Clinical trial NCT02776683
Conditions: Colorectal Neoplasms
Sponsor: Boehringer Ingelheim
Start date: 2016-06-08; Completion date: 2018-10-03
Enrollment: 123 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this trial is to evaluate the safety and tolerability of BI 695502 in combination with leucovorin/5-fluorouracil/oxaliplatin (mFOLFOX6) and as maintenance therapy (when applicable). As well as to evaluate the following efficacy parameters: Progression-free survival (PFS), objective response rate (proportion of patients with complete response \[CR\] plus partial response \[PR\]), overall survival (OS), duration of response (DOR), time to progression (TTP).

Detailed description:

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

Protocol documents:
Prot_001.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c08875184-06
EudraCT No.:
2015-003718-25
BI Trial No.:
1302.3 (INVICTAN®-3)
BI Investigational 
Product(s):
BI 695502
Title:
A single arm, open-label, multicenter, multinational, safety and 
efficacy Phase IIIb trial of BI 695502 plus mFOLFOX6 in 
patients with previously untreated metastatic colorectal cancer
Brief Title:
Open-label, single arm trial of BI 695502 in patients with 
previously untreated metastatic colorectal cancer
Clinical Phase:
IIIb
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
Phone:
Fax: 
Status:
Final Protocol (Revised Protocol based on global amendment 
05)
Version and Date
Version: 6.0
Date: 17 January 2018
Page 1 of 115
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.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
04 NOVEMBER 2015
Trial number:
1302.3
Revision date:
17 January 2018
Title of trial:
A single arm, open-label, multicenter, multinational, safety and efficacy Phase IIIb
trial of BI 695502 plus mFOLFOX6 in patients with previously untreated metastatic 
colorectal cancer
Coordinating
Investigator:
Trial site(s):
Multinational, multicenter trial in approximately 50 clinical sites.
Clinical phase:
IIIb
Objective(s):
Primary objective:

The primary objective of this trial is to evaluate the safety and tolerability of 
BI 695502 in combination with leucovorin/5-fluorouracil/oxaliplatin 
(mFOLFOX6) and as maintenance therapy (when applicable).
Secondary objectives:

To evaluate the following efficacy parameters: Progression-free survival (PFS), 
objective response rate (proportion of patients with complete response [CR] plus 
partial response [PR]), overall survival (OS), and duration of response (DOR), 
time to progression (TTP).
Further objectives:

 

To evaluate the presence of ADAs and nADAs.
Methodology:
This is a Phase IIIb, open-label, multicenter, multinational, single arm trial. The trial 
will investigate the safety, efficacy, 
 immunogenicity of BI 695502 in 
patients with previously untreated metastatic colorectal cancer (mCRC), who will 
receive BI 695502 in combination with mFOLFOX6 chemotherapy every 2 weeks 
until disease progression, death, unacceptable toxicity or the end of the trial, 
whichever occurs earlier. Based on patient tolerability, at least 8 cycles of 
mFOLFOX6 should be given to all patients. If the Investigator decides to stop 
oxaliplatin at any time during the study, patients should continue to receive 
infusional 5FU + leucovorin with BI 695502 until progression. The efficacy analysis 
will be based upon the evaluation of tumor imaging as per the Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 and as assessed by central imaging review.
Starting as of 21 Dec 2017, the Sponsor recommends that patients should be 
switched from BI 695502 to the reference product bevacizumab (commercially 
available Avastin®, 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. Patients will continue the study
with no additional visits in the scheduled visit cycle as per protocol.
Patients who discontinue treatment with chemotherapy or BI 695502 or both, but do 
not have disease progression and have not started a new anticancer therapy, will 


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Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
04 NOVEMBER 2015
Trial number:
1302.3
Revision date:
17 January 2018
continue in the trial in the non-treatment period until disease progression or initiation 
of a new anticancer therapy, whichever occurs first.
All patients who receive at least one infusion of BI 695502 will attend a Follow-up 
visit 30 days after the last administration of BI 695502 or Avastin® whichever 
occurs later.
Patients will attend a long-term Safety Follow-up (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 BI 695502 dose, then no 
SFU visit will be performed.
After the long-term SFU visit or discontinuation of Avastin® (whichever occurs 
later), all patients will be monitored for survival every 3 months via telephone call 
until death or until the trial is closed, whichever occurs earlier.
The trial will be closed when all enrolled and treated patients have either died, are 
lost to follow-up, have withdrawn consent, or for a maximum of 12 months after the 
last patient enrolled plus the 30-day FU visit, whichever occurs earlier.
No. of patients:
total entered:
Approximately 120 patients will be enrolled in the trial to receive BI 695502 
concentrate for solution for intravenous (i.v.) infusion.
each treatment:
Not applicable.
Diagnosis:
Males and females with histologically confirmed mCRC not amenable to surgical 
curative treatment and eligible to receive therapy with mFOLFOX6 + bevacizumab.
Main criteria
for inclusion:
Patients aged ≥18 (for Japan only: Age ≥20 years at time of signing the informed 
Consent Form [ICF]) who have received no prior therapy for metastatic disease and 
have completed any adjuvant/neoadjuvant therapy at least 12 months before trial
entry. Patients must have at least one measurable lesion according to RECIST 1.1 
that has not been irradiated within 12 weeks prior to enrollment and an Eastern 
Cooperative Oncology Group (ECOG) performance status (PS) 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:
5 mg/kg every 2 weeks (14 days)
mode of 
administration:
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:
None.
Additional protocol 
medication:
Starting as of 21 Dec 2017, the Sponsor recommends that patients should be 
switched from BI 695502 (5 mg/kg every 2 weeks) 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:
Full description of mFOLFOX6 regimen: 

Oxaliplatin 85 mg/m2 i.v. over 2 hours, Day 1 


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Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
04 NOVEMBER 2015
Trial number:
1302.3
Revision date:
17 January 2018

Leucovorin 400 mg/m2 i.v. over 2 hours, Day 1

5-fluorouracil (5-FU) 400 mg/m2 i.v. bolus on Day 1, then 1200 mg/m2/day x 2 
days (total 2400 mg/m2 over 46-48 hours) i.v. continuous infusion
Duration of treatment:
Treatment with BI 695502 or Avastin® in combination with mFOLFOX6 
chemotherapy every 2 weeks until disease progression according to RECIST 1.1,
death, unacceptable toxicity, or the end of the trial, whichever occurs earlier. Based 
on patient tolerability, at least 8 cycles of mFOLFOX6 should be given to all 
patients. If the Investigator decides to stop oxaliplatin at any time during the study, 
patients should continue to receive infusional 5FU + leucovorin with BI 695502 or 
Avastin® until progression.
Based on patient tolerability, the doses of chemotherapy drugs may be decreased as 
per the label or institutional practice. 
Endpoints:
Primary safety endpoint:

Patients with any of the following selected adverse events (AEs):
o
Anaphylactic reactions/hypersensitivity reactions/infusion-related 
reactions
o
Thromboembolic events:

Arterial

Venous
o
Gastrointestinal (GI) perforations
o
Hypertension
o
Proteinuria
o
Pulmonary hemorrhage
o
All hemorrhages and pulmonary hemorrhages
o
Wound-healing complications including abscess and fistulas
o
Posterior reversible encephalopathy syndrome
o
Ovarian failure.
Secondary efficacy endpoints:

PFS is defined as the time from first administration of trial medication until 
disease progression as assessed by central imaging review according to RECIST 
1.1 or death of any cause.

Objective response according to RECIST 1.1 as assessed by central imaging 
review 

DOR defined as the time from first documented CR or PR until time of 
progression as assessed by central imaging review.

TTP defined as the time from first administration of trial medication to the date 
of tumor progression, as assessed by central imaging review.

OS defined as the time from first administration of trial medication until death 
from any cause.
Immunogenicity:
Further Endpoints

ADAs/nADAs at Weeks 0, 4, 8, 16, 24, 32, 40 and 52 and 30-day Follow-up 


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Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
04 NOVEMBER 2015
Trial number:
1302.3
Revision date:
17 January 2018
visits and long-term SFU visit. 
Pharmacokinetics:
 
Safety criteria:
Other safety endpoints

All AEs including AEs related to trial treatment, assessed according to National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 4.0.

All protocol-specified adverse events of special interest.

All AEs potentially related to immunogenicity.
Other safety evaluations will include: physical examination, vital signs (blood
pressure, pulse rate, respiratory rate, and body temperature), weight, 12-lead 
electrocardiogram (ECG), and laboratory findings.
Statistical methods:
Primary safety analysis:
No hypothesis testing will be performed in this single arm trial. All AEs with an 
onset between start of treatment and end of the residual effect period (REP), a period 
of 18 weeks after the last dose of trial medication, will be considered. The 
proportion of patients with at least one AE selected for primary endpoint assessment 
will be displayed including descriptive 95% confidence intervals (CIs) for the 
proportion of patients with selected AEs.
Secondary analyses:
PFS will be analyzed descriptively using Kaplan-Meier methodology. The treated set 
will be used for analysis. The 1-year PFS rate and the median PFS will be estimated 
with 95% CIs.
Objective response rate will be analyzed descriptively with 95% CIs. Duration of 
response, TTP and OS will be analyzed descriptively using Kaplan-Meier 
methodology. 
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 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 main analyses will cover the period during which patients received BI 695502
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.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695502
Protocol date:
04 NOVEMBER 2015
Trial number:
1302.3
Revision date:
17 January 2018
After the transition from BI 695502 to Avastin®, 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. 


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Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
FLOW CHART 1.1 – CYCLE 1 TO CYCLE 13
Trial Period
Screening
Treatment
Visit
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Cycle
NA
1
2
3
4
5
6
7
8
9
10
11
12
13
Week
-4 to -1
0
2
4
6
8
10
12
14
16
18
20
22
24
Day
-28 to -1
1
15
29
43
57
71
85
99
113
127
141
155
169
Permitted visit window (days)*
-
-
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
Informed consent
X
Tumor biopsy/RAS status1
X
Assessment of eligibility 
X
X
Demographics
X
Medical and surgical history
X
Infection screen (hepatitis B, 
hepatitis C), and optional HIV test2
X
TB Test2
X
LABORATORY/SAFETY ASSESSMENTS
Serum pregnancy test3
X
Urine pregnancy test3, 4
X
X
X
X
X
X
X
Urine protein analysis5
X
X
X
X
X
X
X
Physical examination (including 
height at Screening only and 
weight)6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BMI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BSA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests (serum chemistry, 
including DILI if indicated 
hematology, coagulation
urinalysis,)8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG9
X
X
X
X
X
Previous/concomitant 
therapy/medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events10
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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FLOW CHART 1.1 – CYCLE 1 TO CYCLE 13 (continued)
Trial Period
Screening
Treatment
Visit
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Cycle
NA
1
2
3
4
5
6
7
8
9
10
11
12
13
Week
-4 to -1
0
2
4
6
8
10
12
14
16
18
20
22
24
Day
-28 to -1
1
15
29
43
57
71
85
99
113
127
141
155
169
Permitted visit window (days)*
-
-
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
DISEASE ASSESSMENTS
Tumor assessment (CT11/MRI 
scan)
X12
X
X
X
ECOG performance status
X
X
X
X
X
Survival
X--------------------------------------------------------------------------------------------------------------------------------
OTHER ASSESSMENTS
Anti-drug antibodies14
X
X
X
X
X
Neutralizing anti-drug antibodies14
X
X
X
X
X
TRIAL MEDICATION
Enrollment15
X
Contact IXRS®
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial medication infusion
X14
X
X
X
X
X
X
X
X
X
X
X
X
Chemotherapy administration16
X
X
X
X
X
X
X
X
X
X
X
X
X
BMI = body mass index; BSA = body surface area; CT = computerized tomography; DILI = drug induced liver injury ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; HIV human immunodeficiency virus; INR – International normalized ratio, PTT = partial thromboplastin time; IXRS® = Interactive Telephone and Web 
Response System; MRI = magnetic resonance imaging; NA = not applicable; 
TB = tuberculosis.
*
If a visit occurs outside the specified time window, then the next visit will be based on the number of days from the previous visit, and not the number of days from baseline
1.
Tumor histology and RAS status must be confirmed at entry; if not performed/available, and no archival tumor sample is available, a fresh biopsy will be performed if 
possible and analyzed locally (see Section 5.6.2 for details).
2.
Hepatitis B and C testing to be performed at Screening unless obtained within 6 months prior to Screening. Screening for HIV and TB will be performed according to local 
practice and local regulatory guidance.
3.
Only for females of childbearing potential. Serum pregnancy test to be performed at Screening and if a urine pregnancy test is positive.
4.
Only for females of childbearing potential. Urine pregnancy test will be performed every 4 weeks.
5.
Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection as per local laboratory practices. Suspend BI 695502 
administration for proteinuria ≥2 g in 24 hours and resume when proteinuria is <2 g in 24 hours. If moderate to severe proteinuria (2+ or greater urine dipstick reading) cannot 
be controlled within 14 days then the patient should discontinue BI 695502.
6.
Will be performed prior to administration of trial medication. 
7.
Sitting blood pressure (after at least 5 minutes rest), respiratory rate, pulse, and body temperature. Two or more blood pressure readings should be taken at 2 minute intervals 
and averaged. If the first diastolic readings differ by more than 5 mmHg, then an additional reading should be obtained, and all readings averaged.


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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 ECGs may be performed every 3 cycles unless clinically indicated. 
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.
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 long-term Safety Follow-up 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 contrast product injection of, chest, abdomen and pelvis ± involved area. In case of contrast product injection allergy, an abdomen-pelvic MRI will be performed 
together with a non-contrast chest CT scan. Tumor assessment will be performed every 8 weeks (±3 days) up to Visit 21, every 12 weeks (±3 days; ±7 days from Visit 28
onwards) from Visit 21 onwards and every 8 weeks (±3 days) during the non-treatment period. Tumor assessments will be done until progression of disease.
12. To be performed within 28 days of enrollment.
 
 
14. If sampled on a day when trial medication is administered, anti-drug antibody and neutralizing anti-drug antibody samples should be taken prior to trial medication 
administration. 
15. Cycle 1 treatment to be administered within 4 days after enrollment.
16. Chemotherapy will be administered according to the standard preparation and infusion procedures of each investigational site. See Table 4.1.4.1 for details.


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FLOW CHART 1.2 – CYCLE 14 ONWARDS
Visit
14
15
16
17 to 
25
26
27
28 
onwards 
(until 
PD1)
Switch visit, prior to 
Avastin® 
administration19
Non-treatment 
period 2,3
30-
day 
FU4
Long-
term 
SFU5
Survival6
Cycle
14
15
16
17 to 
25
26
27
28 
onwards
Week
26
28
30
32 to 
48
50
52
54 
onwards
Day
183
197
211
225 
to 
337
351
365
379
Permitted visit window (days)*
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 7 days
-
± 3 
days
+ 7 
days
LABORATORY/SAFETY 
ASSESSMENTS
Serum pregnancy test7
X
X
Urine pregnancy test7
X
X
X
X
X
Urine protein analysis8
X
X
X
X
X
Physical examination (including 
weight)
X
X
X
X
X
X
X
X
X
X
X
BMI
X
X
X
X
X
X
X
X
X
X
X
BSA
X
X
X
X
X
X
X
Vital signs9
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests (serum chemistry, 
including DILI if indicated, 
hematology, coagulation and 
urinalysis,)10
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG11
X
X
X
X
X
Previous and concomitant 
therapy/medication12
X
X
X
X
X
X
X
X
X
X
X
Adverse events13
X
X
X
X
X
X
X
X
X
X
X
Date of initiation of new anticancer 
therapy (if applicable)
X
X
X
X
Survival
X-------------------------------------------------------------------------------------------------------------------------------------------X


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FLOW CHART 1.2 – CYCLE 14 ONWARDS (CONTINUED)
Visit
14
15
16
17 to 25
26
27
28 
onwards 
(until 
PD1)
Switch visit, prior to 
Avastin 
administration19
Non-
treatment 
period 2,3
30-
day 
FU4
Long-
term 
SFU5
Survival6
Cycle
14
15
16
17 to 25
26
27
28 
onwards
Week
26
28
30
32 to 48
50
52
54 
onwards
Day
183
197
211
225 to 
337
351
365
379
Permitted visit window (days)*
± 3 
days
± 3 
days
± 3 
days
± 3 days
± 3 
days
± 3 
days
± 7 days
-
± 3 
days
+ 7 days
DISEASE ASSESSMENTS
Tumor assessment (CT14/MRI 
scan)
Cycle 17 
and 21 
X
X
X15
X
X15
ECOG performance status16
Cycle 17 
and 21
X
X
OTHER ASSESSMENTS
 
Anti-drug antibodies17
Cycle 17 
and 21
X
X
X
X
Neutralizing anti-drug 
antibodies17
Cycle 17 
and 21
X
X
X
X
TRIAL MEDICATION
Contact IXRS®18
X
X
X
X
X
X
X
Trial medication infusion18, 20
X
X
X
X
X
X
X
X
Chemotherapy administration18
X
X
X
X
X
X
X
X
End of Trial and Safety Follow 
up
X
ADA = anti-drug antibody; BMI = body mass index; BSA = body surface area; CT = computerized tomography; DILI = drug induced liver injury ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; IXRS® = Interactive Telephone and Web Response System; MRI = magnetic resonance imaging; NA = not applicable; PD = 
progressive disease; 
; SFU = Safety Follow-up
*
If a visit occurs outside the specified time window, then the next visit will be based on the number of days from the previous visit, and not from the number of days from 
baseline


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Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
Patients that continue to receive treatment from Cycle 28 and beyond will attend the trial site every 12 weeks, until disease progression or trial closure, whichever occurs 
earlier.
2.
For all patients who discontinue BI 695502 or Avastin®, do not withdraw consent and who do not have disease progression, visits will occur every 8 weeks until 
initiation of new anti-cancer therapy, disease progression, death, or the end of the trial, whichever occurs earlier
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. Tumor assessments and all AEs (serious and non-serious as well as AEs of special interest), 
regardless of relatedness, will be collected at these visits. The date of initiation of second-line therapy should be recorded (if applicable).
4.
All patients who received at least one infusion of BI 695502 will attend a Follow-up Visit 30 days after the last administration of BI 695502 or Avastin® once they have 
either completed trial therapy or discontinued from trial treatment.
5.
All patients should attend a long-term 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 BI 695502 dose, then no SFU visit will be performed. All patients who prematurely discontinue BI 695502 for 
reasons other than disease progression must be followed up as per Section 6.2.3.
6.
After the long-term SFU visit or discontinuation of Avastin® (whichever occurs later) all patients will be monitored for survival every 3 months via telephone call until 
death, lost to follow-up, withdrawal of consent, or a maximum of 12 months after the last patient enrolled plus the 30-day FU visit, whichever occurs earlier.
7.
Females of childbearing potential only. Urine pregnancy test to be performed every 2 cycles (4 weeks) until Cycle 28 and every 12 weeks thereafter. A serum pregnancy 
test should be performed if urine pregnancy test is positive.
8.
Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection as per local laboratory practices. Suspend 
BI 695502 or Avastin® administration for proteinuria ≥2 g in 24 hours and resume when proteinuria is <2 g in 24 hours. If moderate to severe proteinuria (2+ or greater
urine dipstick reading) cannot be controlled within 14 days then the patient should discontinue BI 695502 or Avastin®.
9.
Sitting blood pressure (after at least 5 minutes rest), 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.
10. 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. Laboratory tests will be performed every 2 weeks until Cycle 28, every 12 weeks from Cycle 28 onwards and during the non-treatment and 
follow-up periods
11. Patients should rest for at least 5 minutes in a supine position before ECG evaluations. Two consecutive ECGs may be performed every 3 cycles until Cycle 28 and every 
12 weeks from Cycle 28 onwards. 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.
12. Concomitant medication to be recorded every 2 weeks until Cycle 27, every 12 weeks from Cycle 28 onwards and during the non-treatment and follow-up periods
13. All adverse events, regardless of relatedness, will be collected from the time of informed consent until 18 weeks after the last administration of trial medication. Adverse 
events continuing at the long-term Safety Follow-up 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. Please see Section 5.3.7 for further details on collection of adverse events. Adverse events will be 
assessed every 2 weeks until Cycle 28, every 12 weeks after Cycle 28 and during the non-treatment and follow-up periods.
14. CT scan with contrast product injection of chest, abdomen and pelvis ± involved area. In case of contrast product injection allergy, an abdomen-pelvic MRI will be 
performed with a non-contrast chest CT scan. Tumor assessment will be performed every 8 weeks (±3 days) up to Visit 21 and every 12 weeks (±3 days; ±7 days from 
Visit 28 onwards) from Visit 21 onwards. No CT scan is needed at Visit 28 if the patient received a CT scan at Visit 27. During the non-treatment period CT scans will 
be performed every 8 weeks (±3 days).
15. To be performed only if a tumor assessment was not performed within the previous 4 weeks. Note: Another unscheduled tumor assessment should be performed 6 weeks 
after the switch visit and no longer than 13 weeks after this visit.
16. ECOG to be performed every 4 cycles from Cycle 5 to Cycle 21, and at Cycle 27.


