors.
Section to be changed
Table 4.2.2.1: 1 Prior and concomitant treatments
Description of change
New row added. For treatment column following 
text was added: “Bisphosphonates”; for 
permitted column, following text was added: 
“These are allowed, according to regular clinical 
institutional practice and PI´s discretion (e.g. 
pamidronate, zoledronate, and alendronate). 
Caution may be exerted as they may affect renal 
function. Nephrotoxicity can be avoided by 
stringent adherence to infusion guidelines”
Rationale for change
To provide further guidance on bisphosphonates 
use
Section to be changed
4.2.2.2
Description of change
The following text was added to the end of the 
first paragraph: “One unit of alcohol is 10 mL (or 
8 g) of pure alcohol. Accordingly it may be 
calculated by using the following formula: 


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Alcohol units = Strength of the beverage 
(Alcohol by volume in %) x volume (mL) ÷ 
1,000”
Rationale for change
To anticipate potential questions from 
investigators about alcohol unit calculation
Section to be changed
5.1.2.1
Description of change
Text was added indicating that: 
-
In the induction phase, tumor assessments 
should be performed before treatment 
administration of Cycles 3 and 5.
-
The Week 18 tumor assessment must be held 
at Week 18 ±14 days, whether or not this 
assessment coincides with Cycle 7
-
In the maintenance phase tumor assessments 
can be delayed in cycles are delayed 
Rationale for change
To provide more clarity about tumor assessment 
time points in the induction phase, at Week 18 
and in the maintenance phase. 
Section to be changed
5.1.2.1
Description of change
Text was added to the fifth paragraph to specify 
that abdominal MRIs will be performed with 
contrast using gadolinium.
Rationale for change
To be aligned with the Investigator Site Image 
Manual from Parexel
Section to be changed
5.2.2.1
Description of change
Text was added to specify that progression of 
cancer (underlying disease) is exempted from 
reporting as an AE.
Rationale for change
For consistency with updated Section 5.2.2.2.
Section to be changed
5.2.2.1 (Protocol-specified adverse events of 
special interest)
Description of change
The elevation of AST and/or ALT required to 
define hepatic injury for patients with impaired 
liver function at baseline was changed from 
“≥3 x ULN” to “≥5 x ULN” 
Additionally, “Marked peak aminotransferase 
(ALT, and/or AST) elevations ≥10 fold ULN” 
was added to the list of laboratory abnormalities 
requiring follow up.
Rationale for change
To ensure consistency with Section 10.4.2.


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Section to be changed
5.2.2.2
Description of change
The guidance for reporting disease progression 
events was updated. A cross-reference was added 
to indicate that local regulations should be 
followed as described in Section 8.4.2. 
Rationale for change
To reflect new guidance for reporting of disease 
progression events.
Section to be changed
5.2.2.2 (Pregnancy)
Description of change
Text was added to clarify that pregnant 
participants must be excluded from the study and 
to provide detail on the procedure when a 
patient’s partner becomes pregnant. 
Rationale for change
Updated to include the Partner Pregnancy 
reporting requirement.
Section to be changed
5.2.3
Description of change
The definitions of active hepatitis B and active 
hepatitis C were updated, and text was added to 
indicate that HIV and TB screening assessments 
are not mandatory but should be done according 
to local practice and local regulatory guidance. 
Rationale for change
To further clarify the requirements for HIV test 
and TB status assessments.
Section to be changed
5.2.3
Description of change
The sentence “International normalized ratio and 
partial thromboplastin time will be measured at 
screening only.” was deleted. Additionally, text 
was added that permits coagulation parameters 
for inclusion criteria to be assessed locally where 
possible.
Rationale for change
To reflect the fact that International normalized 
ratio and partial thromboplastin time will not be 
assessed to the same schedule as other laboratory 
tests, and to ensure consistency with newly added 
inclusion criterion 9.
Section to be changed
5.2.4
Description of change
After “Patients should rest for at least 5 minutes 
in a supine position before ECG evaluations.” the 
following text was added: “Two consecutive 
recordings must be made.”
Rationale for change
To ensure consistency with Flow Chart 1.2.