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18. Chemotherapy will be administered according to the standard preparation and infusion procedures of each investigational site. See Table 4.1.4.1 for details. Based on 
patient tolerability, the doses of chemotherapy drugs may be decreased as per the label or institutional practice. Trial medication infusion and chemotherapy will be 
administered every 2 weeks from Cycle 28 onwards. The sites will not be required to contact IXRS after the switch visit while the patient remains on Avastin®. At the 
time of Avastin® discontinuation, the site must contact IXRS to perform the discontinuation call.
19. 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. 
20. 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 will 
receive Avastin® during the Cycle Visits, as soon as the 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 TO CYCLE 13..................................................................7
FLOW CHART 1.2 – CYCLE 14 ONWARDS...................................................................10
TABLE OF CONTENTS ......................................................................................................14
ABBREVIATIONS................................................................................................................18
1.
INTRODUCTION...............................................................................................20
MEDICAL BACKGROUND.............................................................................20
1.1
DRUG PROFILE................................................................................................20
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....22
RATIONALE FOR PERFORMING THE TRIAL.........................................22
2.1
TRIAL OBJECTIVES........................................................................................22
2.2
2.2.1
Primary objective................................................................................................22
2.2.2
Secondary objectives...........................................................................................23
.............................................................................................23
BENEFIT - RISK ASSESSMENT.....................................................................23
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................26
OVERALL TRIAL DESIGN AND PLAN .......................................................26
3.1
3.1.1
Administrative structure of the trial .................................................................27
DISCUSSION OF TRIAL DESIGN..................................................................27
3.2
SELECTION OF TRIAL POPULATION .......................................................27
3.3
3.3.1
Main diagnosis for trial entry ............................................................................28
3.3.2
Inclusion criteria .................................................................................................28
3.3.3
Exclusion criteria ................................................................................................29
3.3.4
Removal of patients from therapy or assessments...........................................30
Removal of individual patients .............................................................................30
3.3.4.1
Discontinuation of the trial by the Sponsor ..........................................................32
3.3.4.2
4.
TREATMENTS...................................................................................................33
TREATMENTS TO BE ADMINISTERED.....................................................33
4.1
4.1.1
Identity of BI investigational product...............................................................33
4.1.2
Method of assigning patients to treatment groups...........................................33
4.1.3
Selection of doses in the trial..............................................................................33
4.1.4
Drug assignment and administration of doses for each patient......................34
Chemotherapy.......................................................................................................36
4.1.4.1
4.1.5
Blinding and procedures for unblinding...........................................................36
Blinding.................................................................................................................36
4.1.5.1
Unblinding and breaking the code ........................................................................36
4.1.5.2
4.1.6
Packaging, labeling, and re-supply....................................................................36


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4.1.7
Storage conditions...............................................................................................36
4.1.8
Drug accountability.............................................................................................36
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................37
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....37
4.2.2
Restrictions ..........................................................................................................38
Restrictions regarding concomitant treatment ......................................................38
4.2.2.1
Restrictions on diet and life style..........................................................................40
4.2.2.2
Restrictions regarding women of childbearing potential ......................................40
4.2.2.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................41
TRIAL ENDPOINTS..........................................................................................41
5.1
5.1.1
Primary endpoint................................................................................................41
5.1.2
Secondary endpoints...........................................................................................41
5.1.3
Further endpoints ...............................................................................................41
ASSESSMENT OF EFFICACY........................................................................42
5.2
5.2.1
Progression-free survival....................................................................................42
5.2.2
Objective response ..............................................................................................42
5.2.3
Duration of response...........................................................................................43
5.2.4
Time to progression ............................................................................................43
5.2.5
Overall survival...................................................................................................43
ASSESSMENT OF SAFETY.............................................................................43
5.3
5.3.1
Physical examination ..........................................................................................43
5.3.2
Vital signs.............................................................................................................43
5.3.3
Safety laboratory parameters ............................................................................44
5.3.4
Electrocardiogram ..............................................................................................45
5.3.5
Other safety parameters.....................................................................................45
Tuberculosis assessment .......................................................................................45
5.3.5.1
5.3.6
Assessment of adverse events.............................................................................46
Definitions of AEs ................................................................................................46
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................49
 
ASSESSMENT OF EXPLORATORY BIOMARKER(S)..............................52
5.5
OTHER ASSESSMENTS...................................................................................52
5.6
5.6.1
Immunogenicity assessment...............................................................................52
5.6.2
Tumor biopsy.......................................................................................................54
APPROPRIATENESS OF MEASUREMENTS..............................................54
5.7
6.
INVESTIGATIONAL PLAN.............................................................................55
VISIT SCHEDULE.............................................................................................55
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................56
6.2
6.2.1
Screening period..................................................................................................56
6.2.2
Treatment period(s)............................................................................................57
6.2.3
Follow-up Period and Trial Completion...........................................................60


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................63
STATISTICAL DESIGN - MODEL.................................................................63
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................63
7.2
PLANNED ANALYSES.....................................................................................63
7.3
7.3.1
Primary endpoint analyses.................................................................................63
Primary safety analysis .........................................................................................63
7.3.1.1
7.3.2
Secondary endpoint analyses .............................................................................64
7.3.3
Safety analyses.....................................................................................................64
7.3.4
Immunogenicity analyses ...................................................................................65
INTERIM ANALYSES ......................................................................................65
7.4
HANDLING OF MISSING DATA ...................................................................66
7.5
7.5.1
Efficacy endpoints...............................................................................................66
7.5.2
Safety and other endpoints.................................................................................66
RANDOMIZATION...........................................................................................66
7.6
DETERMINATION OF SAMPLE SIZE .........................................................66
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........68
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................68
DATA QUALITY ASSURANCE ......................................................................69
8.2
RECORDS...........................................................................................................69
8.3
8.3.1
Source documents ...............................................................................................69
8.3.2
Direct access to source data and documents.....................................................70
8.3.3
Storage period of records (Japan only).............................................................70
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS71
8.4
8.4.1
Listedness.............................................................................................................71
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................71
STATEMENT OF CONFIDENTIALITY........................................................71
8.5
END OF TRIAL..................................................................................................71
8.6
PROTOCOL VIOLATIONS (JAPAN ONLY)................................................72
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY (JAPAN ONLY) ................................................72
9.
REFERENCES....................................................................................................73
PUBLISHED REFERENCES............................................................................73
9.1
UNPUBLISHED REFERENCES......................................................................75
9.2
10.
APPENDICES.....................................................................................................76
GUIDELINES FOR EVALUATION OF OBJECTIVE RESPONSE USING 
10.1
RECIST 1.1 CRITERIA (RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS) ..............................................................................................76
GUIDELINES FOR BI 695502 OR AVASTIN® PREPARATION AND 
10.2
ADMINISTRATION ..........................................................................................84


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CHEMOTHERAPY REGIMENS AND RECOMMENDATIONS FOR 
10.3
DOSE MODIFICATIONS IN CASES OF TOXICITY..................................85
CLINICAL EVALUATION OF LIVER INJURY ..........................................85
10.4
10.4.1
Introduction.........................................................................................................85
10.4.2
Procedures ...........................................................................................................85
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................88


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ABBREVIATIONS
5-FU
5-Fluorouracil
ADA
Antidrug antibody
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BSA
Body surface area
BMI
Body mass index
CA
Competent Authority
CI
Confidence interval
CR 
Complete response
CRC
Colorectal cancer
CRO
Contract Research Organization
CT 
Computed tomography
CTP
Clinical Trial Protocol
DILI
Drug-induced liver injury
DOR
Duration of response
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid 
EMA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C
HIV
Human immunodeficiency virus
i.v.
Intravenous
ICF
Informed consent form
ICH 
International Conference on Harmonisation
IEC
Independent Ethics Committee
Ig
Immunoglobulin
INR
International normalized ratio
INVICTAN®-3
Trial name
IRB
Institutional Review Board
ISF
Investigator Site File
IXRS
Interactive Telephone and Web Response System


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KM
Kaplan-Meier
mCRC
Metastatic colorectal cancer
MedDRA 
Medical Dictionary for Regulatory Activities
mFOLFOX6
Leucovorin/5-Fluorouracil/Oxaliplatin
MRI
Magnetic resonance imaging
nADA
Neutralizing antidrug antibody
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse 
Events
NE
Not evaluable
NSAIDs
Non-steroidal anti-inflammatory drugs 
NSCLC
Non-small cell lung cancer
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetic(s)
PPD
Purified protein derivative
PR
Partial response
PRES
Posterior reversible encephalopathy syndrome
PS
Performance status
PT
Prothrombin time
PTT
Partial thromboplastin time
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
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
TB
Tuberculosis
TSAP
Trial Statistical Analysis Plan
TTP
Time to Progression
ULN
Upper limit of normal
US
United States
VEGF
Vascular endothelial growth factor


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Colorectal cancer (CRC) is the third most common cancer in men (746,000 cases, 10.0% of 
the total cancers) and the second most common cancer in women (614,000 cases, 9.2% of the 
total cancers) worldwide. Almost 55% of the cases occur in developed regions. About 
694,000 deaths from CRC are estimated worldwide, accounting for 8.5% of all cancer deaths, 
making it the fourth most common cause of death from cancer (R15-3504). 
While surgery is the cornerstone treatment for early stage cancer (stage I–III), chemotherapy 
is the first treatment option for metastatic disease (stage IV) when metastases are not 
resectable. Approximately 25% of patients will present with metastases at time of initial 
diagnosis and almost 50% of patients will develop metastases after initial surgery with or 
without adjuvant therapy, contributing to the high mortality rates reported for CRC. The 
CRC-related 5-year survival rate approaches 60% (R15-4644).
Many different trials have shown that the addition of bevacizumab to standard chemotherapy 
regimens (5-fluorouracil [5-FU]/leucovorin, capecitabine, oxaliplatin) improved outcomes in 
patients with metastatic CRC (mCRC) in the first-line (R05-2504, R13-1115, R11-2707) and 
second-line settings (R06-2690, R07-4623, R13-1117, R13-1112).
Avastin® was approved for treatment of mCRC, in first-line setting by the European 
Medicines Agency (EMA) in January 2005 and by the FDA in February 2004, and was 
approved by the Food and Drug Administration (FDA) in second-line setting in June 2006.
DRUG PROFILE
1.2
BI 695502, a monoclonal antibody, is being developed as a proposed biosimilar product to 
the bevacizumab product Avastin® approved in the European Union (EU), the United States 
(US) (R18-0043, R15-1223) and in Japan. BI 695502 is a genetically engineered humanized 
monoclonal antibody directed against human vascular endothelial growth factor (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.
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 mCRC (US, EU), 
advanced non-small cell lung cancer (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) (R18-0043, R15-1223). The local approval status for 
Avastin® can differ in countries outside of the US and the EU.


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For a more detailed description of the drug profile refer to the current Investigator’s 
Brochure, which is included in the Investigator Site File (ISF).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
BI 695502 is being developed as a proposed biosimilar to Avastin®, 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 sequentially a high degree of similarity 
(i.e., statistical similarity) between the biosimilar and originator compound, while also 
demonstrating a high degree of similarity (but not necessarily statistical similarity) for safety 
and immunogenicity.
The demonstration of equivalent efficacy and safety will be made in the most sensitive 
indication to comply with the agency advice, i.e., in non-squamous NSCLC using objective
response rate as the most sensitive endpoint to detect any meaningful differences.
However, the addition of bevacizumab to chemotherapy has also been shown to be effective 
in both wild-type and mutated K-ras mCRC (R18-0043, R15-1223, R13-1110). 
The results of the Phase I trial (1302.1) have already demonstrated pharmacokinetic 
similarity between BI 695502, EU-approved Avastin®, and US-licensed Avastin® (see 
Section 2.3 for details). The demonstration of equivalence in efficacy is being conducted in 
the most sensitive indication of NSCLC to comply with the regulatory requirements. The 
value of addition of bevacizumab to chemotherapy has been shown to be effective in mCRC 
and is the most widely prescribed indication for bevacizumab (R18-0043, R15-1223,
R13-1110). While the Sponsor plans to obtain extrapolation across all labeled indications for 
bevacizumab based on the NSCLC data through the biosimilar regulatory pathway, 
generation of additional safety and efficacy data of BI 695502 in mCRC will be of value to 
the treating physician and patients. The trial will be a single arm trial to further assess the 
safety, tolerability and efficacy of BI 695502 in mCRC.
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.
TRIAL OBJECTIVES
2.2
2.2.1
Primary objective
The primary objective of this trial is to evaluate the safety and tolerability of BI 695502 in 
combination with mFOLFOX6 and as maintenance therapy (when applicable). 


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2.2.2
Secondary objectives
The secondary objectives of the trial are:  

To evaluate the following efficacy parameters: Progression-free survival (PFS), objective 
response rate (proportion of patients with complete response [CR] plus partial response 
[PR]), overall survival (OS), duration of response (DOR), time to progression (TTP).
BENEFIT - RISK ASSESSMENT
2.3
Patient risk will be minimized by implementing conservative eligibility criteria and 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 in selected liver laboratory parameters to 
ensure patients´ safety, see also Section 5.3.6.1.
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 
(R18-0043, R15-1223). 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 mCRC 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. 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 


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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 5.3.7). 
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 anti-hypertensive therapy) are excluded from this trial. Blood pressure will be 
monitored every 2 weeks during the trial. Patients who develop hypertension should be 
treated with appropriate anti-hypertensive 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 of patients (R18-0043, 
R15-1223). The Investigator should discuss fertility preservation strategies with the patient 
prior to starting treatment in this trial, as appropriate.
Avastin® may cause fetal harm based on the drug’s mechanism of action and findings from 
animal studies. Limited postmarketing reports describe cases of fetal malformations with use 
of Avastin® in pregnancy; however, these reports are insufficient to determine drug 
associated risks. In animal reproduction studies, intravenous administration of bevacizumab 
to pregnant rabbits every 3 days during organogenesis at doses approximately 1 to 10 times 
the clinical dose of 10 mg/kg produced fetal resorptions, decreased maternal and fetal weight 
gain and multiple congenital malformations including corneal opacities and abnormal 
ossification of the skull and skeleton including limb and phalangeal defects. Furthermore, 
animal models link angiogenesis and VEGF and VEGF Receptor 2 (VEGFR2) to critical 
aspects of female reproduction, embryofetal development, and postnatal development. 
Women who are pregnant, nursing, or who plan to become pregnant are excluded from 
entering the trial. Women of reproductive potential should be advised to use effective 
contraception during treatment with, and for 6 months after the last dose of Avastin®.
Due consideration has been given to previous experience with Avastin® in mCRC patients 
and toxicity management advice (e.g., for hypersensitivity reactions) is provided in this CTP. 


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Trial 1302.1 was a Phase I 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 I data described above, BI 695502, as a proposed 
biosimilar to Avastin®, is expected to show a similar efficacy, safety, immunogenicity and 
PK profile in patients with mCRC.
While the pivotal Phase III trial in NSCLC (Trial 1302.5) is currently ongoing, the first 
independent Data Safety Monitoring Board (DSMB) feedback on the safety and efficacy of 
BI 695502 is anticipated by May 2016. The mCRC trial shall start dosing only upon DSMB 
recommendation to continue the 1302.5 study without modification. Since May 2016, there 
have been 5 regularly spaced 1302.5 DSMB meetings, all of which recommended 
continuation of the trial without modification. Considering that the 1302.3 study is an open-
label study, all safety aspects will be regularly monitored by both Sponsor and Contract 
Research Organization (CRO) during the Medical Quality Review Meeting.
The benefit-risk profile for the patients participating in this trial remains favorable and 
similar to the originator product. While medical coverage is generally available for such 
indications in the developed world, it is anticipated that this trial could be more appealing to 
patients with inadequate or no medical insurance coverage. Generation of such evidence will 
help patients and physicians to gain trust in the value that biosimilars would bring to our 
health care systems.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a Phase IIIb, open-label, multicenter, multinational, single arm trial. 
Approximately 120 patients with previously untreated mCRC will be enrolled in this trial. 
Patients will receive treatment with 5 mg/kg of BI 695502 every 14 days (each cycle) 
followed by mFOLFOX6 chemotherapy until disease progression (monitored by common 
radiologic methods and assessed according to Response Evaluation Criteria in Solid Tumors 
[RECIST 1.1]), death, or unacceptable toxicity or the end of the trial, whichever occurs 
earlier. Based on patient tolerability, at least 8 cycles of mFOLFOX6 should be given to all 
patients. If the Investigator decides to stop oxaliplatin at any time during the study, patients 
should continue to receive infusional 5FU + leucovorin with BI 695502 until progression. 
Approval from the Sponsor must be obtained prior to implementing any changes to the 
mFOLFOX6 regimen necessitated by local best practice.
Patients will undergo visits and trial procedures as shown in Flow chart 1.1 and 
Flow chart 1.2.
The primary endpoint of the trial is the proportion of patients with any of the following 
selected AEs: anaphylactic reactions/hypersensitivity reactions/infusion-related reactions, 
arterial and venous thromboembolic events, GI perforations, hypertension, proteinuria, 
pulmonary hemorrhage, other hemorrhages, wound-healing complications/abscess/fistulas, 
posterior reversible encephalopathy syndrome, and ovarian failure.
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 (commercially available Avastin®, 
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. Patients will continue the study with no additional visits in the scheduled visit 
cycle as per protocol.
Patients who discontinue treatment with chemotherapy, BI 695502, or Avastin®, or both, but 
do not have disease progression and have not started a new anticancer therapy, will continue 
in the trial in the non-treatment period until disease progression, initiation of a new 
anti-cancer therapy, or the end of the trial, whichever occurs first. 
All patients who receive at least one infusion of BI 695502 will have a Follow-up visit 
30 days after the last dose of BI 695502 or Avastin®, whichever occurs later. 


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Patients will attend a long-term Safety Follow-up (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 BI 695502 dose, then no SFU visit will 
be performed. 
After the long-term SFU visit or discontinuation of Avastin® (whichever occurs later), all
patients will be monitored for survival every 3 months via telephone call until death or the 
end of the trial, whichever occurs earlier.
3.1.1
Administrative structure of the trial
Quintiles will perform Project Management, Clinical Field Monitoring, Medical Monitoring, 
Data Management, and Statistical Evaluation according to Quintiles Standard Operating 
Procedures (SOPs). A list of responsible persons and relevant local information can be found 
in the trial reference manual in the ISF.
A Coordinating Investigator will be nominated and will be responsible for coordinating
Investigators at different centers participating in this multicenter trial. Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in the electronic trial master file (eTMF).
DISCUSSION OF TRIAL DESIGN
3.2
This is a Phase IIIb, open-label, multicenter, multinational, single arm trial to investigate 
safety, efficacy, 
immunogenicity of BI 695502 in patients with previously untreated 
mCRC. Patients will receive BI 695502 in combination with mFOLFOX6 chemotherapy 
every 2 weeks or as monotherapy.
mFOLFOX6 plus bevacizumab is an accepted first-line chemotherapy regimen for patients 
with mCRC. This regimen was shown to improve outcomes in bevacizumab-naïve patients
(R05-2504, R13-1115, R11-2707).
The primary focus of this trial is to evaluate safety and tolerability in mCRC patients treated 
with BI 695502 in combination with mFOLFOX6 chemotherapy (see Section 2.1 for details
on rationale for performing the trial).
SELECTION OF TRIAL POPULATION
3.3
A log of all patients enrolled into the trial (i.e., who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
Patients who do not meet all of the inclusion criteria or meet at least one of the exclusion 
criteria will not be enrolled, 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 


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will be allowed on a case-by-case basis based on discussion with the medical monitor and 
after approval of the Sponsor’s study representative.
Approximately 120 patients will be enrolled in this trial across approximately 50 sites.
3.3.1
Main diagnosis for trial entry
The main requirements for trial entry include adult patients ≥18 years of age (for Japan only: 
Age ≥20 years at time of signing the informed consent form [ICF]), with histologically 
confirmed metastatic CRC not amenable to surgical curative treatment, who are eligible to 
receive therapy with mFOLFOX6 + bevacizumab, have received no prior therapy for 
metastatic disease and should have completed any adjuvant/neoadjuvant therapy at least 12 
months before trial entry. Patients must have an Eastern Cooperative Oncology Group 
(ECOG) performance status (PS) of 0 or 1 and must have at least one measurable lesion 
according to RECIST 1.1 criteria that has not been irradiated within 12 weeks prior to 
enrollment. Patients will have no known sensitivity to any of the trial drugs or their excipients 
and must have adequate hepatic, renal, and bone marrow function.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1. Males and females aged ≥18 years (for Japan only: Age ≥20 years at time of signing 
ICF) with histologically confirmed mCRC.
2. All patients must sign and date an ICF 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.
3. Metastatic disease not amenable to surgical curative treatment and eligible to receive 
therapy with mFOLFOX6 + bevacizumab.
4. At least one measurable lesion according to RECIST 1.1 that has not been irradiated 
within 12 weeks prior to enrollment.
5. ECOG PS 0 or 1.
6. 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 total 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 Cockcroft-Gault formula.
e.
Proteinuria <2 g in 24 hours or an equivalent protein/creatinine ratio of 
<2000 mg/g creatinine (or <226.0 mg/mmol creatinine)
f.
Absolute neutrophil count >1.5 x109/L.
g.
Platelet count >100 x109/L. 


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h. Hemoglobin ≥9 g/dL (without transfusion within 2 weeks prior to 
randomization).
7. 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
8. Life expectancy ≥12 months based on clinical investigator’s judgment.
9. 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. 
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 systemic therapy for metastatic disease. Any adjuvant/neoadjuvant therapy must 
have been completed >12 months prior to screening.
2. Prior therapy with monoclonal antibodies or small molecule inhibitors against VEGF or 
VEGF receptors, including Avastin® or Avastin® biosimilars.
3. Previous malignancy other than CRC in the last 5 years except for basal cell cancer of the 
skin or pre-invasive cancer of the cervix.
4. Spinal cord compression or brain metastases unless asymptomatic, stable and not 
requiring steroids for at least 6 weeks prior to start of study treatment. 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.
5. Any unresolved toxicity > Common Toxicity Criteria Grade 1 (except alopecia) from 
previous anticancer therapy (including radiotherapy). 
6. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of 
bleeding.
7. 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). 
8. 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.
9. Current or recent (within 10 days of first dose of BI 695502) regular use of aspirin 
(>325 mg/day) or other non-steroidal anti-inflammatory drugs (NSAIDs) with 
anti-platelet activity or treatment with dipyridamole, ticlopidine, clopidogrel and 
cilostazol.


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10. 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. Intravenous, intramuscular, interarticular or parenteral corticosteroids are 
restricted within 6 weeks prior to Day 1. The use of corticosteroids as antiemetics for 
oxaliplatin and 5-FU is allowed according to regular institutional practice
(see Table 4.2.2.1: 1 for details).
11. Current or recent (within 10 days of first dose of BI 695502) 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) non-healing 
wounds, or incompletely healed bone fracture.
12. Patients who are expecting to receive any live vaccine or bacterial vaccinations during the 
trial, or receive one up to 12 weeks prior to the first dose of trial medication.
13. 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 anti-hypertensive 
therapy (see Section 5.3.2). 
14. Any surgical procedure within 28 days of first dose of BI 695502 or anticipated elective 
surgery during the trial (see Table 4.2.2.1: 1 for details).
15. History of active gastroduodenal ulcer(s) within 18 months of study enrolment.
16. History of abdominal fistula as well as non-GI fistula, GI perforation or intra-abdominal 
abscess within 6 months prior to screening.
17. Active or chronic hepatitis B or C, ongoing human immunodeficiency virus (HIV) 
infection, or tuberculosis (TB) (see Section 5.3.3). Screening for HIV and TB to be 
performed according to local practice and local regulatory guidance. 
18. Treatment in 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.
19. 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 study).
20. Known hypersensitivity to the trial drug or its excipients.
21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
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.
If a patient discontinues (drops out or withdraws after enrollment) from this trial, the patient 
will not be replaced.
An individual patient will be discontinued from trial treatment if:


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
Investigator decision because of an intolerable AE or a clinically significant laboratory 
value including but not limited to:

Progressive disease

Life-threatening reaction, including anaphylaxis, hypersensitivity reaction, renal 
failure, severe cardiopulmonary event and severe muco-cutaneous reaction

GI perforation (including fistula formation in the GI tract, intra-abdominal abscess)

Tracheoesophageal or any Grade 4 fistula

Fistula formation involving an internal organ

Wound dehiscence and wound healing complications requiring medical intervention
In these cases the trial medication is to be discontinued and appropriate measures are to 
be taken. The Sponsor or Sponsor designee is to be notified immediately. 

Serious hemorrhage (i.e., requiring medical intervention)

Severe arterial thromboembolic events

Life-threatening (Grade 4) venous thromboembolic events, including pulmonary 
embolism

Hypertensive crisis or hypertensive encephalopathy

RPLS/ Posterior Reversible Encephalopathy Syndrome (PRES)

Nephrotic syndrome

Necrotizing fasciitis

Congestive heart failure, any degree

Severe hypertension, moderate or severe proteinuria, severe infusion reactions if the event 
cannot be adequately controlled within 14 days

Initiation of a new treatment (i.e. another chemotherapy or radiotherapy at any time)

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 5.3.7).

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 (i.e., withdraws consent). 

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.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow-up as outlined in Flowchart 1.2 and Section 6.2.3.
For all patients, the reason for withdrawal (e.g., AEs) must be recorded in the eCRF. These 
data will be included in the trial database and reported.
For details of pregnancy reporting and follow-up procedures, see Section 5.3.7.


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Discontinuation of the trial by the Sponsor
3.3.4.2
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 case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
4.1.1
Identity of BI investigational product
Details of the trial medications are provided in Table 4.1.1: 1. 
Table 4.1.1: 1
Trial medication
Substance:
BI 695502
Pharmaceutical formulation:
Concentrate for solution for infusion
Manufacturer:
Boehringer Ingelheim
Unit strength:
400 mg/16 mL solution in a single use vial
Excipients:
disodium phosphate dihydrate, 
sodium dihydrogenphosphate dihydrate,
trehalose dihydrate, polysorbate 20 and
water for injection.
Route of administration:
Intravenous (i.v.)
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. All patients will continue the study with no 
additional visits in the scheduled visit cycle as per protocol.
4.1.2
Method of assigning patients to treatment groups
This is an open-label, single arm trial. All patients will receive BI 695502 in combination 
with mFOLFOX6 chemotherapy every 2 weeks. Based on patient tolerability, the doses of 
chemotherapy drugs may be decreased as per the label or institutional practice. 
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. All patients will continue the study with no additional visits in the scheduled visit 
cycle as per protocol.
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 mCRC, in combination with fluoropyrimidine-based chemotherapy. The 
dose of BI 695502 selected for this trial is based on the clinically effective dose of Avastin®. 


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The 5 mg/kg dose of Avastin® is the dose recommended by the National Comprehensive 
Cancer Network (NCCN) in this indication and in combination with mFOLFOX6. 
The primary focus of this trial is to assess safety in patients with untreated mCRC, following 
multiple infusions of BI 695502 in combination with mFOLFOX6. The recommended dose 
of Avastin®, administered as an intravenous (i.v.) infusion, is either 5 mg/kg or 10 mg/kg of 
body weight given once every 2 weeks. In this trial, patients will receive 5 mg/kg BI 695502
i.v. once every 2 weeks (R18-0043) as recommended by the NCCN. The dose administered 
to each patient is to be recalculated at each visit based on their body weight at that visit. The 
same applies to the Avastin® administration after the switch from BI 695502.
Patients will continue to receive treatment every 2 weeks until disease progression, death, 
unacceptable toxicity, or the end of the trial, whichever occurs earlier. Based on patient 
tolerability, at least 8 cycles of mFOLFOX6 should be given to all patients. If the Investigator 
decides to stop oxaliplatin at any time during the study, patients should continue to receive 
infusional 5FU+ leucovorin with BI 695502 (before the switch visit) or Avastin® (after the 
switch visit) until progression, unacceptable toxicity or end of the trial, whichever occurs 
earlier. Based on patient tolerability, the doses of chemotherapy drugs may be decreased as 
per the label or institutional practice. 
4.1.4
Drug assignment and administration of doses for each patient
BI 695502 will be provided by the Sponsor. Avastin® will be provided, or financially 
covered, by the Sponsor.
BI 695502 or Avastin® infusion will be administered first, i.e., prior to the administration of 
mFOLFOX6 chemotherapy. 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 SAE).
The recommended initial dose for the first BI 695502 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.
After the patient is switched to Avastin®, 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.


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Cycle 1 treatment is to be administered within 4 days after enrollment.
BI 695502 or 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 or 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.
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.
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 or Avastin® plus chemotherapy is provided in 
Table 4.1.4: 1.
Table 4.1.4: 1
BI 695502 or Avastin® plus mFOLFOX6
Immunochemotherapy 
regimen
Dose
Mode
Day 1 of 
cycle
Day 2 of 
cycle
Day 3
of cycle
BI 695502 or Avastin®
5 mg/kg
i.v.
X
Oxaliplatin
85 mg/m2 over 2 hours
i.v.
X
Leucovorin 
400 mg/m2 over 2 hours
i.v. 
X
5-FU 
400 mg/m2 on Day 1 then 
1200 mg/m2/day x 2 days (total 
2400 mg/m2 over 46-48 hours) 
continuous infusion
i.v. 
X
X
X
5-FU = 5-fluorouracil
Upon availability of Avastin® at the clinical site, BI 695502 will be replaced by Avastin®
following the administration procedure and treatment regimen as described in the Avastin® 
label, with the exception of the use of filters which must be used according to the BI 695502 
administration procedure.


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Chemotherapy
4.1.4.1
Administration of chemotherapy will be according to the standard preparation and infusion 
procedures of each investigational site. The formula used to calculate body surface area 
(BSA) should be recorded on the eCRF at each visit.
For mFOLFOX6 chemotherapy, oxaliplatin 85 mg/m2 i.v. over 2 hours on Day 1, leucovorin 
400 mg/m2 i.v. (or levoleucovorin 200 mg/m2 i.v.) over 2 hours on Day 1, 5-FU 400 mg/m2
i.v. bolus on Day 1, then 1200 mg/m2/day x 2 days (total 2400 mg/m2 over 46-48 hours) i.v. 
continuous infusion (R13-1134).
Further details on the chemotherapy regimen are provided in Appendix 10.3.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
In this open-label trial, treatment allocation will not be concealed throughout the trial. See 
Section 3.2 for detailed discussion on trial design.
Unblinding and breaking the code
4.1.5.2
Not applicable since this is an open-label trial with only one treatment group.
4.1.6
Packaging, labeling, and re-supply
For details of packaging and the description of the label, refer to the ISF. Avastin® will be 
provided as commercially labeled drug. Relabeling 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 GCP. The medication must be stored in a refrigerator at a controlled 
temperature (2 to 8°C [36 to 46°F]). 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. If the storage conditions are found to be outside the specified range, the local 
clinical monitor (as provided in the list of contacts) must be contacted immediately.
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. 


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The Investigator/pharmacist or the designated person will receive the investigational drugs 
delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the Institutional Review Board (IRB)/ethics committee.

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site.

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 clinical trial protocol.

Availability of the proof of a medical license for the principal Investigator, if applicable.

Availability of Form FDA 1572 for sites in US.
The Investigator/pharmacist or the 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 disposal 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 and trial patients. Once 
patients are switched from BI 695502 to Avastin®, the date of administration, the batch 
number, and expiry dates of Avastin® are to be recorded.
The Investigator/pharmacist or the designated person will maintain records that document 
adequately that the patients were provided the doses specified by the CTP and reconcile all 
investigational products received from the Sponsor. At the time of return to the Sponsor
and/or the appointed CRO, the Investigator/pharmacist or the designated person must verify 
that no remaining supplies are in the Investigator’s possession.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
There are no special emergency procedures to be followed.
There are no recommended dose reductions or rescue medications for BI 695502 or 
Avastin®.
BI 695502 or Avastin® should be permanently discontinued in patients with GI perforations 
(including fistula formation in the GI tract, intra-abdominal abscess), tracheoesophageal or 
any Grade 4 fistula, 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 and life-threatening 
(Grade 4) venous thromboembolic events(including pulmonary embolism); hypertensive 
crisis or hypertensive encephalopathy; RPLS/PRES; nephrotic syndrome;  necrotizing 
fasciitis; or congestive heart failure of any grade.


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Patients with severe hypertension, moderate to severe proteinuria, or severe infusion
reactions will not receive further treatment with BI 695502 or Avastin® if the event cannot 
be adequately controlled within 14 days.
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. 
BI 695502 or Avastin® 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 
BI 695502 or Avastin®.
Based on patient tolerability, subsequent doses of chemotherapy drugs may be decreased as 
per the label or institutional practice.
Prophylactic anti-emetics or other pre-medications may be administered per standard of care 
prior to chemotherapy administration.
All concomitant medication/therapies will be recorded on the eCRF.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
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 prior to prescription. 
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 treatment
Treatment
Restriction
mFOLFOX6 chemotherapy
Refer to Appendix 10.3
Radiotherapy
No radiotherapy will be allowed at any time during the trial
Other anticancer regimens
Patients should not have received previous systemic treatment for their 
mCRC. Patients who have received adjuvant chemotherapy are eligible if 
the last administration of the prior adjuvant regimen occurred >12 months 
prior to Screening. Other anticancer treatment is not permitted.
Intravenous, intramuscular, 
intra-articular, or parenteral 
corticosteroids
Not permitted within 6 weeks prior to Day 1 or throughout the trial. The 
use of corticosteroids as antiemetics for oxaliplatin and 5-FU is allowed 
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. The use of corticosteroids as 
antiemetics for oxaliplatin and 5-FU is allowed according to regular 
institutional practice.
Oral or parenteral anticoagulants 
Full-dose oral or parenteral anticoagulants or other thrombolytic agents
for therapeutic (as opposed to prophylactic) purposes (including 
coumadin or warfarin) are not permitted within 10 days of the first dose 
of BI 695502 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 are not permitted within 10 days of first dose of BI 695502 or 
throughout the trial. Acetaminophen (paracetamol) as well as natural and 
synthetic opioids can 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 is not permitted. 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.
Surgical procedures
Invasive procedures (major surgical procedure, open biopsy or significant 
traumatic injury) are not permitted within 28 days prior to the first dose 
of BI 695502 (see details below). Surgery incision should be fully healed.
Placement of a vascular access device is not considered as a major 
surgical procedure if performed more than 24 hours prior to BI 695502 
administration.
Calcium/magnesium
Caution in the concomitant or prophylactic use of calcium or magnesium 
due to the possibility of reduced response rate to mFOLFOX6 treatment.
Live/attenuated vaccine
Not permitted within 12 weeks prior to the Screening Visit or throughout 
the trial.


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Table 4.2.2.1: 1
Prior and concomitant treatment (continued)
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.
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
Any surgical procedure (including biopsy for RAS determination) is not permitted within 28 
days prior to the first dose of BI 695502 or for the duration of the trial. If it is not possible to 
arrange a biopsy during the screening period then the patient can be re-screened after the 
procedure has been undertaken.
For elective surgery during the trial, the interval between termination of the BI 695502 or 
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 (except for biopsy if required for 
determination of RAS status) will not be enrolled into the trial.
Restrictions on diet and life style
4.2.2.2
Participation in contact sports (e.g., ice-hockey, rugby, martial arts) should be avoided during 
the course of the trial.
Restrictions regarding women of childbearing potential
4.2.2.3
Women who are pregnant, nursing, or who plan to become pregnant while in the trial will be 
excluded from the trial. Women of childbearing potential must be ready and able to use 
highly effective methods of birth control. See Section 3.3.2 and Section 3.3.3 for details.
In addition, male patients with female partners of childbearing potential must also agree to 
use a medically acceptable method of contraception during the trial and for 6 months after the 
last dose of trial medication.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary endpoint
The primary safety endpoint of the trial is patients with any of the following selected AEs:

Anaphylactic reactions/hypersensitivity reactions/infusion-related reactions.

Thromboembolic events:
o
Arterial
o
Venous

GI perforations

Hypertension

Proteinuria

Pulmonary hemorrhage

All hemorrhages and pulmonary hemorrhages

Wound-healing complications including abscess and fistulas

Posterior reversible encephalopathy syndrome

Ovarian failure
5.1.2
Secondary endpoints
The secondary efficacy endpoints of the trial are:

PFS is defined as the time from first administration of trial medication until disease 
progression as assessed by central imaging review according to RECIST 1.1 or death of 
any cause.

Objective Response according to RECIST 1.1 as assessed by central imaging review.

DOR defined as the time from first documented CR or PR until time of progression as 
assessed by central imaging review.

TTP defined as the time from first administration of trial medication to the date of tumor 
progression as assessed by central imaging review.