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Section to be changed
5.2.5
Description of change
Second paragraph under Physical examination 
heading. The requirement for rectal examination 
was removed. 
Rationale for change
Rectal examination is not necessary unless signs 
or symptoms are present, as it is not a target area 
to be assessed. 
Section to be changed
6
Description of change
After the first sentence the following paragraph 
was added “Cycles must not be missed but delays 
may occur according to Tables 10.3:1 and 10.3:2. 
The maximum timeframe for treatment delay 
should be assessed based on the investigator´s 
clinical judgement and discussed with the trial 
medical monitor. However, patients with severe 
hypertension, moderate to severe proteinuria, or 
severe infusion reactions will not receive further 
treatment with Avastin®/BI695502 if the event 
cannot be adequately controlled within 14 days.”
Rationale for change
To further clarify the frequency of cycles
Section to be changed
6.1
Description of change
The bullet point “Each subsequent cycle will 
occur within 3 days (±3 days) of completion of 
the previous cycle.” Was amended to “Each 
subsequent cycle will occur 3 weeks (±3 days) 
after completion of the previous cycle.”
Rationale for change
To further clarify the timing of cycles


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Section to be changed
Table 6.1: 1
Description of change
Blood sample volumes for INR/PT/PTT were 
updated. The approximate total was also 
increased accordingly. 
Rationale for change
To reflect the increased number of measures of 
coagulation parameters. 
Section to be changed
6.2.1
Description of change
The third bullet point “Hepatitis B and hepatitis 
C (unless status has previously been confirmed 
within 6 months prior to Screening) and HIV test 
(all tests will be performed according to local 
practice and local regulatory guidance).” was 
replaced with two bullet points as follows: 
“•
Hepatitis B and hepatitis C (unless status 
has previously been confirmed within 6 months 
prior to Screening). • HIV test should be 
performed only if required per local practice and 
regulatory guidance.”
Rationale for change
To further clarify the requirements for HIV test 
and hepatitis B and hepatitis C assessments.
Section to be changed
6.2.1
Description of change
The following text was added to the end of the 
section: “Subjects are only allowed to be 
re-screened once and he/she must be 
re-consented before re-screening occurs.”
Rationale for change
To clarify the procedure for re-screening.
Section to be changed
6.2.2 (Cycles 2, 3, 4, 5, 6)
Description of change
The following text was added to the end of the 
eighth bullet point: “During the induction phase, 
the tumor evaluations must be performed every 2 
cycles. Therefore, if a cycle is delayed, the next 
tumor evaluation will also be delayed.”
Rationale for change
To further clarify the procedure for tumor 
assessments where a treatment cycle delay 
occurs.
Section to be changed
6.2.2 (Cycle 7 to Cycle 10 and onwards)
Description of change
The following text was added to the end of the 
eighth bullet point: “In case of a treatment cycle 
delay (i.e. due to toxicity), imaging assessment 
(e.g. CT, MRI) for the primary endpoint will be 
performed at Week 18 ±14 days (fixed time 


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point), regardless of the number of cycles 
administered to date and whether or not this 
assessment coincides with Cycle 7. After cycle 7, 
if a cycle is delayed, tumor assessment will also 
be delayed.”
Rationale for change
To further clarify the procedure for tumor 
assessments where a treatment cycle delay 
occurs.
Section to be changed
6.2.3
Description of change
Assessment of vital signs was added as a 
procedure for the safety follow-up visit.
Rationale for change
To clarify that vital signs should be assessed at 
safety follow-up.
Section to be changed
7.3.1.1
Description of change
Text specifying that a window of ±14 days will 
apply to the assessment of the primary efficacy 
endpoint at Week 18 was added
Rationale for change
To clarify handling of assessments performed 
within ±14 days of the planned Week 18 
assessment.
Section to be changed
7.3.6
Description of change
Details of pharmacokinetic analyses were 
updated
Rationale for change
To clarify the pharmacokinetic analyses that will 
be performed, and that details will be described 
in a separate analysis plan.
Section to be changed
8.1
Description of change
The following text was added to the end of the 
section: “In case of partner’s pregnancy, written 
Consent for Pregnancy Follow-up will be 
requested to the subject's partner in case of 
pregnancy. Follow-up on the pregnancy and its 