OS defined as the time from first administration of trial medication until death from any 
cause.
5.1.3
Further endpoints
The further endpoints of the trial are:

ADAs/nADAs at Weeks 0, 4, 8, 16, 24, 32, 40 and 52 and 30-day Follow-up visits and 
long-term SFU visit.

All AEs including AEs related to trial treatment, assessed according to National Cancer 
Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

All AEs potentially related to immunogenicity.

All protocol-specified adverse events of special interest (AESIs).


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ASSESSMENT OF EFFICACY
5.2
A central review of all patient images will be performed. Details will be described in the 
imaging charter. The results of the central review imaging data (independent assessments of 
objective response) will be used for the secondary efficacy analysis. The results of the 
Investigator assessment will be used for sensitivity analysis (see Section 7.3.2.1).
5.2.1
Progression-free survival
PFS: proportion/amount of patients who have neither progressed as per central imaging 
review nor died censored on the date of last radiological tumor assessment. Progression-free 
survival is defined as the time from first administration of trial medication until disease 
progression as assessed by central review or death. Disease progression is assessed according 
to RECIST 1.1 (see Appendix 10.1).
5.2.2
Objective response
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 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 

PR 

SD (stable disease)

PD (progressive disease)

NE (not evaluable, insufficient data).
Complete response and PR do not need to be confirmed by a subsequent tumor assessment 
(detailed rules will be listed in the imaging charter). 
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 and Flow chart 1.2. 
Tumor assessments should be performed prior to trial treatment administration. 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. 
Tumor assessment will be performed every 8 weeks (±3 days) up to Visit 21. From Visit 21
onwards tumor assessment will be performed every 12 weeks (±3 days; ±7 days from Visit 
28 onwards). This means that no CT scan is needed at Visit 28 if the patient received a CT 
scan at Visit 27. During the non-treatment period CT scans will be performed every 8 weeks 
(±3 days) weeks.


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A CT scan with i.v. contrast product injection will be performed on the, chest, abdomen and 
pelvis ± involved area. In case of a contrast product injection allergy, an abdomen-pelvic
MRI will be performed with a non-contrast chest CT scan.
5.2.3
Duration of response
Duration of response (DOR) is the time from first documented CR or PR until time of 
progression as assessed by central review.
5.2.4
Time to progression
Time to Progression (TTP) is defined as the time from first administration of trial medication 
to the date of tumor progression as assessed by central review.
5.2.5
Overall survival
Overall survival (OS) is defined as the time from first administration of trial medication until 
death from any cause.
ASSESSMENT OF SAFETY
5.3
5.3.1
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 and an optional rectal examination, as per the local practice, 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.
5.3.2
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 5.3.6).


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5.3.3
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:
• aPTT, INR at screening and subsequent visits
• Neutrophil count and creatinine clearance at every visit 
• Monocytes (abs‚ %), eosinophils (abs‚ %), basophils (abs‚ %) at every visit
• Reticulocyte count at every visit 
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.
In addition, the following parameters will be analyzed at the visits indicated in Flow chart 1.1
and Flow chart 1.2:

Infection screen (for hepatitis B, hepatitis C):
o
Active hepatitis B may be 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 hepatitis C virus (HCV) and/or positive 
antibody. If any of these tests are positive, the result should be confirmed by a 
positive hepatitis virus RNA.

HIV and TB (QuantiFERON Gold assay or purified protein derivative [PPD] skin test) 
screening 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 5.3.6), 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 


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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.
5.3.4
Electrocardiogram
Two consecutive resting 12-lead electrocardiograms (ECG) 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 the Investigator or 
designee.
5.3.5
Other safety parameters
Tuberculosis assessment
5.3.5.1
Screening for HIV and TB should be performed according to local practice and local 
regulatory guidance. There should be no radiographic or clinical evidence of active TB. Thus, 
although a PPD skin test or the QuantiFERON®-TB Gold Assay may be used to assess TB 
status at Screening, none of these tests are mandatory. Local practice and local regulatory 
guidance should be followed.
Purified protein derivative skin test
A PPD skin test may be used to assess TB status at Screening.
QuantiFERON®-TB Gold Assay or T-SPOT Assay
QuantiFERON Gold or T-SPOT assay may be used to assess TB status at Screening.


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5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorization or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
An SAE is defined as any AE which:

results in death,

is life-threatening; this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalization, or 

prolongation of existing hospitalization,

results in persistent or significant disability or incapacity,

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.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.


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Japan only: The following events will be handled as “deemed serious for any other reason”. 
An AE which possibly leads to disability will be reported as an SAE.
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be reported as a serious event 
regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the EMA initiative on Important Medical Events, Boehringer Ingelheim 
has set up a list of AEs, which by their nature, can always be considered to be “serious” even 
though they may not have met the criteria of an SAE as given above.
A copy of the latest list of “Always Serious AEs” will be provided to you upon request. The 
list of these AEs can be found in the ISF. These events should always be reported as SAEs as 
described earlier in this section.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, see Section 5.3.7.
The following are considered as AESIs:
1. Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
Patients showing the following laboratory abnormalities need to be followed up according 
to Section 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 x 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 the 
baseline value combined with an elevation of total bilirubin ≥2 x the baseline value 
measured in the same blood draw sample.
o
Marked peak aminotransferase (ALT, and/or AST) elevations >10 x ULN.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without laboratory
results (ALT, AST, total bilirubin) available, the Investigator should make sure these 
parameters are analyzed, if necessary in an unscheduled blood test. Should the results meet 
the criteria of hepatic injury alert, the procedures described in the DILI checklist should be 
followed and an SAE form should be completed and sent to the Sponsor.


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2. Anaphylactic reactions.
3. GI perforations.
4. 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).
Local tolerability
The assessment of injection site reactions will be done by the investigator/designee who will 
assess the presence of: ‘swelling’, ‘hardening’, ‘heat’, ‘redness’, ‘pain’, ‘itching’, ‘bruising’, 
or ‘other symptoms’. If any injection site reactions are observed, these findings should also 
be reported on the AE eCRF page.
Intensity of AEs
The intensity of AEs should be classified and recorded in the eCRF according to the CTCAE 
version 4.0 (R10-4848).
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an adverse event. An adverse
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship
between a medicinal product and an occurrence is suspected.
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.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g., 
preexisting or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g., Stevens-Johnson syndrome).

An indication of dose-response (i.e., greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 


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drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g., 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Japan only: The reason for the decision on causal relationship for unlisted AEs needs to be 
provided in the eCRF.
5.3.7
Adverse event collection and reporting
AE collection
The following must be collected and documented on the appropriate eCRFs by the 
Investigator:
-
From signing the informed consent onwards through the Residual Effect Period
(REP)/Long-term SFU, all AEs (serious and non-serious), and AESIs. If in an 
individual patient only vital status information is collected after the long term SFU or 
discontinuation from Avastin® (whichever occurs later), from then on and until the 
individual patient’s end of trial the Investigator does not need to actively monitor the 
patient for AEs but should only report fatal AEs, relevant SAEs and relevant AESIs of 
which the Investigator may become aware of. However, if a patient remains in the 
non-treatment period beyond 18 weeks post last dose of trial medication prior to the 
switch visit (i.e., beyond the long term SFU), all AEs, SAEs and AESI will continue 
to be collected until disease progression, initiation of new anti-cancer therapy, death, 
or the end of the trial. Once disease progression, initiation of new anti-cancer therapy 
is confirmed and only vital status information is collected, report fatal AEs, relevant 
SAEs and relevant AESIs of which the Investigator may become aware.
The REP is defined as 126 days/18 weeks after the last trial medication administration prior 
to the switch visit. All AEs which occur through the treatment phase and throughout the REP 
will be considered as on treatment, please see Section 7.3.3. Events which occur after the 
REP will be considered as post treatment events. All AEs will be reported up until the end of 
the long-term SFU visit (18 weeks after the last dose of BI 695502) or until discontinuation 
from Avastin®, whichever occurs later.
AE reporting to Sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
Sponsor’s/Sponsor’s designee unique entry point (specific contact details will be provided in 
the ISF). The same timeline applies if follow-up information becomes available. In specific 


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occasions the Investigator could inform the Sponsor/Sponsor designee directly via telephone. 
This does not replace the requirement to complete and fax the BI SAE form.
Japan only: All SAEs and AESIs must be reported immediately to the head of the trial site. 
With receipt of any further information for these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, outcome, 
seriousness, and action taken with the investigational drug(s). The Investigator should 
determine the causal relationship to the trial medication, and any possible interactions 
between the investigational drug(s) and a non-investigational product.
The following should also be recorded as an (S)AE in the eCRF and SAE form (if 
applicable):
Worsening of other pre-existing conditions (see also Exemption of SAE reporting 
below)
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after trial completion, must be followed up until they 
have resolved, have been sufficiently characterized, or no further information can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a female patient has been enrolled 
into the clinical trial, after having taken trial medication, the Investigator must report 
immediately (within 24 hours) any potential drug exposure during pregnancy (DEDP) to the 
Sponsor/Sponsor designee unique entry point (specific contact details will be provided in the 
ISF).  The Pregnancy Monitoring Form for Clinical Trials (Part A) should be used. The 
pregnant study participant must be withdrawn from the study.
This applies also to the rare cases of pregnancy of a female partner of a male patient that has 
been enrolled into the clinical trial, after having taken trial medication. If a female partner of 
a male patient is confirmed as being pregnant, an ICF for a Pregnant Partner will be provided 
to the female partner to allow pregnancy follow-up.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor/Sponsor designee unique entry point on the 
Pregnancy Monitoring Form for Clinical Trials (Part B). The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).


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As pregnancy itself is not to be reported as an AE. In the absence of an (S)AE and/or AESI, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is a SAE and/or AESI associated with the pregnancy a SAE form must be 
completed in addition.
Exemptions to SAE reporting
Protocol-specified outcome events should be collected on the appropriate eCRF page only.
Disease Progression in oncology trials is a trial endpoint for analysis of efficacy and as such 
is exempted from reporting as a (S)AE. Progression of the patient’s underlying mCRC 
(underlying disease) 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 in 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 trial 
medication and the progression of the underlying malignancy, the event must be reported as a 
(S)AE 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 by the Quintiles Medical Monitor. 
Cancers with new histology are always considered serious and should be reported in an 
expedited manner by using an SAE form.
 
 
 
 
 
 


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ASSESSMENT OF EXPLORATORY BIOMARKER(S)
5.5
Not applicable.
OTHER ASSESSMENTS
5.6
5.6.1
Immunogenicity assessment
For all ADA/nADA samples, the day and time of sampling will be accurately recorded. 
Wherever possible, ADA/nADA blood samples will be taken at the same time as blood is 
drawn for other analyses to limit repeated venipuncture. The ADA/nADA samples should be 
obtained from the forearm not used in the BI 695502 or Avastin® i.v. administration.


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In the event of early withdrawal from treatment, every effort should be made to take 
ADA/nADA samples as part of the early withdrawal procedures, if possible, with date and 
time of sample and time of dose prior to this sample recorded. Every effort should be made to 
take ADA/nADA samples at the SFU visit or at 18 weeks after the last administration of 
BI 695502 prior to the switch visit.
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.6.2
Tumor biopsy
Tumor histology and RAS status will be confirmed before enrolment; if not 
performed/available, and no archival tumor sample is available, a fresh biopsy will be 
performed, if possible, and analyzed locally.  
APPROPRIATENESS OF MEASUREMENTS
5.7
The RECIST 1.1 guideline (R09-0262) is well established and scientifically accepted and will 
be used for the evaluation of objective 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 mCRC patients.


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6.
INVESTIGATIONAL PLAN
For all visits, there will be a window of ±3 days unless otherwise specified.
VISIT SCHEDULE
6.1
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 with the maximum 
time window of ±3 days unless otherwise specified: 

Administration of BI 695502 will occur on Day 1 of each cycle (every 2 weeks).

Administration of chemotherapy will start on Day 1 of each cycle (see Table 4.1.4.1).

Each subsequent cycle will occur within 3 days (±3 days) of completion of the previous 
cycle, including after the switch from BI 695502 to Avastin®. 

During the Switch visit prior to infusion with Avastin®, the assessments as described in 
Flow Chart 1.2 will be performed.  

The 30-day Follow-up visit will be performed 30 days (±3 days) after the last BI 695502
or Avastin® dose, whichever occurs later.

Non-treatment period: visits will be performed every 8 weeks until initiation of new 
treatment or death for patients who discontinue BI 695502 or Avastin® 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.

The long-term SFU visit will be performed 18 weeks (+7 days) after the last dose of trial 
medication prior to the switch visit. If the patient continues to receive treatment with 
Avastin® beyond the 18 weeks post last BI 695502 dose, then no SFU visit will be 
performed.  
Clinical assessments will be performed within 3 days before trial medication infusion. 
Laboratory samples must be drawn prior to infusions of 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.
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 
that will be drawn from each patient who receives 27 cycles of treatment during the course of 
the trial, plus the 30-day Follow-up and long-term SFU visits is shown in Table 6.1: 1.


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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
31
108.5
Hematology
2
31
62
INR/PT/PTT
2.7
31
83.7
ADAs
3
11
33
nADA
5
11
55
Infection screen
12
1
12
TB
3
1
3
Approximate total
396.2
ADAs = antidrug antibodies; nADA = neutralizing ADAs; 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.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening period
Screening period Visit 0 (Week -4 to -1)
Once the patient has provided informed consent (before any trial-specific procedures or 
assessments are performed), the trial site will enter the screened patient into the system using 
the Interactive Telephone and Web Response System (IXRS®). Once the patient meets all 
inclusion criteria and none of the exclusion criteria (see Section 3.3), the patient will be 
enrolled into the trial.
The following assessments will be performed/collected:

Tumor biopsy (performed and assessed locally) and RAS status assessment.

Demographic information (including sex, date of birth, ethnicity and race), medical and 
surgical history, and smoking status. 

Hepatitis B and hepatitis C (unless status has previously been confirmed within 6 months 
prior to Screening) and HIV test (should be performed only if required per local practice 
and local regulatory guidance).

TB test (PPD skin test or QuantiFERON TB Gold test or T-SPOT 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) (see Section 5.3.1).


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
Measurement of body mass index (BMI). The formula used to measure BSA will be 
recorded.

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.3.2).

Laboratory testing (serum chemistry, hematology, coagulation and urinalysis; see 
Section 5.3.3).

12-lead ECG (see Section 5.3.4).

Previous and concomitant therapies/medications (see Section 4.2).

Assessment of AEs (see Section 5.3.6). 

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and the 
involved area, if applicable) (see Section 5.2.2). To be performed within 28 days of 
enrolment.

ECOG PS.

Contact IXRS®.
6.2.2
Treatment period(s)
Cycle 1 (Day 1)
Eligible patients will be enrolled and treatment will be administered 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).

Urine protein analysis.

Physical examination, including weight (kg) (see Section 5.3.1).

Measurement of BMI. The formula used to measure BSA will be recorded.

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.3.2).

Laboratory testing (serum chemistry, hematology, coagulation and urinalysis; see
Section 5.3.3).

Previous and concomitant medications (see Section 4.2).

Assessment of AEs (see Section 5.3.6).

ECOG PS.

Survival.

Blood samples for the level of ADAs/nADAs, sample should be taken prior to trial 
medication administration (see Section 5.6.1).

 

Trial medication infusion (see Section 4.1.4).

Administration of chemotherapy (see Table 4.1.4.1). 

Contact IXRS®.


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Cycle 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26

Physical examination, including weight (kg) (see Section 5.3.1).

Measurement of BMI. The formula used to measure BSA will be recorded.

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.3.2).

Laboratory testing (serum chemistry, hematology, coagulation and urinalysis; see 
Section 5.3.3).

12-lead ECG every three cycles (per the Flow chart 1.1 and Flow chart 1.2).

Concomitant therapies/medications (see Section 4.2).

Assessment of AEs (see Section 5.3.6).

Survival.

Trial medication infusion (see Section 4.1.4).

Administration of chemotherapy (see Table 4.1.4.1). 

Contact IXRS®. Not required from the switch visit onwards. Note: at the time of 
Avastin® discontinuation, contact IXRS to perform the discontinuation call.
Cycles 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27.

Urine pregnancy test for women of childbearing potential (serum pregnancy test to be 
performed in case of positive urine pregnancy test) (serum pregnancy test at Cycle 27).

Urine protein analysis.

Physical examination, including weight (kg) (see Section 5.3.1).

Measurement of BMI. The formula used to measure BSA will be recorded.

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature
(see Section 5.3.2).

Laboratory testing (serum chemistry, hematology, coagulation and urinalysis;
see Section 5.3.3).

12-lead ECG (every 3 cycles per the Flow chart 1.1 and Flow chart 1.2).

Concomitant medications (see Section 4.2).

Assessment of AEs (see Section 5.3.6).

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and the 
involved area, if applicable) (see Section 5.2.2). To be performed every 8 weeks from 
Cycle 5 to Cycle 21. From Cycle 21 onwards, it should be done every 12 weeks.

ECOG PS. To be performed every 4 cycles from Cycle 5 to Cycle 21 and at Cycle 27.

Survival.

Blood samples for the level of ADAs/nADAs, sample should be taken prior to trial 
medication administration (see Section 5.6.1). Samples to be collected at Cycles 3, 5, then 
every 4 cycles to Cycle 21 and at Cycle 27.

 
 

Trial medication infusion (see Section 4.1.4).

Administration of chemotherapy (see Table 4.1.4.1). 


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
Contact IXRS®. Not required from the switch visit cycle onwards. Note: at the time of 
Avastin® discontinuation, contact IXRS to perform the discontinuation call.
Cycle 28 onwards
Patients that continue to receive treatment from Cycle 28 and beyond will attend the trial site 
every 12 weeks for the following assessments:

Measurement of BMI. The formula used to measure BSA will be recorded

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.3.2).

Physical examination, including weight (kg) (see Section 5.3.1).

Urine pregnancy test for women of childbearing potential (serum pregnancy test to be 
performed in case of positive urine pregnancy test).

Urine protein analysis.

Laboratory testing (serum chemistry, hematology coagulation and urinalysis; see
Section 5.3.3).

Concomitant therapies/medications (see Section 4.2).

Assessment of AEs (see Section 5.3.6).

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and the 
involved area, if applicable) (see Section 5.2.2). To be performed every 12 weeks or per 
the Investigator’s discretion. This means that no CT scan is needed at Visit 28 if the 
patient received a CT scan at Visit 27.

Trial medication infusion (see Section 4.1.4). To be performed every 2 weeks.

Administration of chemotherapy (see Table 4.1.4.1). To be performed every 2 weeks.

Contact IXRS®. To be performed every 2 weeks. Not required from the switch visit
onwards. Note: at the time of Avastin® discontinuation, contact IXRS to perform the 
discontinuation call.

12-lead ECG (see Section 5.3.4)
Switch Visit, prior to Avastin® administration:
Prior to Avastin® administration, all patients on active treatment must undergo the following 
assessments.  

Physical examination, including weight (kg) (see Section 5.3.1).

Urine pregnancy test for women of childbearing potential (serum pregnancy test to be 
performed in case of positive urine pregnancy test).

Urine protein analysis.

Measurement of BMI. The formula used to measure BSA will be recorded.

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature 
(see Section 5.3.2).

Laboratory testing (serum chemistry, hematology, coagulation and urinalysis 
(see Section 5.3.3).

12-lead ECG


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
Concomitant therapies/medications (see Section 4.2).

Assessment of AEs (see Section 5.3.6).

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) (see Section 5.2.2).
Note: Another unscheduled tumor assessment should be performed 6 weeks after 
the switch visit and no longer than 13 weeks after this visit.

Survival.

Blood samples for the level of ADAs/nADAs (see Section 5.6.1). (only one sample 
between 2 hours and 5 minutes prior to the start of infusion needs to be taken)

 
Subjects are allowed to be re-screened up to two times and must be re-consented before each 
re-screening occurs.
6.2.3
Follow-up Period and Trial Completion
30-day Follow-up Visit
The following will be performed/collected:

Physical examination, including weight (kg) (see Section 5.3.1).

Measurement of BMI.

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature
(see Section 5.3.2).

Laboratory testing (serum chemistry, hematology, coagulation and urinalysis
(see Section 5.3.3).

Concomitant therapies/medications (see Section 4.2).

Assessment of AEs (see Section 5.3.6).

Date of initiation of new anticancer therapy, if applicable.

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) (see Section 5.2.2).

Survival.

Blood samples for the level of ADAs/nADAs (see Section 5.6.1).

.


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In addition, all patients who receive at least one infusion of BI 695502 or Avastin® and who 
discontinue the trial treatment at any time after Day 1 (but do not withdraw their consent) will 
be required to have all of the evaluations for the Follow-up visit 30 days after the last trial 
medication administration (BI 695502 or Avastin®, whichever occurs later). 
Non-treatment period
For all patients who discontinue trial medication for reasons other than progressive disease, 
but do not withdraw consent, the following will be performed/collected every 8 weeks until 
death or initiation of a new treatment, whichever occurs earlier. 

Physical examination, including weight (kg) (see Section 5.3.1).

Measurement of BMI. 

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; 
see Section 5.3.2).

Laboratory testing (serum chemistry, hematology, coagulation and urinalysis; 
see Section 5.3.3).

12-lead ECG (see Section 5.3.4).

Concomitant therapies/medications (see Section 4.2).

Assessment of AEs (see Section 5.3.6).

Date of initiation of new anticancer therapy, if applicable.

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and involved 
area, if applicable) (see Section 5.2.2) at a minimum of every 8 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 to 9 weeks according to clinical judgment until disease progression, 
death, or the end of the trial, whichever occurs first. The following will be 
performed/collected:

Tumor assessment (CT/MRI scan of chest and abdomen, including adrenals and involved 
area, if applicable) (see Section 5.2.2).

Assessment of AEs (see Section 5.3.6).

Date of disease progression (if applicable).

Survival
Long-term Safety Follow-up Visit
The SFU visit will be performed 18 weeks after the last administration of BI 695502 prior to 
the switch visit. If the patient continues to receive treatment with Avastin® beyond 18 weeks 
post last BI 695502 dose, then no SFU visit will be performed.
The following will be performed/collected:

Physical examination, including weight (kg) (see Section 5.3.1).


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
Measurement of BMI.

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.3.2).

Laboratory testing (serum chemistry, hematology, coagulation and urinalysis; see 
Section 5.3.3).

Concomitant therapies/medications (see Section 4.2).

Assessment of AEs (see Section 5.3.6).

Date of initiation of second-line therapy (if applicable).

Survival.

Blood samples for the level of ADAs/nADAs (see Section 5.6.1).

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 until
death, lost to follow-up, withdrawal of consent, or a maximum of 12 months after the last 
patient enrolled plus the 30-day FU visit, whichever occurs earlier.
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
STATISTICAL DESIGN - MODEL
7.1
This is a single arm, open-label, multicenter trial. The primary objective is to evaluate safety 
and tolerability of BI 695502.
The primary endpoint will be patients with any of the selected AEs (see Section 5.1.1).
Secondary objectives comprise the evaluation of efficacy parameters and further safety. A 
further objective is the evaluation of immunogenicity
No formal hypothesis testing will be performed. The analysis of the data will be performed 
descriptively.
NULL AND ALTERNATIVE HYPOTHESES
7.2
No formal hypothesis testing will be performed. Where confidence intervals or p-values are 
presented, they will be interpreted in an exploratory fashion only.
PLANNED ANALYSES
7.3
All patients treated with at least one dose of trial medication (treated set) will be included in 
efficacy and safety evaluations. Efficacy and safety analyses will be based on the treated set.
The main analyses will cover the period during which patients received BI 695502 and data 
will be analyzed to the extent available also taking differences in exposure to BI 695502 into 
account, i.e. using censoring of data and exposure corrected adverse events rates. These 
methods will be defined in the TSAP. Adverse events will be presented by underlying 
treatment and taking the corresponding exposure into account.
After the transition to commercially available Avastin®, the impact of switching will be 
assessed in an exploratory manner 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. 
7.3.1
Primary endpoint analyses
Primary safety analysis
7.3.1.1
The primary endpoint of the study is patients with any of the selected AEs defined in
Section 5.1.1.
All AEs with an onset between start of treatment and end of the REP, a period of 18 weeks 
after the last dose of trial medication, will be considered. The proportion of patients with at 


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least one AE selected for primary endpoint assessment will be displayed including descriptive 
95% confidence intervals (CIs) for the proportion of patients with selected AEs. See 
Section 7.3.3 for details on safety analysis. The proportion of patients for the AE categories 
will be presented.  
7.3.2
Secondary endpoint analyses
Objective response according to RECIST 1.1 as assessed by central imaging review will be 
analyzed using objective response rate, defined as proportion of patients with complete 
response [CR] plus partial response [PR]. Objective response rate will be summarized using 
descriptive statistics including descriptive 95% CIs. Additionally, the response categories will 
be analyzed descriptively. See Section 5.2.2 for the definition of response categories and 
objective response.
For other secondary endpoints listed below, descriptive analyses using Kaplan Meier (KM)
methodology will be performed.
Date of PD will be the date of radiological diagnosis of PD for patients progressed according 
to central review assessment.
For PFS calculation, patients who have neither progressed as per central imaging review nor 
died will be censored on the date of last radiological tumor assessment (see Section 7.5.1).
For TTP and DOR evaluation, patients who have not progressed as per central imaging 
review will be censored on the date of last evaluable tumor assessment.
For OS, OS time will be censored at the last date that the patient is known to be alive. 
The PFS will be analyzed descriptively using KM methodology. The KM survival rate will 
be presented graphically. The 1-year PFS rate and median PFS will be estimated with two-
sided 95% CI. The CI for 1-year PFS rates will be determined using Greenwood’s variance 
estimate (R14-3846).  The CI for the median will be calculated according to the Brookmeyer 
and Crowley method (R09-6372).
 
7.3.3
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. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. All AEs with an onset between start of treatment and end of 


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the REP, a period of 18 weeks after the last dose of trial medication, will be assigned to the 
treatment period for evaluation and will be considered as treatment-emergent AEs. In the 
context of switching from BI 695502 to Avastin®, TEAE definitions will be specified in the 
TSAP.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Severity of AEs will be reported using the NCI-CTCAE version 4.0 criteria. For all 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. 
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 18 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. 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 vital signs, weight, physical examination and ECG parameters, compared to 
findings before start of treatment, will be summarized.
7.3.4
Immunogenicity analyses
If data allow, the antibody response, antibody titer and neutralizing antibody response will be 
summarized as appropriate (frequency/proportions for ADA positive samples, descriptive 
statistics for titer and frequency/proportions of characterization of the neutralizing potential 
of the ADA for ADA positive samples assayed) by scheduled assessments (Week 0, Week 4, 
Week 8, Week 16, Week 24, Week 32, Week 40 and Week 52, and 30-day Follow-up visits 
and long-term SFU visit) and overall (for ADA positive subjects only). 
 
. 
INTERIM ANALYSES
7.4
No interim analysis is planned for this study.


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HANDLING OF MISSING DATA
7.5
7.5.1
Efficacy endpoints
For the primary analysis, the rules described in Table 7.5.1: 1 for censoring and assignment 
of progression date will be applied.
Table 7.5.1: 1
Censoring and handling of missing data for PFS
Situation 
Outcome
Date of Progression or Censoring
No baseline assessment
Censored
Date of first administration of trial 
medication
Consecutive missed 
radiological assessments
Censored
Date of last radiological assessment of 
measured lesions
New anticancer treatment 
started
Censored
Date of last radiological assessment of 
measured lesions
No progression/no death
Censored
Date of last radiological assessment of 
measured lesions
Progression according to 
RECIST 1.1 and not 
censored for any reason 
above
Progressed
Date of radiological assessment that 
demonstrates progression
Death and not censored for
any reason above
Progressed 
Date of death
For other efficacy endpoints, rules for handling of missing data will be specified in the Trial 
Statistical Analysis Plan (TSAP) if necessary.
7.5.2
Safety and other endpoints
Adverse events with missing relationship will be considered as drug related. Other missing 
safety data will be not be imputed.
 
RANDOMIZATION
7.6
This is an open-label, single arm trial. No randomization will be performed.
DETERMINATION OF SAMPLE SIZE
7.7
This is an exploratory trial. No formal statistical hypothesis will be tested or powered for.
Based on historical data (R10-2544, R11-2707, R13-5293), a proportion of about 30% to 
50% of patients are expected to experience an AE of the primary endpoint. For these 


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proportions, a sample size of N=120 patients will lead to a width of the CI for the AE rate of 
16.2% to 17.6% as shown in Table 7.7: 1 below.
Table 7.7: 1
95% Wilson Confidence interval for proportion of patients with 
primary endpoint AE
Assumed AE rate
Lower bound
Upper bound
30%
22.5%
38.7%
40%
31.7%
48.9%
50%
41.2%
58.8%
Furthermore, the sample size of N=120 allows to observe relatively rare AEs with high 
probability as shown in Table 7.7: 2.
Table 7.7: 2
Probability to observe at least 1 AE with a given probability of 
occurring.
Underlying 
probability of event
Probability to 
observe at least 1 
case
1%
70.0%
2%
91.1%
3%
97.4%
5%
99.8%
Therefore the sample size of N=120 is chosen for this trial.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for GCP and relevant BI SOPs, and the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997).
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
Japan only: The rights of the Investigator/trial site and of the Sponsor with regard to 
publication of the results of this trial are described in the Investigator contract/trial site’s 
contract. As a general rule, no trial results should be published prior to finalization of the 
Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF.
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/Independent Ethics Committee (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.
Partner pregnancy: If a female partner of a male patient is confirmed as being pregnant, an 
ICF for a Pregnant Partner will be provided to the female partner to allow pregnancy follow-
up.


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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 the regulatory and legal requirements of the participating country.  
Japan only: The Investigator must give a full explanation of the study procedures to trial 
patients using the patient information form, which avoids the use of technical terms and 
expressions. The patient will be given sufficient time to consider participation in the trial. The 
Investigator will obtain the patient’s written consent on the informed consent form after 
confirming that the patient understands its 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. Re-consenting may become necessary when new relevant information becomes 
available and should be conducted according to the Sponsor’s instructions.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB/IEC 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.
RECORDS
8.3
Electronic Case Report Forms for individual patients will be provided by the Sponsor. 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 reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For the eCRF, the following data need to be derived from source documents:

Patient identification (gender, date of birth)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date (mandatory), and end date (if available))

SAEs (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)


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
Originals or copies of laboratory results (in validated electronic format, if available)

Completion of patient’s participation in the trial

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g., medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
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. eCRF 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 Clinical Research Associate, on 
site monitor and auditor may review all eCRF, and written informed consents. The accuracy 
of the data will be verified by reviewing the documents described in Section 8.3.1.
8.3.3
Storage period of records (Japan only)
Trial site(s):
The trial site(s) must retain the source documents and essential documents for a period 
defined by the Japanese GCP regulation and trial site’s contract with the Sponsor.
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.


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LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil 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. 
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 product (mFOLFOX6), the reference document for 
fluorouracil is the EU Summary of Product Characteristics (SPC) and for leucovorin and 
oxaliplatin the United Kingdom (UK) SPC for each product should be used.
The current versions of these reference documents are provided in the ISF. No AEs are 
classified as listed for trial design.
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of SAEs, e.g. suspected unexpected serious adverse reactions to health 
authorities and IEC/IRB, will be done according to local regulatory requirements. When there 
is no evidence suggesting a causal relationship between the trial medication and the 
progression of the underlying malignancy, 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.
STATEMENT OF CONFIDENTIALITY
8.5
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.
END OF TRIAL
8.6
The end of the trial is defined as when all enrolled and treated patients have either died, are 
lost to follow-up, or have withdrawn consent, or for a maximum of 12 months after the last 
patient enrolled plus the 30-day FU visit, whichever occurs earlier. 
The IEC/CA in each participating EU member state needs to be notified about the end of the 
trial or early termination of the trial.


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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.
PROTOCOL VIOLATIONS (JAPAN ONLY)
8.7
The Investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reasons, the principal Investigator should prepare 
and submit the records explaining the reasons thereof to the Sponsor, and retain a copy of the 
records.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
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
PUBLISHED REFERENCES
9.1
R05-2504
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, 
Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin 
for metastatic colorectal cancer. N Engl J Med. 2004;350:2235-42.
R13-1115
Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar 
S. Combined analysis of efficacy: the addition of bevacizumab to 
fluorouracil/leucovorin improves survival for patients with metastatic 
colorectal cancer. J Clin Oncol. 2005;23:3706–12.
R11-2707
Saltz LB, Clarke S, Diaz-Rubio E, Scheitauer W, Figer A, Wong R, et al. 
Bevacizumab in combination with oxaliplatin-based chemotherapy as 
first-line therapy in metastatic colorectal cancer: a randomized phase III 
study. J Clin Oncol. 2008;26:2013-19.
R06-2690
Tournigand C, Andre´ T, Achille E, Lledo G, Flesh M, Mery-Mignard D, 
et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in 
advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 
2004;22:229–37.
R07-4623
Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts
SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and 
leucovorin (FOLFOX4) for previously treated metastatic colorectal 
cancer: results from the Eastern Cooperative Oncology Group Study 
E3200. J Clin Oncol. 2007;25:1539-44.
R13-1117
Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, et al. 
Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid 
plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic 
colorectal cancer: a randomized phase III non inferiority study. Ann 
Oncol. 2008;19:1720–6.
R13-1112
Bennouna J, Borg C, Delord JP, Husseini F, Trillet-Lenoir V, Faroux R, et 
al. Bevacizumab combined with chemotherapy in the second-line 
treatment of metastatic colorectal cancer: results from the phase II 
BEVACOLOR study. Clin Colorectal Cancer. 2012;11:38–44.
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.
R10-4848
National Cancer Institute Common Terminology Criteria Adverse Events 
(NCI-CTCAE); Version 4.0. website: ctep.cancer.gov/reporting/ctc.html.


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R13-1134
Engstrom PF, Arnoletti JP, Benson AB 3rd, Chen YJ, Choti MA, Cooper 
HS, et al. NCCN Clinical Practice Guidelines in Oncology: colon cancer. 
J Natl Compr Canc Netw. 2009;7:778-831.
R13-1110
Rosen O, Yi J, Hurwitz H, Ince W, Novotny W, and Holmgren E. Clinical 
benefit of bevacizumab in metastatic colorectal cancer is independent of 
K-RAS mutation status: analysis of a phase III study of bevacizumab with 
chemotherapy in previously untreated metastatic colorectal cancer. Ann 
Oncol. 2008;19(Suppl. 6): vi19; abstract 0-035.
R15-4644
Van Cutsem E, Cervantes A, Nordlinger B. ESMO Guidelines Working 
Group. Advanced colorectal cancer: ESMO Clinical Practice Guidelines 
for treatment. Ann Oncol. 2014;25(Suppl. 3): iii1–iii9.
R15-3504
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. 
Cancer incidence and mortality worldwide: sources, methods and major 
patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86.
R14-3846
Kalbfleisch JD and Prentice RL. The Statistical Analysis of Failure Time 
Data, New York: 2nd ed. Hoboken: John Wiley & Sons (2002).
R09-6372
Brookmeyer R, Crowley J. A confidence interval for the median survival 
time. Biometrics. 1982;38:29-41.
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/2017/125085s319l
bl.pdf
(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)
R10-2544
Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, 
DiBartolomeo M, et al. Safety and efficacy of first-line bevacizumab with 
FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic 
colorectal cancer: the BEAT study. Ann Oncol. 2009;20:1842-7.
R13-5293
Schmoll HJ, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski
SL, et al. Cediranib With mFOLFOX6 Versus Bevacizumab With 
mFOLFOX6 As First-Line Treatment for Patients With Advanced 


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Colorectal Cancer: A Double-Blind, Randomized Phase III Study 
(HORIZON III). J Clin Oncol. 2012;30:3588-95.
UNPUBLISHED REFERENCES
9.2
Not applicable.


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10.
APPENDICES
GUIDELINES FOR EVALUATION OF OBJECTIVE RESPONSE USING 
10.1
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 1302.3 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 enrollment.
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 (TL) and lesions irradiated within 12 weeks of 
enrollment.


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
Skin lesions assessed by clinical examination.
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 TLs.
Target lesions:
A maximum of five measurable lesions (with a maximum of two lesions per organ), 
representative of all lesions involved suitable for accurate repeated measurement, should be 
identified as TLs 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 1302.3 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 
intravenous (i.v.) contrast media administration is the preferred method. MRI 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 1302.3 trial, clinical examination will not be used for assessment of TL. Clinically 
detected lesions can be selected as TLs 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 1302.3 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 1302.3 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 1302.3 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 1302.3 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 1302.3 trial, tumor markers will not be used for objective response assessments as per 
RECIST 1.1.
Cytology and histology
In the 1302.3 trial, histology will not be used as part of the objective 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 (SD) (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 


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appearance of 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 1302.3 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 trial. 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.
OBJECTIVE 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 28 days (see 
Flow chart 1.1) before the start of trial treatment. Follow-up assessments will be performed 
every 8 weeks (± 3 days) after enrollment 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.
Target lesions (TL)
Documentation of target lesions
A maximum of five measurable lesions, with a maximum of two 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 


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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 >5 mm, 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., embolization, surgery etc., during the study, 
the size of the TL should still be provided where possible.
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 TLs since baseline. Any pathological lymph 
nodes selected as TLs 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 TLs, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on 


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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 TLs were not assessed or not evaluable or 
had a lesion intervention at this visit. Note: If the sum of diameters meets the PD criteria, PD
overrides not NE as a TL 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 NTLs 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 NTLs were not assessed and, in 
the Investigator's opinion, they are not able to provide an evaluable overall NTL assessment 
at this visit.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more NTLs 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.


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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.
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; NA = not applicable (only relevant if there were no target lesions/non-target lesions at baseline); 
NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease.


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CENTRAL REVIEW
Radiological examinations performed in the conduct of this trial for RECIST 1.1 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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GUIDELINES FOR BI 695502 OR AVASTIN® PREPARATION AND 
10.2
ADMINISTRATION
Supply
BI 695502 will be provided as a concentrate for solution for infusion 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 or Avastin®; therefore, the vials are intended for single 
use only. BI 695502 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 (PVC) or 
polyolefin bags/lines have been observed for BI 695502, only bags/lines made of these 
materials are to be used for 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 tubing include a 0.2 µm infusion filter
BR = Polybutadiene; DEHP = di-(2-ethylhexyl)phthalate; PE = Polyethylene; PP = Polypropylene; PUR = Polyurethane; 
PVC = Polyvinyl chloride; 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.
Preparation of BI 695502 or Avastin® for Intravenous Administration
The recommended dose is 5 mg/kg every 2 weeks when used in combination with i.v. 5-FU-
based chemotherapy. The dose of BI 695502 or Avastin® should be recalculated prior to each 
infusion.