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outcome will be done to evaluate whether there 
are risks to the pregnant women or the unborn 
fetus.”
Rationale for change
To include the partner pregnancy ICF in the 
study protocol.
Section to be changed
Appendix 10.1
Description of change
The short axis measurement of nodal lesions that 
is considered pathologically enlarged and 
measurable was updated from >15 mm to 
≥15 mm. 
Rationale for change
To ensure consistency with RECIST guidelines. 
Section to be changed
Appendix 10.1 (CT and MRI)
Description of change
In the second paragraph, text was added to 
specify that MRIs will be performed with 
contrast using gadolinium.
Rationale for change
To be aligned with the Investigator Site Image 
Manual from Parexel
Section to be changed
Appendix 10.2
Description of change
Text was added to state that the dose of Avastin/
BI 695502 should be recalculated prior to each 
infusion. Clarifying text was also added to 
provide further guidance on IMP preparation.
Rationale for change
To clarify that the correct dose needs to be 
calculated at each infusion, and to provide further 
recommendations on preparation of IMP. 
Section to be changed
Appendix 10.3
Description of change
The following paragraph was added “Cycles are 
not skipped but delay may occur according to the 
Clinical Trial Protocol, Tables 10.3:1 and 10.3:2. 
Maximum timeframe treatment delay should be 
assessed based on the investigator´s clinical 
judgment and should be discussed with the study 
Medical Monitor. However, patients with severe 
hypertension, moderate to severe proteinuria, or 
severe infusion reactions will not receive further 
treatment with Avastin®/BI 695502 if the event 
cannot be adequately controlled within 14 days.
Rationale for change
To provide further information regarding delays 
to cycles 
Section to be changed
Appendix 10.3
Description of change
The following paragraph was added: “During the 


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induction phase, any chemotherapy delay 
mandates a bevacizumab/BI 695502 infusion 
delay. All three drugs of this regimen (paclitaxel 
+ carboplatin + bevacizumab/BI 695502) should 
always be administered together during the 
induction phase, if the patients fulfills the criteria 
for receiving the next treatment cycle.”
Rationale for change
To clarify how delays to chemotherapy affect 
bevacizumab treatment during the induction 
phase.
Section to be changed
Appendix 10.3
Description of change
In the fourth paragraph. “(according to regular 
institutional practice)” and the final sentence 
were deleted. The following text was added to 
the end of the paragraph: “The initial dose of 
paclitaxel (day 1, cycle 1) must be fixed to 200 
mg/m² for all study patients, as well as a dose of 
carboplatin to AUC: 6 mg/mL/min. In case of 
toxicity after this initial dose, the dose can be 
reduced in the event of toxicity according to the 
protocol guideline Table 4.1.4.1:1 and 10.3.1.”
Rationale for change
This change was made at the request of the 
regulatory authority, and to obtain a more 
homogeneous trial treatment population. The 
change was also made in anticipation of requests 
for initial dose at 175 mg.
Section to be changed
Appendix 10.3
Description of change
Text was added to instruct against the use of 
needles or intravenous sets containing aluminum 
parts that may come into contact with carboplatin 
when preparing or administering carboplatin, and 
to provide guidance on the preparation of 
carboplatin intravenous solutions. 
Rationale for change
To provide further guidance on carboplatin 
preparation and administration. 
Section to be changed
Appendix 10.3
Description of change
The following text was added to the end of the 
paragraph under Table 10.3: 1: “Other additional 
uses of G-CSF are allowed, according to regular 
institutional practice and the PI´s judgment.”
Rationale for change
Updated in response to investigator questions 
regarding use of G-CSF


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Section to be changed
Appendix 10.4.2
Description of change
The following text was added after the sentence 
following the third bullet point: “A copy of the 
DILI checklist should also be provided along 
with the SAE form.” to read “and report these via 
the electronic case report form. A copy of the 
DILI checklist should also be provided along 
with the SAE form.”
Rationale for change
To clarify that a copy of the DILI checklist 
should be sent along with the paper SAE form.