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Use appropriate aseptic technique. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container 
permit. The necessary amount of BI 695502 will be withdrawn and diluted in 0.9% of 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 respecting the mandatory 
concentration of 16.5 mg/mL. 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.
After switch from BI 695502 to Avastin®, the recommended concentration for Avastin® is 
from 1.4 mg/mL to 16.5 mg/mL.
CHEMOTHERAPY REGIMENS AND RECOMMENDATIONS FOR 
10.3
DOSE MODIFICATIONS IN CASES OF TOXICITY
Patients will receive mFOLFOX6 as outlined in earlier sections of the protocol. 
In case of any toxicity > grade 2 (according to the NCI CTCAE version 4.0), chemotherapy 
will be discontinued. 
Neurotoxicity related to oxaliplatin requires particular attention. The National 
Comprehensive Cancer Network (NCCN) recommends to discontinue oxaliplatin in case of 
significant neurotoxicity with other drugs maintained until disease progression. 
However, 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 eCRF page.
Based on patient tolerability, the doses of chemotherapy drugs may be decreased as per the 
label or institutional practice.
CLINICAL EVALUATION OF LIVER INJURY
10.4
10.4.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.3.6.1 (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 


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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, ceruloplasmin, α-1 antitrypsin, transferrin, 
amylase, lipase, fasting glucose, cholesterol, triglycerides, cholinesterase, INR, aPTT.
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 judgment and Good Clinical Practice (GCP).


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
22 April 2016
EudraCT number
2015-003718-25
BI Trial number
1302.3
BI Investigational Product(s)
BI 695502
Title of protocol
A single arm, open-label, multicenter, 
multinational, safety and efficacy Phase IIIb
trial of BI 695502 plus mFOLFOX6 in 
patients with previously untreated 
metastatic colorectal 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: Study Title, Brief title and 
Coordinating Investigator details
Description of change
Locally advanced removed
Contact details changed
Rationale for change
To allow all patients with untreated 
metastatic colorectal cancer to be included 
in the study
Administrative change of contact details 
added
Section to be changed
Synopsis: Study title 
Description of change
Locally advanced removed
Rationale for change
To allow all patients with untreated 
metastatic colorectal cancer to be included 
in the study
Section to be changed
Synopsis: No of Patients: total entered 
Description of change
Removal of number of patients to be entered 
in Japan
Rationale for change
Local information not required in the global 
protocol
Section to be changed
Synopsis: Main criteria for inclusion


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Description of change
Text changed from: Patients aged ≥18 (for 
Japan only: Age ≥20 years at Visit 1) to:
Patients aged ≥18 (for Japan only: Age ≥20 
years at time of signing the informed 
consent form [ICF])
Requirement for locally advanced disease 
removed
Text updated to state the patients must have 
at least one measurable lesion according to 
RECIST 1.1, that has not been irradiated 
within 12 weeks prior to enrollment
Rationale for change
To align with study flow chart, to allow all 
patients with metastatic disease to enter the 
study and to restrict entry of patients who 
have recently undergone radiotherapy 
 
Section to be changed
Synopsis: Statistical Methods
Description of change
Provision of an interim analysis has been 
deleted
The subsection Further analyses has been 
deleted to remove repetition
Rationale for change
No interim analysis is needed for this study
Section to be changed
Flow Chart 1.1 
Description of change
Assessment of DILI (if needed) and 
coagulation parameters added.
Row for INR/PTT deleted
Footnotes added to state that a Central 
Laboratory will be used for hematology, 
clinical biochemistry urinalysis and 
coagulation tests
Footnotes amended to state that: screening 
biopsy should be obtained locally, that 
sitting BP is measured after at least 
5 minutes rest, that two consecutive ECGs 
should be taken, that tumor assessments will 
be performed every 8 weeks up to Visit 28, 
every 12 weeks from Visit 28 onwards and 
every 8 weeks in the non-treatment period; 
CT scans of the neck are now deleted;
 
 
A new footnote also states that if a visit 
occurs outside the specified time window, 


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then the next visit will be based on the 
number of days from the previous visit, and 
the number of days from not from baseline
Rationale for change
To include completion of the DILI checklist 
for patients with elevated LFTs and to 
include regular assessment of coagulation 
parameters
To permit centers to take local biopsy 
samples if archival material is not available
To align ECG evaluations with those in 
Study 1302.5
To reduce the number of CT scans that are 
required
To add clarity on the timing and procedures 
for study assessments
Section to be changed
Flow Chart 1.2 – Cycle 14 onwards
Description of change
Assessment of DILI (if needed) and 
coagulation parameters added.
Footnotes added to state that a Central 
Laboratory will be used for hematology, 
clinical biochemistry urinalysis and 
coagulation tests
ECG assessments were aligned with 3 cycle 
frequency.
Urine pregnancy and protein analysis added 
at Week 27
Concurrent medication check added at 
Cycle 28 onwards
Footnotes amended to increase the visit 
interval during the non-treatment phase 
from 8 weeks to 12 weeks, to state that two 
consecutive ECGs should be taken, to 
specify that sitting BP is measured after at 
least 5 minutes rest, and to clarify the 
procedure for PK sampling
Footnotes also clarify that from Cycle 28 
onwards CT scans will be performed every 
12 weeks. CT scans of the neck have been 
deleted. During the non-treatment period CT 
scans will be performed every 8 weeks
Footnote added to state that if a visit occurs 
outside the specified time window, then the 


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next visit will be based on the number of 
days from the previous visit, and the 
number of days from not from baseline
Rationale for change
To align assessments with those stated in 
the study design sections of the protocol and 
with Protocol 1302.5
To reduce the number of assessments and 
CT scans required after Cycle 27
To add clarity on the timing and procedures 
for study assessments
Section to be changed
2.1 Rationale for Performing the Trial 
Description of change
Text changed to state that… generation of 
additional safety and efficacy data of BI 
695502 in mCRC will be of value to the 
treating physician and patients
Rationale for change
To add clarity to the rationale
Section to be changed
2.3 Benefit-Risk Assessment
Description of change
The following paragraph has been added:
Avastin® may cause fetal harm based on the 
drug’s mechanism of action and findings 
from animal studies. Limited postmarketing 
reports describe cases of fetal 
malformations with use of Avastin® in 
pregnancy; however, these reports are 
insufficient to determine drug associated 
risks. In animal reproduction studies, 
intravenous administration of bevacizumab 
to pregnant rabbits every 3 days during 
organogenesis at doses approximately 1 to 
10 times the clinical dose of 10 mg/kg 
produced fetal resorptions, decreased 
maternal and fetal weight gain and multiple 
congenital malformations including corneal 
opacities and abnormal ossification of the 
skull and skeleton including limb and 
phalangeal defects. Furthermore, animal 
models link angiogenesis and VEGF and 
VEGF Receptor 2 (VEGFR2) to critical 
aspects of female reproduction, embryofetal 
development, and postnatal development. 
Women who are pregnant, nursing, or who 
plan to become pregnant are excluded from 
entering the trial. Women of reproductive 
potential should be advised to use effective 


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contraception during treatment with, and for 
6 months after the last dose of Avastin®.
Rationale for change
To alert Investigators of the risks of fetal 
harm in women taking Avastin and to 
update the protocol in line with the revised 
labelling (Dec 2015)
Section to be changed
3.1: Overall Design 
Description of change
Provision of an interim analysis has been 
deleted
Proposed number of Japanese patients 
deleted.
Provision for changes to the mFOLFOX6 
regimen to be allowed following agreement 
by the Sponsor
Rationale for change
No interim analysis is needed for this study
Regional information removed from the 
protocol
Changes to mFOLFOX regimen may be 
required in centers where leucovorin is not 
obtainable
Section to be changed
3.3: selection of Trial Population 
Description of change
Text added to state that re-screening can 
only occur after approval of the Sponsor
The number of subjects planned for Japan 
has been deleted
Rationale for change
Administrative and to remove country 
specific information.
Section to be changed
3.3.1 Main diagnosis for trial entry
Description of change
Text changed from: Patients aged ≥18 (for 
Japan only: Age ≥20 years at Visit 1) to:
Patients aged ≥18 (for Japan only: Age ≥20 
years at time of signing ICF)
Text changed to state that patients 
measurable lesions must not have been 
irradiated within 12 weeks prior to 
enrollment
‘Locally advanced’ removed to allow 
patients with metastatic CRC to enter the 
study
Rationale for change
To align with study flow chart and to 
exclude recently irradiated patients
To extend the population eligible for study 
entry
Section to be changed
3.3.1 Main diagnosis for trial entry
Description of change
The description of the main diagnosis for 
trial entry was modified from:


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subjects who ‘have not completed any 
adjuvant/neoadjuvant therapy at least 12 
months before trial entry to:
subjects  ‘should have completed any 
adjuvant/neoadjuvant therapy at least 12 
months
Rationale for change
To align text with Exclusion criterion 1 and 
text in Table 4.2.2.1:1
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criterion 1 has been changed from: 
Patients aged ≥18 (for Japan only: Age ≥20 
years at Visit 1) to:
Patients aged ≥18 (for Japan only: Age ≥20 
years at time of signing ICF)
‘Locally advanced’ removed to allow 
patients with metastatic CRC to enter the 
study
Criterion 6 re-ordered to align with Study 
1302.5
INR criterion revised in line with Study 
1302.5 and added as a separate criterion
Text changed to state exclude patients with 
measurable lesions that have been irradiated 
within 12 weeks prior to enrollment
Rationale for change
To align with study flow chart and exclude 
recently irradiated patients. To extend the 
population eligible for study entry
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criterion 6d has been changed 
from:
Hemoglobin ≥9 g/dL (without transfusion 
within 2 weeks prior to randomization) to:
Hemoglobin ≥9 g/dL (without transfusion 
within 2 weeks prior to screening).
Criterion 6g has been amended to specify 
total bilirubin
Criterion 6h has been clarified to include 
subjects with non-clinically significant 
deviations in INR ≤1.4 or PTT within 
normal limits
Criterion 7 has been amended to specify life 
expectancy should be based on the clinical 
Investigators judgment
Rationale for change
To align with the single arm open label 
study design and to more clearly specify 
subject inclusion criteria


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Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criterion 4 has been amended as 
follows:
Spinal cord compression or brain metastases 
unless asymptomatic, stable and not 
requiring steroids for at least 4 weeks prior 
to start of study treatment. 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.
The following text has been added to 
exclusion criterion 10:
Intravenous, intramuscular, interarticular or 
parenteral corticosteroids are restricted 
within 6 weeks prior to Day 1. The use of 
corticosteroids as antiemetics for oxaliplatin 
and 5-FU is allowed according to regular 
institutional practice
In Criterion 12: 3 months has been replaced 
by 12 weeks
Criterion 15 has been changed to state that 
history of active gastroduodenal ulcer refers
to within 18 month of study inclusion
Rationale for change
To provide more detailed information about 
exclusion of patients with brain metastases
To provide consistency with information 
provided in Table 4.2.2.1:1 and to allow 
these drugs to be given for antiemetic use in 
line with regular Institutional practice in 
each country / study center participating in 
the study 
12 weeks stated for consistency with 
subsequent sections of the protocol
To allow inclusion of patients with history 
of gastroduodenal ulcer more than 18 
months ago
Section to be changed
Section 3.3.4 Removal of patients from 
therapy or assessments


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Description of change
Text added to state that:
if pregnancy occurs the sponsor designee is 
to be notified immediately
New chemotherapy or radiotherapy added 
as an additional criterion
Rationale for change
Safety monitoring 
No new chemotherapy or radiotherapy to be 
allowed during the study
Section to be changed
Section 4.1.3 Selection of doses in the trial
Description of change
Text added to state that:
The dose administered to each patient is to 
be recalculated at each visit based on their 
body weight at that visit.
Rationale for change
To account for potential weight loss during 
the study
Section to be changed
Section 3.3.4 Removal of patients from 
therapy or assessments
Description of change
The criteria for patient discontinuation have 
been expanded
Rationale for change
To align with Protocol 1302.5 and with 
Sections 4.1.4 and 4.2.1 of this protocol
Section to be changed
Section 4.1.4 1 Chemotherapy
Description of change
The text now states that:
The formula used to calculate BSA should 
be recorded on the eCRF at each visit
Rationale for change
To account for the variety of formulas that 
can be used to estimate BSA and to account 
for different study personnel at a given site 
estimating BSA at different visits
Section to be changed
Section 4.2.2 Restrictions
Description of change
Radiotherapy at any time during the study 
has been added as a restriction in 
Table 4.2.2.1:1 
Rationale for change
To prevent concomitant radiotherapy during 
the study
Section to be changed
Section 4.2.2 Restrictions
Description of change
The following changes have been made to 
Table 4.2.2.1:1 concerning corticosteroid 
use.
For ‘Intravenous intramuscular, intra-
articular, or parenteral corticosteroids’ and 
for ‘Oral, inhaled or topical corticosteroids’ 
the following sentence has been added to 
the restrictions: 
The use of corticosteroids as antiemetics for 
oxaliplatin and 5-FU is allowed according 


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to regular institutional practice
Rationale for change
To allow these drugs to be given for 
antiemetic used in line with regular 
Institutional practice in each country / study 
center participating in the study
Section to be changed
Section 4.2.2 Restrictions
Description of change
The restrictions in Table 4.2.2.1:1 
concerning the use of oral or parenteral 
anticoagulants have been rewritten as 
follows:
Full-dose oral or parenteral anticoagulants 
or other thrombolytic agents for therapeutic 
(as opposed to prophylactic) purposes 
(including coumadin or warfarin) are not 
permitted within 10 days of the first dose of 
BI 695502 or throughout the trial. 
Text has been added to state that:
All patients will have a biopsy taken and 
RAS determination performed during the 
28-day screening period, before the first 
dose of study drug. If it is not possible to 
arrange a biopsy during the screening period 
then the patient can be re-screened after the 
procedure has been undertaken
Rationale for change
To bring the text in line with exclusion 
criterion 11 
To ensure that study drug is not given 
within 28 days of any surgical procedure 
needed to obtain a biopsy
Section to be changed
Section 4.2.2 Restrictions
Description of change
The text in Table 4.2.2.1:1 has been 
amended to indicate that treatment with 
dipyridamole, ticlopidine, clopidogrel and 
cilostazol are not permitted within 10 days 
of first dose of BI 695502 or throughout the 
trial
Rationale for change
This brings the text in line with exclusion 
criterion 9
Section to be changed
Section 4.2.2 Restrictions
Description of change
The text in Table 4.2.2.1:1 has been 
amended to indicate that treatment within a 
clinical trial within 4 weeks prior to 
initiation of trial treatment is not permitted.
Rationale for change
This brings the text in line with exclusion 
criterion 18
Section to be changed
Section 4.2.2 Restrictions


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Description of change
The text in Table 4.2.2.1:1 concerning 
surgical procedures now states that any 
surgical incisions should be fully healed
Rationale for change
Safety
Section to be changed
Section 4.2.2.1 Restrictions regarding 
concomitant treatment
Description of change
The text has been added to ensure that 
investigators do not prescribe concomitant 
medication prior to discussing with the 
Sponsor.
Rationale for change
To improve consistency throughout the 
study and protect patient safety 
Section to be changed
Section 4.2.2.1 Restrictions regarding 
concomitant treatment
Description of change
The text has been added to state that 
acetaminophen (paracetamol) as well as 
natural and synthetic opioids can be used as 
pain relievers and to provide guidance on 
the use of bisphosphonates
Rationale for change
To improve consistency across studies and 
protect patient safety 
Section to be changed
Section 4.2.2.1 Restrictions regarding 
concomitant treatment
Description of change
The text has been amended to clarify no 
surgical procedure including that for RAS 
determination is permitted within 28 days of 
the first dose of trial drug
Rationale for change
To align with other sections of the protocol 
Section to be changed
Description of change
Rationale for change
Section to be changed
5.2.2 Objective response
Description of change
The text relating to CT scans has been 
amended as follows: Tumor assessment will 
be performed every 8 weeks (±3 days) up to 
Visit 27. From Visit 28 onwards tumor 
assessment will be performed every 12 
weeks (±3 days). This means that no CT 
scan is needed at Visit 28 if the patient 
received a CT scan at Visit 27. During the 
non-treatment period CT scans will be 
performed every 8 weeks (±3 days) weeks.
CT scans of the neck have been excluded
Rationale for change
To reduce the number of CT scans and other 
assessments required during the non-


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treatment period
Section to be changed
5.3.3 Safety laboratory parameters
Description of change
The laboratory parameters to be evaluated 
have been added to the text.
Text has been added to the infection screen 
for hepatitis B and C to state that if any of 
these tests are positive, the result should be 
confirmed by a positive hepatitis B virus 
DNA. The text also clarifies that HIV and 
TB screen will be analyzed locally and that 
coagulation assessments for study inclusion 
should also be analyzed locally whenever 
possible.
Active hepatitis C is defined as positive 
hepatitis C virus (HCV) and/or positive 
antibody. If any of these test are positive, 
the result should be confirmed by a positive 
hepatitis virus RNA
Rationale for change
To add clarity
Section to be changed
5.3.4 Electrocardiogram
Description of change
The text has been amended to state that two 
consecutive ECGs will be taken
Rationale for change
To align with Study 1302.5
Section to be changed
5.3.6 Assessment of adverse events
Description of change
The following text has been deleted
These laboratory findings constitute a 
hepatic injury alert and the patients showing 
these laboratory abnormalities need to be 
followed up according to the “DILI 
checklist” provided in the ISF
Rationale for change
To remove repetition
Section to be changed
5.3.6 1 Definitions of AEs - AESIs
Description of change
A full definition of TEAEs suggestive of 
hepatic injury has been provided to assist 
investigators in deciding whether the DILI 
checklist needs to be completed. 
Investigators are also instructed to complete 
an SAE form for these subjects
A section has been added to define the 
procedure for assessing and reporting local 
tolerability
Rationale for change
To align with Study 1302.5
Section to be changed
5.3.7 Adverse event collection and reporting
Description of change
Pregnancy
The text for reporting pregnancy has been 
updated


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Instructions have also been added for the 
completion of an Informed Consent Form 
for a Pregnant Partner within 24 h in the 
event that a female partner of a male study 
patient is confirmed as being pregnant. 
It has also been specified that pregnant 
study participants must be withdrawn from 
the study.
Rationale for change
To clarify procedures to be adopted in the 
case of pregnancy and make provision for 
female partners who become pregnant to be 
followed up as part of the study procedures
 
Section to be changed
5.6.2 Tumor biopsy
Description of change
This section has been amended to state that 
tumor histology and RAS status will be 
confirmed during the screening period; if 
not performed/available, and no archival 
tumor sample is available, a fresh biopsy 
will be performed, if possible, and analyzed 
locally.
Rationale for change
To clarify study procedures and align with 
entry criteria
  Section to be changed
Section 6.1 Visit Schedule 
Description of change
The visit frequency for the non-treatment 
period has been changed to  8 weeks
Blood volumes have been updated in 
Table 6.1:1
Rationale for change
To reduce the number of assessments and 
CT scans required after Cycle 27
To align blood volumes with the study 
schedule
Section to be changed
6.2.1 Screening Period
Description of change
This section has been amended to state that 
biopsies can be performed locally, that the 
formula used to estimate BSA should be 
recorded, and to include coagulation tests 
Rationale for change
To clarify study procedures
Section to be changed
6.2.2 Treatment period
Description of change
This section has been amended to state that 
patients will continue to receive treatment 