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Number of global amendment
4
Date of CTP revision
18 July 2016
EudraCT number
2014-002161-30
BI Trial number
1302.5
BI Investigational Product(s)
BI 695502
Title of protocol
A multicenter, randomized, double-blind Phase 
III trial to evaluate efficacy and safety of 
BI 695502 plus chemotherapy versus Avastin®
plus chemotherapy in patients with advanced 
nonsquamous Non-Small Cell Lung Cancer
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
3.3.2 
Description of change
In inclusion criterion 2, <22.6 mg/mmol 
creatinine was amended to <226 mg/mmol 
creatinine.
Rationale for change
To correct a typographical error.
Section to be changed
4.1.4.1
Description of change
The Cockroft-Gault formula was amended.
Rationale for change
To correct a typographical error.
Section to be changed
Throughout the protocol
Description of change
The trial number has been updated to 1302.5 
INVICTAN®-2
Rationale for change
The new brand name for the trial has been 
secured by BI Trade Marks and therefore the 
protocol has been updated to reflect the new trial 
name.


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Number of global amendment
5
Date of CTP revision
03 May 2017
EudraCT number
2014-002161-30
BI Trial number
1302.5 
BI Investigational Product(s)
BI 695502
Title of protocol
A multicenter, randomized, double-blind Phase 
III trial to evaluate efficacy and safety of 
BI 695502 plus chemotherapy versus Avastin® 
plus chemotherapy in patients with advanced 
nonsquamous Non-Small Cell Lung Cancer
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flowchart 1.2
Description of change
Clarification of non-treatment period visits added 
to footnote 17.
Rationale for change
To clarify the non-treatment period visits in the 
protocol and to ensure consistency with the ICF 
description.
Section to be changed
3.1, 6.1, 6.2.3
Description of change
Clarification of non-treatment period visits added
Rationale for change
To clarify the non-treatment period visits in the 
protocol and to ensure consistency with the ICF 
description.


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Number of global amendment
6
Date of CTP revision
26 October 2017
EudraCT number
2014-002161-30
BI Trial number
1302.5 
BI Investigational Product(s)
BI 695502
Title of protocol
A multicenter, randomized, double-blind Phase 
III trial to evaluate efficacy and safety of 
BI 695502 plus chemotherapy versus Avastin® 
plus chemotherapy in patients with advanced 
nonsquamous Non-Small Cell Lung Cancer
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title page
Description of change
Trial Clinical Monitor details updated to:
Phone:
Fax: 
Rationale for change
Administrative update.
Section to be changed
Flow chart 1.1, Flow chart 1.2
Description of change
The following text was added to the 12-lead ECG 
footnote:
The first of the consecutive ECGs is mandatory. 
The second of the consecutive ECGs is optional, 
at the discretion of the Investigator in case of 
clinical significance.
Rationale for change
To clarify that the second of the consecutive 


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ECGs is optional.
Section to be changed
4.1.4
Description of change
The following text was added:
Slight variations in BI 695502/US-licensed 
Avastin® dose may occur due to a change in a 
patient’s body weight; dose deviations with a 
margin of <5% will NOT be considered protocol 
deviations.
Rationale for change
To clarify the criteria for dose deviations to be 
considered protocol deviations. 
Section to be changed
5.2.4
Description of change
The first two paragraphs in this section were 
updated to:
Two consecutive resting 12-lead ECGs may be 
performed prior to administration of trial 
medication at the visits indicated in Flow 
chart 1.1 and Flow chart 1.2. The first of the 
consecutive ECGs is mandatory. The second of 
the consecutive ECGs is optional, at the 
discretion of the Investigator in case of clinical 
significance. Additional ECGs will be performed 
if clinically indicated.
Patients should rest for at least 5 minutes in a 
supine position before each of the two 
consecutive ECG evaluations.
Rationale for change
To clarify that the second of the consecutive 
ECGs is optional.
Section to be changed
9.1
Description of change
Details for references R15-1222 and R15-1223 
were updated.
Rationale for change
Administrative update.
Section to be changed
10.2
Description of change
Polyethylene bags and infusion sets made of 
polybutadiene were added to the table of special 
infusion sets that must be used for administration 
of BI 695502/US-licensed Avastin®.
Rationale for change
The use of polyethylene bags for infusion of 
BI 695502/US-licensed Avastin® is now 
permitted in this trial.
The use of polybutadiene infusion sets is 
common in day-to-day practice. The use of 
infusion sets made of polybutadiene for 


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administration of BI 695502 is now permitted in 
this trial.
Section to be changed
10.2
Description of change
The mandatory concentration of 
BI 695502/US-licensed Avastin® for intravenous 
infusion was updated to 16.5 mg/mL. Previously, 
the recommended concentration was from 
1.4 mg/mL to 16.5 mg/mL.
The following text was added:
If appropriate infusion materials are not 
available, a smaller investigational product
concentration of 1.4 mg/mL up to 16.5 mg/mL 
can be temporarily used until the required 
materials are available.
Rationale for change
Sponsor decision to change the administration 
instruction to allow only the use of 16.5 mg/mL 
concentration of BI 695502. In new compatibility 
studies, acceptance criteria were only fully met 
for the highest concentration tested 
(16.5 mg/mL) in all tested bags and infusion sets; 
visible and subvisible particles exceeded 
compendial limits for the lower concentration 
(1.4 mg/mL). This change of preparation of study 
medication does not increase the volume of 
investigational medicinal product preparation or 
the speed of infusion; therefore, there is no 
change in risk for the patient. The change in 
administration instructions also applies to US-
licensed Avastin® to avoid unintentional 
unblinding.


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Number of global amendment
7
Date of CTP revision
17 January 2018
EudraCT number
2014-002161-30
BI Trial number
1302.5
BI Investigational Product(s)
BI 695502
Title of protocol
A multicenter, randomized, double-blind Phase 
III trial to evaluate efficacy and safety of 
BI 695502 plus chemotherapy versus Avastin® 
plus chemotherapy in patients with advanced 
nonsquamous Non-Small Cell Lung Cancer
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synopsis, Flow chart 1.2, 3.1, 4.1.1, 4.1.2
Description of change
Text has been added to describe the 
recommendation of the Sponsor to switch from 
BI 695502 to Avastin® starting from 
21 Dec 2017. In addition, text is included to 
clarify that patients may continue temporarily to 
receive BI 695502 if Avastin® is not 
immediately available at the site.
Rationale for change
As a consequence of the observation of particles 
for IMP batches E6719F01 and E6719F02, the 
Sponsor has recommended that patients be 
switched from IMP BI 695502 to the reference 
medicinal product as soon as it is available at the 
respective clinical site. 
Section to be changed
Flow chart 1.2
Description of change
A new column has been added for the Switch 
Visit and assessments to be done at the new visit 
are included


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Rationale for change
To provide detailed information on what 
assessments need to be performed at the Switch 
Visit
Section to be changed
3.1, 3.3.4.1, 6.1, 6.2.3
Description of change
The End of Treatment (EOT) visit has been 
changed to 21 days after the last administration 
of trial medication (BI 695502 or Avastin®)
Rationale for change
To bring the EOT visit in line with the study 
visits which occur every 3 weeks.
Section to be changed
3.3.4.1, 4.2.1
Description of change
‘Congestive heart failure, any degree’ has been 
added to the possible reasons for permanently 
discontinuing trial treatment
Rationale for change
To clarify that the trial medication should be 
discontinued if the patient experiences 
congestive heart failure of any kind.
Section to be changed
4.1.3
Description of change
Text added to state that the recommended dose 
for Avastin® remains the same after the switch 
from BI 695502
Rationale for change
To clarify the administration of Avastin®
Section to be changed
4.1.4
Description of change
Text has been added to state that the first 
infusion of Avastin® for all patients after the 
switch visit should be delivered over 90 minutes. 
If well-tolerated, the second infusion should be 
delivered over 60 minutes, and if the 60 minute 
infusion is well tolerated all subsequent infusions 
can be administered over 30 minutes. 
Rationale for change
As this may be the first time a patient is exposed 
to Avastin®, the administration procedure should 
be according to the Avastin® label. This is for 
patient safety and also to maintain the blind
Section to be changed
4.1.5.1
Description of change
Text has been added to clarify that no unblinding 
of patients or sites will occur as a result of 
switching from BI 695502 to Avastin®
Rationale for change
To clarify that the double-blind of the trial will 
not be impacted by the switch from BI 695502 to 
Avastin®