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every 2 weeks from Cycle 28 onwards and 
that they will attend the trial site every 12 
weeks for assessment (the study flow chart 
has been amended accordingly)
The formula used to estimate BSA should 
be recorded and to include coagulation tests. 
 the 
frequency of CT scans have been aligned to 
the study schedule
It is also specified that subjects are allowed 
to be re-screened up to two times and must 
be re-consented before each re-screening 
occurs.
Rationale for change
To clarify study procedures
Section to be changed
6.2.3 Follow up period and Trial 
Completion
Description of change
The text has been modified to state that 
subjects will be assessed every 8 weeks 
(instead of every 12 weeks)
For the follow-up visit , the text now 
specifies that  tumor assessment is to be 
performed only if a tumor assessment was 
not performed within the previous 4 weeks
Rationale for change
To clarify study procedures and reduce the 
number of CT scans and other assessments 
required during the non-treatment period
Section to be changed
7.3.3 Safety analyses
Description of change
The text now states that Laboratory values 
will be graded according to the NCI-
CTCAE version 4.0 and reported by 
frequency. (i.e. for each treatment group has 
been deleted) 
Rationale for change
To add clarity to the procedures
 
 
Section to be changed
7.4: Interim Analysis
Description of change
Provision of an interim analysis has been 
deleted
Rationale for change
No interim analysis is needed for this study
Rationale for change
This is a single-arm open label study


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Section to be changed
8.1 Trial Approval, Patient Information and 
Informed Consent
Description of change
Text relating to the pregnant partner consent 
form has been added as follows:
Partner pregnancy: If a female partner of a 
male patient is confirmed as being pregnant, 
an Informed Consent Form for a Pregnant 
Partner will be provided to the female 
partner to allow pregnancy follow-up.
Text relating to informed consent in Japan 
has been modified for clarity
Rationale for change
To make provision for female partners who 
become pregnant to be followed up as part 
of the study procedures.
To clarify and improve the translation of the 
procedure for informed consent to be 
adopted in Japanese centers
Section to be changed
8.4.2 Expedited reporting to health
authorities and IEC/IRB
Description of change
The following text has been added to better 
define cases where disease progression does 
not require expedited reporting:
When there is no evidence suggesting a 
causal relationship between the trial 
medication and the progression of the 
underlying malignancy, 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.
Rationale for change
To make consistent with Section 5.3.7
Section to be changed
10.1 Guidelines for evaluation of an 
objective response
Description of change
Special cases now excludes radiotherapy 
during the study
Rationale for change
No radiotherapy will be allowed during the 
study
Section to be changed
10.2 Guidelines for BI695502 preparation 
and administration
Description of change
The guidelines have been updated to align 
with product labeling and with study 
1302.5. 
Rationale for change
Administrative  
Section to be changed
10.3 Chemotherapy Regimens and 
Recommendations for Dose Modifications 


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in Cases of Toxicity
Description of change
The version of the NCI CTCAE has been 
added to the following sentence:
In case of any toxicity > grade 2 (according 
to the NCI CTCAE version 4.0), 
chemotherapy will be discontinued. 
Rationale for change
For consistency with Section 7.3.3
Section to be changed
10.4.2 Procedures
Description of change
The text has been updated to state that a 
copy of the DILI checklist should be 
provided in addition to an SAE form for 
patients with suspected liver injury
Clinical chemistry now includes coagulation 
tests
Rationale for change
To align with preceding sections of the 
protocol


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Number of global amendment
2
Date of CTP revision
25 May 2016
EudraCT number
2015-003718-25
BI Trial number
1302.3
BI Investigational Product(s)
BI 695502
Title of protocol
A single arm, open-label, multicenter, 
multinational, safety and efficacy Phase IIIb
trial of BI 695502 plus mFOLFOX6 in 
patients with previously untreated 
metastatic colorectal 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
Flow Chart 1.1 
Description of change
Separate line added to show schedule of 
assessments for BSA
BSA added to list of abbreviations in table 
footnote
Footnote numbers 13 and 14 aligned 
Typo in IXRS corrected in footnote
Rationale for change
For added clarity
Section to be changed
Flow Chart 1.2
Description of change
Chart corrected to make provision for 
measurement of vital signs and weight at 
Week 28 onwards for measurement of BMI 
at Week 28 onwards and during non-
treatment period 
Separate line added to schedule for BSA
measurement
BSA and IXRS added to list of 
abbreviations in table footnote
Measurement of weight specified as part of 
physical examination
Rationale for change
To add clarity and make consistent with 
Section 6.2
Section to be changed
Abbreviations
Description of change
BSA added to list of abbreviations


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Rationale for change
To add clarity
Section to be changed
5.3.3 Safety laboratory parameters
Description of change
The following text has been deleted:
International normalized ratio and partial 
thromboplastin time will be measured at 
screening only.
Rationale for change
To ensure that all coagulation tests are 
collected post screening
Section to be changed
6.2 Details of trial procedures at selected 
visits. 6.2.2 Treatment period
Description of change
Physical examination (including weight),
measurement of BMI, BSA and vital signs 
added to Cycle 28 onwards
Rationale for change
For consistency with Flow Chart 1.2
Section to be changed
6.2 Details of trial procedures at selected 
visits. 6.2.3 Follow-up period
Description of change
Coagulation added to list of laboratory tests
at 30-day follow-up, non-treatment period 
and long-term safety follow-up visits.
Measurement of BMI added to 
non-treatment period
Rationale for change
For consistency with Flow Chart 1.2


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Number of global amendment
3
Date of CTP revision
13 April 2017
EudraCT number
2015-003718-25
BI Trial number
1302.3
BI Investigational Product(s)
BI 695502
Title of protocol
A single arm, open-label, multicenter, 
multinational, safety and efficacy Phase IIIb 
trial of BI 695502 plus mFOLFOX6 in 
patients with previously untreated 
metastatic colorectal 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
5.3.1, Physical Examination
Description of change
The rectal examination was made optional.
Rationale for change
The rectal examination was made optional 
since it is not routinely done in all the US 
practices as part of physical examination 
and to allow the use of alternate reliable 
diagnostic methods if needed. 


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Number of global amendment
4
Date of CTP revision
26 October 2017
EudraCT number
2015-003718-25
BI Trial number
1302.3
BI Investigational Product(s)
BI 695502
Title of protocol
A single arm, open-label, multicenter, 
multinational, safety and efficacy Phase IIIb
trial of BI 695502 plus mFOLFOX6 in 
patients with previously untreated 
metastatic colorectal 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
The trial number has been updated to:
1302.3 (INVICTAN®-3).
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.
Section to be changed
Flow chart 1.1. Flow chart 1.2.
Description of change
The following footnote was added:
Patients with a 2+ or greater urine dipstick 
reading should undergo further assessment 
with a 24-hour urine collection as per local 
laboratory practices. Suspend BI 695502 
administration for proteinuria ≥2 g in 
24 hours and resume when proteinuria is 
<2 g in 24 hours. If moderate to severe 
proteinuria (2+ or greater urine dipstick 
reading) cannot be controlled within 
14 days then the patient should discontinue 
BI 695502.
Rationale for change
To clarify how to manage proteinuria in 
patients with a 2+ or greater urine dipstick 
reading.


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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 
ECGs is optional.
Section to be changed
Flow chart 1.1. Flow chart 1.2. 5.2.2, 
Objective response.
Description of change
Text updated to clarify that tumor 
assessment will be performed every 8 weeks 
(±3 days) up to Visit 21, every 12 weeks 
(±3 days; ±7 days from Visit 28 onwards) 
from Visit 21 onwards and every 8 weeks 
(±3 days) during the non-treatment period.
In addition, the following text was added to 
the footnote in Flow chart 1.2:
No CT scan is needed at Visit 28 if the 
patient received a CT scan at Visit 27.
Rationale for change
To clarify the timing of tumor assessments; 
specifically, to highlight that tumor 
assessment is not required at Visit 28 if the 
patient received a tumor assessment at 
Visit 27.
 
 
 
 
 
 
 
 
 
 
 
 
 


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.
Section to be changed
4.1.4, Drug assignment and administration 
of doses for each patient
Description of change
The following text was added:
Slight variations in BI 695502 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
5.3.4, Electrocardiogram.
Description of change
The first paragraph in the section was 
updated to:
Two consecutive resting 12-lead 
electrocardiograms (ECG) 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.
Rationale for change
To clarify that the second of the consecutive 
ECGs is optional.
Section to be changed
9.1, Published references.
Description of change
Details for references R15-2488, R15-4640, 
R10-2544 and R13-5293 were updated.
Rationale for change
Administrative update.
Section to be changed
10.2, Guidelines for BI 695502 preparation 
and administration.
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.
Rationale for change
The use of polyethylene bags for infusion of 
BI 695502 is now permitted in this trial. 
The use of polybutadiene infusion sets is 
common in day-to-day clinical practice. The 
use of infusion sets made of polybutadiene 


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for administration of BI 695502 is now 
permitted in this trial. 
Section to be changed
10.2, Guidelines for BI 695502 preparation 
and administration.
Description of change
The mandatory concentration of BI 695502 
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 
the risk for the patient.


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Number of global amendment
5
Date of CTP revision
17 January 2018
EudraCT number
2015-003718-25
BI Trial number
1302.3
BI Investigational Product(s)
BI 695502
Title of protocol
A single arm, open-label, multicenter, 
multinational, safety and efficacy Phase IIIb
trial of BI 695502 plus mFOLFOX6 in 
patients with previously untreated 
metastatic colorectal 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 the protocol
Description of change
Text has been revised where applicable to 
state “BI 695505 or Avastin®” instead of BI 
695502
Rationale for change
To clarify where applicable that the trial 
medication may be either BI 695502 or 
Avastin® as a result of the switch
Section to be changed
Synopsis, 3.1, 4.1.1, 4.1.2, Flow chart 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. 


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Section to be changed
Synopsis, Flow chart 1.2, 3.1, 6.1, 6.2.3
Description of change
The text has been modified to state that the 
30-day follow-up visit will take place after 
the last administration of BI 695502 or 
Avastin®, whichever occurs later
Rationale for change
To clarify that the 30-day FU visit will take 
place after the last dose of medication in the 
trial, which could be either BI 695502 or 
Avastin® after the swtich visit
Section to be changed
Synopsis, 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
Synopsis, Flow chart 1.2, 6.2.3, 8.6
Description of change
The end of trial definition has been updated 
to take account of patients that may 
continue to receive Avastin beyond the 18-
week SFU visit.
Rationale for change
To update the end of trial definition to 
accurately reflect the updated trial design
Section to be changed
Synopsis, 4.1.4, Appendix 10.2
Description of change
Text has been added to state that filters must 
be used for Avastin® administration
Rationale for change
To ensure patients safety, filters must be 
used for all Avastin® infusions the same as 
for BI 695502 administration
Section to be changed
Synopsis, 7.3
Description of change
Text has been added to describe the period 
covered by the main analyses plus that 


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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
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
Rationale for change
To provide detailed information on what 
assessments need to be performed at the 
Switch Visit
Section to be changed
2.3
Description of change
Text has been added to state that 5 DSMB 
meetings have taken place during the 1302.5
study to date
Rationale for change
To provide further information on the 
DSMB meetings that have occurred in study 
1302.5 and that all meetings recommended 
the continuation of the trial without 
modification 
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 


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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.
Section to be changed
4.1.6
Description of change
Text has been added to state that Avastin® 
will be provided as commercially labeled 
drug and that relabeling for trial purposes is 
not required
Rationale for change
To clarify Avastin® supply and labeling
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 not need to
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
5.6.1
Description of change
The text has been updated to clarify the 
shipping process for nADA samples.
Rationale for change
To ensure consistency in the shipment 
frequency for nADA samples between the 
protocol and the laboratory manual


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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 assessments to be performed
Section to be changed
Table 6.1: 1
Description of change
The blood volumes have been updated to 
include the addition sampling for the Switch 
visit
Rationale for change
To update the total estimated blood 
volumes.
Section to be changed
6.2.2
Description of change
Text has been added to state that the sites 
will not be required to contact IXRS after 
the switch onwards, but when the patient 
discontinues treatment, IXRS should be 
contacted to perform the discontinuation 
call.
Rationale for change
To clarify the process for contacting IXRS 
after the switch visit 
Section to be changed
7.3.3
Description of change
Text has been added to describe that TEAE 
definitions after the switch visit will be 
defined in the TSAP
Rationale for change
To clarify that the definition of TEAEs after 
switching will be clarified in the TSAP and 
not explained in the protocol
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
8.4.1
Description of change
Text has been added to provide the 
reference documents for the evaluation of 
listedness for Avastin®
Rationale for change
To provide the reference documents for the 
evaluation of listedness for new trial 


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medication, Avastin®
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08875184
6.0
clinical-trial-protocol-version-06
A single arm, open-label, multicenter, multinational, safety and efficacy Phase IIIb
trial of BI 695502 plus mFOLFOX6 in patients with previously untreated metastatic
colorectal cancer
Approval-Clinical Pharmacokinetics
18 Jan 2018 10:52 CET
Approval-Team Member Medicine
18 Jan 2018 10:53 CET
Author-Trial Clinical Monitor
18 Jan 2018 10:56 CET
Author-Trial Statistician
18 Jan 2018 11:25 CET
Approval-Therapeutic Area 
18 Jan 2018 15:27 CET
Verification-Paper Signature
Completion
23 Jan 2018 16:43 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08875184
6.0

SAP_000.pdf: 
 
Statistical Analysis Plan 
 
PROTOCOL 1302.3 INVICTAN®-3 
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disclosure or reproduction is strictly prohibited. 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
1302.3 INVICTAN®-3 
A SINGLE ARM, OPEN-LABEL, MULTICENTER, MULTINATIONAL, SAFETY AND EFFICACY 
PHASE IIIB TRIAL OF BI 695502 PLUS MFOLFOX6 IN SUBJECTS WITH PREVIOUSLY 
UNTREATED METASTATIC COLORECTAL CANCER 
 
 
 
 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: V5.0, 13DEC2018 
 
 
 
 
 
 
 
 


 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V5.0 (Dated 13DEC2018) for Protocol 1302.3. 
 
 
Name 
Signature 
Date 
Author: 
 
See below for 
electronic signature 
DDMMMYYYY 
 
Position: 
Statistical Team 
 
 
Company: 
 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, 
authorizing that the content is acceptable for the reporting of this trial. 
 
Name 
Signature 
Date 
Approved By: 
 
See below for 
electronic signature 
DDMMMYYYY 
 
Position: 
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Company: 
 
 
Approved By: 
 
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electronic signature 
DDMMMYYYY 
 
Position: 
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Company: 
 
 
Approved By: 
 
 
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Company: 
Boehringer Ingelheim 
 


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Company: 
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Approved By: 
 
 
 
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Company: 
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Company: 
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Statistical Analysis Plan Reviewed By 
 
Team Role 
Project Statistician  
Trial Statistician 
PSTAT-Asia 
Project Programmer  
Project Medical Writer 
Senior Clinical Program 
 
Clinical Program
Clinical Program
Project Pharmacometrician 
Clinical Project 
 
ADA/nADA Specialist 
Pharmacovigilance (PV) 
Project Clinical Pharmacokineticist 
Medical Affairs 
Therapeutic Area Statistician 
Team Role 
Senior Reviewer 
Trial Lead Programmer 
Global Project 
 
Global Trial Medical Advisor 
Medical Writer 
 
 


 
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OUTPUT TEMPLATES SIGNATURE PAGE 
Please refer to Output Templates V4.0 (Dated 07NOV2018) for Protocol 1302.3 INVICTAN®-3. 
 
 


 
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MODIFICATION HISTORY 
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
23MAR2017 
Not Applicable – First Version 
1.0 
24APR2017 
Update based on sponsor comments 
received on 1302.5 dry run 1. 
1.1 
08JUN2017 
Update based on sponsor comments 
received on TSAP 1302.5 and 
comments received on dry run 1 
2.0 
04AUG2017 
Update based on sponsor comments 
after reviewing TSAP version 1.1 and 
comments received  on 1302.5 dry run 2. 
3.0 
08JUN2018 
Update based on the protocol 
amendments version 6.0 - Switch of all 
subjects on trial medication to Avastin®, 
Update to Appendix 7 based on review 
by medical advisor, 
Inclusion of applicable comments 
received on TSAP 1302.5 version 4.0. 
4.0 
07NOV2018 
Update based on comments received 
from dry run TFL delivery 
5.0 
13DEC2018 
Update definition of dose increase and 
dose decrease in section 13 and update 
appendix 7. 
 
 


 
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TABLE OF CONTENTS 
Statistical Analysis Plan Signature Page 
2 
Output Templates Signature Page 
5 
Modification History 
6 
Table of Contents 
7 
List of Abbreviations and Definitions of Terms 
14 
1. 
Introduction 
17 
2. 
Trial Objectives 
17 
2.1. 
Primary Objective 
17 
2.2. 
Secondary Objectives 
17 
2.3. 
Further Objectives 
18 
3. 
Trial Design 
18 
3.1. 
General Description 
18 
3.2. 
Schedule of Events 
19 
3.3. 
Changes to Analysis from Protocol 
19 
4. 
Planned Analyses 
20 
4.1. 
Preliminary Analysis 
21 
4.2. 
Final Analysis 
21 
5. 
Analysis Sets 
21 
5.1. 
Screened Set [SCR] 
22 
5.2. 
Treated Set [TS] 
22 
5.3. 
Switched Set [SWS] 
22 


 
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disclosure or reproduction is strictly prohibited. 
 