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Section to be changed
4.1.6
Description of change
Text has been added to state that relabeling of 
commercially available Avastin® for trial 
purposes is not required
Rationale for change
To clarify that commercially available Avastin® 
will not be relabeled
Section to be changed
4.1.7
Description of change
Text has been added to state that after the switch 
visit, the sites should monitor the storage 
conditions of Avastin® in accordance with local 
requirements
Rationale for change
To clarify that the sites will no longer maintain 
the temperature log for Avastin®
Section to be changed
4.1.8
Description of change
Text has been added to clarify that after the 
patient has switched from BI 695502 to 
Avastin® the drug accountability details will be 
recorded
Rationale for change
To clarify the process for drug accountability 
after the switch from BI 695502 to Avastin®
Section to be changed
4.2.1
Description of change
Text added to provide clarification on process for 
evaluating proteinuria
Rationale for change
A memo has been provided to the sites to provide 
clarification on proteinuria assessment. The 
information from the memo has been added to 
the protocol for completeness
Section to be changed
6.1, 6.2.2
Description of change
Text added to describe the switch visit
Rationale for change
Clarification on timing of switch visit and the 


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assessments to be performed
Section to be changed
Flow chart 1.2, 3.1, 5.3.7, 6.1, 6.2.3
Description of change
The text has been modified to state that the 18-
week SFU visit will take place 18 weeks after the 
last dose of trial medication prior to the switch 
visit.
Also, text has been added to state that any patient 
who is still receiving treatment with Avastin® at 
18 weeks post the last BI 695502 dose will not 
have a SFU visit.
Rationale for change
The clarify the REP is 18 weeks after the last 
dose of trial medication and thus this is when the 
SFU should be performed.
Patients who are still being seen at the site every 
3 weeks will not need an additional SFU visit.
Section to be changed
6.2.3
Description of change
The end of trial definition has been updated to 
take into account that patients may continue to 
receive Avastin® after the SFU visit. The 
definition now states: “The trial will be closed 
when all randomized and treated patients have 
either died, are lost to follow-up, or have 
withdrawn consent, or for a maximum of 20 
months after the last patient randomized plus the 
EOT visit, whichever occurs earlier.”
Rationale for change
To update the end of trial definition to accurately 
reflect the updated trial design
Section to be changed
Synopsis, 7.1, 7.3
Description of change
Text has been added to state that the primary 
analysis was not impacted by the switch.
Text has been added to described the period 
covered by the main analyses plus that 
appropriate censoring methods will be applied at 
the time of switching.
Text has been added to describe how the impact 
of switching will be assessed.
Rationale for change
To provide clarification on the statistical methods 
to be used to analyze the study data as a result of 
switching
Section to be changed
7.3.5.1
Description of change
Text has been added to state that 5 DSMB 
meetings have taken place during the study to 


Boehringer Ingelheim
17 January 2018
BI Trial No.: 1302.5
Doc. No.: c02191106-09
Trial Protocol
Page 146 of 146
Proprietary confidential information. 
2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
date
Rationale for change
To provide further information on the DSMB 
meetings that have occurred and that all meetings 
recommended the continuation of the trial 
without modification 
Section to be changed
8.1
Description of change
Text has been added to state that patients will be 
informed orally by the investigator about the 
switch from BI 695502 to Avastin®. As soon as 
the updated ICF is available, informed consent 
will be obtained from all patients in the trial. 
Rationale for change
To clarify the informed consent procedures
Section to be changed
9.1
Description of change
Details for reference R15-1222 were updated to 
reflect latest version of the US Prescribing 
Information for Avastin®
Rationale for change
Administrative update.
Section to be changed
Appendix 10.2
Description of change
Text has been added to clarify the administration 
procedures to be used for Avastin®, to state that 
the Sponsor highly recommends the use of the 
same filters as for BI 695502 administration, and
to clarify the recommended concentration of 
Avastin® after switching
Rationale for change
To provide clarification on administration of 
Avastin®


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02191106
9.0
clinical-trial-protocol-version-08
A multicenter, randomized, double-blind Phase III trial to evaluate efficacy and
safety of BI 695502 plus chemotherapy versus Avastin plus chemotherapy in patients
with advanced nonsquamous Non-Small Cell Lung Cancer
Approval-Team Member Medicine
18 Jan 2018 10:54 CET
Approval-Clinical Pharmacokinetics
18 Jan 2018 10:55 CET
Author-Trial Clinical Monitor
18 Jan 2018 10:59 CET
Author-Trial Statistician
18 Jan 2018 11:27 CET
Approval-Therapeutic Area 
19 Jan 2018 09:43 CET
Verification-Paper Signature
Completion
23 Jan 2018 16:51 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02191106
9.0

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