 
 
6. 
General Considerations 
23 
6.1. 
Reference Start Date and Study Day 
23 
6.2. 
Baseline 
23 
6.3. 
Retests, Unscheduled Visits and Early Termination 
24 
6.4. 
Windowing Conventions 
24 
6.5. 
Switch Visit 
25 
6.6. 
Safety Follow Up Visit 
25 
6.7. 
Definition of Pre-switch and Post-switch Period 
25 
6.8. 
Statistical Tests 
26 
6.9. 
Common Calculations 
26 
6.10. 
Software Version 
26 
7. 
Statistical Considerations 
26 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses 
26 
7.2. 
Multicenter Studies 
27 
7.3. 
Missing Data 
27 
7.4. 
Multiple Comparisons/ Multiplicity 
27 
 
 
 
8. 
Output Presentations 
28 
9. 
Disposition and Withdrawals 
28 
10. 
Demographic and other Baseline Characteristics 
31 
10.1. 
Derivations 
32 


 
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11. 
Surgical and Medical History 
33 
11.1. 
MEDICAL HISTORY AND PREVIOUS SURGICAL PROCEDURES 
33 
11.2. 
PRIOR RADIOTHERAPY 
33 
12. 
Medications 
34 
12.1. 
PRIOR ANTI-CANCER DRUG THERAPIES 
34 
12.2. 
PREVIOUS, CONCOMITANT AND POST-TRIAL MEDICATION THERAPY 
34 
12.3. 
CONCOMITANT ANTI-HYPERTENSIVE MEDICATION 
35 
13. 
Trial Medication Exposure 
36 
14. 
DOSE INTENSITY AND RELATIVE DOSE INTENSITY 
38 
14.1. 
Derivations 
39 
15. 
Efficacy Outcomes 
40 
15.1. 
Primary Efficacy 
40 
15.2. 
Secondary Efficacy 
40 
15.2.1. 
Secondary Efficacy Variables & Derivations 
40 
15.2.1.1. 
Progression-free survival 
40 
15.2.1.2. 
Objective response rate 
42 
15.2.1.3. 
Duration of response 
43 
15.2.1.4. 
Time to progression 
44 
15.2.1.5. 
Overall survival 
46 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) 
46 
15.2.3. 
Analysis of Secondary Efficacy Variables 
47 
15.2.3.1. 
Analysis of Objective response rate 
47 


 
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15.2.3.2. 
Analysis of Progression-free survival 
48 
15.2.3.3. 
Analysis of Duration of response, Time to progression and Overall survival 
48 
15.2.4. 
Sensitivity Analysis of Secondary Efficacy Variables 
48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16. 
Safety Outcomes 
50 
16.1. 
Adverse Events 
50 
16.1.1. 
Post-Treatment AEs 
53 
16.1.2. 
TEAEs Specific Derivation 
53 
16.1.2.1. 
Patient-Years incidence rate 
53 
16.1.2.2. 
Wilson score Confidence Limits 
54 
16.1.3. 
All TEAEs 
54 
16.1.3.1. 
Intensity 
55 
16.1.3.2. 
Relationship to Trial Medication 
55 
16.1.4. 
TEAEs Leading to Temporary Interruption of Trial Medication, Oxaliplatin, Leucovorin or 5FU 
55 
16.1.5. 
TEAEs Leading to Discontinuation of Trial Medication, Oxaliplatin, Leucovorin  or 5FU 
56 
16.1.6. 
TEAEs Leading to Reduction of Chemotherapy 
56 
16.1.7. 
Serious TEAEs 
56 


 
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16.1.8. 
Non-Serious TEAEs 
57 
16.1.9. 
TEAEs Leading to Death 
57 
16.1.10. 
AEs Selected 
57 
16.1.10.1. 
AEs Selected for Primary Endpoint Assessment (Primary Endpoint) 
57 
16.1.10.2. 
AEs Selected for Exploratory Analysis 
58 
16.1.11. 
TEAEs Of Special Interest 
58 
16.1.11.1. 
Hepatic injury 
59 
16.1.11.2. 
Gastrointestinal Perforations 
59 
16.1.11.3. 
Anaphylactic Reactions 
59 
16.1.11.4. 
Pulmonary Haemorrhages 
60 
16.1.11.5. 
Other AESIs 
60 
16.1.12. 
TEAEs Potentially Related to Immunogenicity 
60 
16.1.13. 
Local Tolerability 
61 
16.1.14. 
Grade 3 or 4 TEAEs 
61 
16.2. 
Exempted Events of Disease Progression 
61 
16.3. 
Deaths 
61 
16.4. 
Laboratory Evaluations 
62 
16.4.1. 
Regular Safety Laboratory Evaluations 
62 
16.4.1.1. 
Laboratory Specific Derivations 
63 
16.4.1.2. 
Laboratory Reference Ranges and Markedly Abnormal Criteria 
64 
16.4.1.3. 
CTC Grading for Laboratory Data 
64 
16.4.2. 
Other Safety Laboratory Evaluations 
64 


 
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16.4.2.1. 
Infection screen 
64 
16.4.2.2. 
Human immunodeficiency virus test 
64 
16.4.2.3. 
Tuberculosis test 
64 
16.4.2.4. 
Pregnancy test 
65 
16.5. 
Hypertension 
65 
16.6. 
Brain Lesions 
65 
16.7. 
ECG Evaluations 
65 
16.8. 
Vital Signs 
65 
16.9. 
Physical Examination 
66 
16.10. 
ECOG 
66 
16.11. 
Other Safety Assessments 
66 
16.11.1. 
Immunogenicity Evaluation 
66 
 
 
 
 
 
 
 
 
 
 
 
 
17. 
References 
70 
 
 
 
 
 
 
APPENDIX 3. 
Laboratory Assessments 
85 
APPENDIX 4. 
EMA SOC order for presentation of the AE in the tables 
87 
APPENDIX 5. 
Cut-Off Application Rules 
88 


 
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APPENDIX 6. 
Important Protocol Violations 
89 
APPENDIX 7. 
BIcMQs, SMQs and Selected PTs 
90 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
5FU 
5-fluorouracil 
30-day FU 
Follow-up visit 30 days after the last trial drug administration 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BIcMQ 
Boehringer Ingelheim-customised MedDRA query 
BLQ 
Below the lower Limit of Quantification 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
BP 
Blood Pressure 
CI 
Confidence Interval 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
CV 
Coefficient of Variation 
DBL 
DataBase Lock 
DOR 
Duration Of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
EOI 
End of Infusion 
gCV 
geometric Coefficient of Variation 


 
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GI 
Gastrointestinal 
gMean 
geometric Mean 
HIV 
Human Immunodeficiency Virus 
KM 
Kaplan-Meier 
mCRC 
Metastatic Colorectal Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFOLFOX6 
Leucovorin/5-Fluorouracil/Oxaliplatin 
NA 
Not Applicable 
NE 
Not Evaluable 
nADA 
Neutralizing Anti-Drug Antibody 
NCI CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NTP 
Non-Treatment Period 
OR 
Objective Response 
OS 
Overall Survival 
P10 
10% percentile 
P90 
90% percentile 
PD 
Progression Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic Analysis Set 
PR 
Partial Response 
PT 
Preferred Term 
Q1 
25th percentile 
Q3 
75th percentile 
RECIST 
REP 
Response Evaluation Criteria in Solid Tumors 
Residual Effect Period 
SAE 
Serious Adverse Event 
SCR 
Screened set 


 
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SD 
Stable Disease 
SFU 
Safety Follow-up 
SI 
System International 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
Std Dev 
Standard Deviation 
SWS 
Switched Set 
TB 
Tuberculosis 
TBL 
Total Bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Table Figure Listing 
TS 
Treated Set 
TSAP 
Trial Statistical Analysis Plan 
TTP 
Time To Progression 
ULN 
Upper Limit of Normal 
ULQ 
Upper Limit of Quantification 
US 
United States of America 
WHO DD 
World Health Organization Drug Dictionary 
 
 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy, safety, 
immunogenicity data for Protocol 1302.3 INVICTAN®-3. It 
describes the data to be summarized and analyzed, including specifics of the statistical analyses to be 
performed.  
The document pertains to: 
 
Preliminary analysis: the analysis that will be performed at the time point of the primary analysis of 
trial 1302.5, 
 
Final analysis: the final analysis at the end of the trial. 
This trial statistical analysis plan (TSAP) is based on Protocol version 6.0, dated 17 January 2018, 
following the recommendation of the sponsor on 21 DEC 2017 that all subjects should be switched from 
BI 695502 to the reference product bevacizumab (commercially available Avastin®, hereafter referred to 
as Avastin®) as soon as it is available at the respective clinical site. Limited safety data (adverse events, 
immunogenicity 
) will be analysed for the post-switch period. 
2. TRIAL OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this trial is to evaluate the safety and tolerability of BI 695502 in combination 
with leucovorin/5-fluorouracil/oxaliplatin (mFOLFOX6) and as maintenance therapy (when applicable). 
2.2. 
Secondary Objectives 
The secondary objectives are to evaluate the following efficacy parameters:  
 
Progression-free survival (PFS),  
 
Objective response (OR) rate (proportion of subjects with complete response [CR] or partial 
response [PR]),  
 
Overall survival (OS),  
 
Duration of response (DOR),  
 
Time to progression (TTP). 


 
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2.3. 
Further Objectives 
The other objectives of the trial are: 
o 
To evaluate the presence of anti-drug antibodies (ADAs) and neutralizing antidrug 
antibodies (nADA). 
3. TRIAL DESIGN 
3.1. 
General Description 
This is a Phase IIIb, open-label, multicenter, multinational, single-arm trial. The trial will investigate the 
safety, efficacy, 
 immunogenicity of BI 695502 (corresponding to the trial medication) in subjects 
with previously untreated metastatic colorectal cancer (mCRC), who will receive BI 695502 in 
combination with mFOLFOX6 chemotherapy every 2 weeks until disease progression, death, 
unacceptable toxicity or the end of the trial (See protocol Section 8.6 for ‘end of the trial’  definition), 
whichever occurs earliest. Based on subject tolerability, at least 8 cycles of mFOLFOX6 should be given 
to all subjects. If the investigator decides to stop Oxaliplatin at any time during the trial, subjects should 
continue to receive infusional 5-Fluorouracil (5FU) +leucovorin with BI 695502 until progression, 
unacceptable toxicity or withdrawal of consent, whichever occurs first. The efficacy analysis will be 
based upon the evaluation of tumor imaging as per the Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 [1] and as assessed by central imaging review. 
Per the sponsor’s 21 Dec 2017 recommendation, subjects should be switched from BI 695502 to the 
reference product, bevacizumab (commercially available Avastin®, hereafter referred to as Avastin®), as 
soon as it is available at the respective clinical site. The Switch Visit is defined in Section 6.5. If Avastin® is 
not immediately available, the investigators may temporarily allow continuation on BI 695502.  
Each subject will continue the study with the same visit schedule as described in the protocol. 
 
Subjects who discontinue treatment with chemotherapy or BI 695502 or Avastin®, but do not have 
disease progression and have not started a new anticancer therapy, will continue in the trial in the non-
treatment period until disease progression or initiation of a new anticancer therapy, whichever occurs 
first. 
All subjects who receive at least one infusion of BI 695502 will attend a Follow-up visit 30 days (30-day 
FU) after the last BI 695502 dose or last Avastin® dose is administered whichever occurs later. 
Subjects will attend a long-term Safety Follow-up (SFU) visit 18 weeks after the last administration of trial 
medication prior to the switch visit. If the subject continues to receive treatment with Avastin® beyond 18 
weeks post last BI 695502 dose, then no SFU visit will be performed. 
 


 
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After the long-term SFU visit or discontinuation of Avastin® (whichever occurs later), all subjects will be 
monitored for survival every 3 months via telephone call until death, withdrawal of consent for the study 
or until the trial is closed, whichever occurs earlier. 
The trial will be closed when all screened and treated subjects have either died, are lost to follow-up, 
have withdrawn consent for the study, or when a maximum of 12 months after the last subject assigned 
to trial medication has the 30-day FU visit has elapsed, whichever occurs earlier. 
Further details of the trial design can be found in the protocol Section 3.1. 
3.2. 
Schedule of Events 
Schedule of events can be found in Sections “Flow Chart 1.1 – Cycle 1 to Cycle 13” and “Flow Chart 1.2 
– Cycle 14 Onwards” of the protocol. 
3.3. 
Changes to Analysis from Protocol 
The protocol Section 7.3.2.1 defines that a sensitivity analysis for the objective response (OR) secondary 
efficacy endpoint will be performed using the investigator-assessed OR. As the OR rate based on the 
investigator assessment is not defined as an endpoint in protocol Section 5.1 it will be defined as an other 
efficacy endpoint. 
In addition, “further” safety endpoints are defined in protocol Section 5.1.3. These endpoints will be 
renamed to “other” safety endpoints. 
In protocol Section 7.3, only the treated set, all subjects treated with at least one dose of trial medication, 
is defined. 
 
Observed value thresholds that define observed dose reductions and increases for Oxaliplatin, Leucovorin 
and 5FU were specified and any dose classified per the definition will be classified as an important 
protocol violation (See section 13). 
Censoring rules for PFS are defined in protocol Table 7.5.1:1. For harmonization with 1302.5 analysis, a 
more detailed version of censoring rules table will be used compared to the table available in the protocol 
(see Section 15.2.1.1). This more detailed version of the censoring rules table will lead to some deviations 
from the protocol: 
- 
In case of no baseline assessment: per protocol, the subject’s PFS time should be censored at the 
date of first administration of trial medication. However, if the subject died on or before the second 
planned tumor assessment, e.g. on or before the assessment of a progressive disease would have 
been possible if a baseline assessment would have been available, then the subject’s PFS time won’t 
be censored and the date of death will be the date of the event. 
- 
In case of consecutive missed radiological assessments: per protocol, the subject’s PFS time should 
be censored at the date of last radiological assessment of measured lesions. For the purpose of the 
analysis, “consecutive missed radiological assessments” will be defined as two or more consecutively 
missed tumor radiological assessments. In addition, for the censoring date, the date of last 


 
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radiological assessment prior to missed tumor assessments will be used. 
- 
In case of new anticancer therapy started: per protocol, the subject’s PFS time should be censored at 
the date of last radiological assessment of measured lesions. However, the subject’s PFS time will be 
censored only if the new anticancer therapy is initiated before PD and the date of last tumor 
assessment before initiation of new anti-cancer therapy will be used as censoring date.  
Per protocol Section 5.1.1, the AEs selected for primary safety endpoint include the category “All 
haemorrhages and pulmonary haemorrhages”. For more clarity, this category will be renamed as “All 
haemorrhages including pulmonary haemorrhages. 
 
In the protocol, the definition of enrolled subjects is not clear. Per the first paragraph of the protocol 
Section 3.3, enrolled subjects are subjects who have signed informed consent, while in the second 
paragraph, it is stated that subjects considered screen failures won’t be enrolled in this trial. However, 
screen failures subjects should also have signed an informed consent. Due to this contradiction in the 
protocol and to avoid any confusion in the analysis, the wording “screened” will be used for subjects who 
have signed an informed consent. 
 
 
 
The following additional analyses will be performed, compared to the analyses planned in the protocol:  
- 
Section 4.1: Preliminary analysis (selected safety parameters). 
 
4. PLANNED ANALYSES 
The following analysis will be performed for this trial: 
o 
Preliminary Analysis  
o 
Final Analysis  
The preliminary analysis and final analysis described in this TSAP will be performed by 
 
Biostatistics following Sponsor Authorization of this TSAP, Sponsor Authorization of Analysis Sets and 
after Data Snapshot/Database Lock (DBL) takes place. 


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4.1. 
Preliminary Analysis 
The preliminary analysis that will include an analysis of selected safety data (Adverse Events) as well as 
some important background information. The analysis will be based on treated set (TS) and will be 
indicated specifically in the table of contents of the output shells. 
This preliminary analysis will take place at the time point of 1302.5 primary analysis, and the data cut-off 
for this supportive analysis will coincide with the data cut-off for the primary analysis of 1302.5. Details 
of the cut-off date used for 1302.3 can be found in APPENDIX 5. 
For the purposes of this supportive analysis, all safety data observed prior to the cut-off date will be 
cleaned. 
No Clinical Trial Report (CTR) will be produced for this preliminary analysis, rather a selection of 
displays that will be identified in the table of contents. 
4.2. 
Final Analysis  
The final analysis will be performed at the end of the trial.  
This final analysis will include all analyses specified in the TSAP on the global population. That is to say, 
the analyses of the primary safety, as well as, all secondary and other efficacy endpoints and safety, 
immunogenicity, 
 background information data. The analysis will be based on the TS, SWS 
 
  
The final analysis will take place after the last treated subject in the trial will have received his/ her last 
treatment and completed the relevant follow-up, e.g. at time of last subject last planned visit (including 
non-treatment period [NTP] and follow-up visits).  
For efficacy analysis, data for switched subjects will be considered censored at the switch visit. There 
will be no analysis of efficacy or laboratory data post-switch. 
Post-switch data will only be tabulated where specified in the relevant sections below. All availabe post-
switch data will be listed. 
For safety analysis post-switch, AEs that started on the Switch Visit up to the 30-day follow-up visit will 
be handled as treatment emergent. 
   
 All data will be cleaned and evaluated and the results summarized in the CTR. 
5. ANALYSIS SETS 
A data review meeting will be set up to decide on the final allocation rules to assign subjects to the 
analysis sets. 


 
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5.1. 
 Screened Set [SCR] 
The screened (SCR) set will contain all subjects who provide informed consent for this trial. 
5.2. 
Treated Set [TS] 
The treated set (TS) will contain all subjects who signed informed consent and who receive at least one 
dose of trial medication. 
If there is any doubt as to whether a subject was treated or not (for example, a subject with date of 
administration of trial medication and/or start dose available but the information on the total dose 
administered is missing), he/she will be assumed treated for the purposes of analysis. 
5.3. 
Switched Set [SWS] 
The Switched Set (SWS) will contain all subjects who provided verbal informed consent to switch to 
commercial Avastin® and who received at least one dose of Avastin® post-switch. 
The SWS is applicable for the post-switch period (see Section 6.7 for definition) analyses. 
Note that data for subjects who had completed treatment, or were no longer in the study at the time of 
the switch will be analysed to the extent available. These subjects will not have performed a Switch 
Visit, and to distinguish from the Switched Set are referred to as ‘non-switched’ subjects. Data for ‘non-
switched’ subjects will be analyzed to the extent available and corresponds to the pre-switch period only 
(see Section 6.7 for definition). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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6. GENERAL CONSIDERATIONS 
6.1. 
Reference Start Date and Study Day 
Study Day will be calculated from the reference start date, and will be used to show start/stop day of 
assessments and events.  
For the pre-switch period, the reference start date (Study Day 1) is defined as the date of the first dose 
of trial medication. For subjects assigned to trial medication but not treated, it is the day of assignment 
to trial medication (as recorded on electronic Case Report Form [eCRF] page “Eligibility”). This will be 
applied for all endpoints except for DOR where the first documented CR or PR date will be used as 
reference start date. 
For the post-switch period (see Section 6.7 for definition), the reference start date (Study Day 1) is 
defined as the day of first dose of Avastin® post-switch. This is applicable for SWS. 
Reference start date or study day will appear in every listing where an assessment date or event date 
appears.  
If the start date of the event is on or after the reference start date then:  
o 
Study Day = (start date of event – reference start date) + 1. 
If the start date of the event is prior to the reference start date then:  
o 
Study Day = (start date of event – reference start date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations, 
will appear as partial or missing in the listings. For tables, the imputation rules from APPENDIX 2 will be 
used.  
6.2. 
Baseline 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to 
reference start date (including unscheduled assessments). In the case where the last non-missing 
measurement (date and time, whenever time is recorded) and the reference start date/time coincide, 
then that measurement will be considered as baseline. Adverse Events (AEs) and medications 
commencing on the reference start date will be considered as happening on-treatment. 


 
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For the post-switch period (see Section 6.7 for definition), the Switch Visit (see Section 6.5) will form the 
post-switch baseline. 
6.3. 
Retests, Unscheduled Visits and Early Termination  
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled 
measurements will not be included in by-visit table summaries and by-visit graphs, but will be presented 
in the listings, individual data graphs and hepatic injury / Hy’s Law by visit tables. 
Unscheduled tumor assessments will be used for the derivation of all efficacy endpoints, and in the re-
calculation of cycles for by-visit table summaries. 
In the case of a retest (recorded as unscheduled visit), the latest available measurement within 3 days 
after the planned assessment will be used for by-visit summaries. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
6.4. 
Windowing Conventions  
This section describes the windows used for the statistical analysis of tumor assessment in this trial. 
For the analysis of PFS, TTP, DOR and ORR the following windows will be used: 
    
Tumor Assessment Windows: 
Assessment Number   
Window 
Tumor assessment 1 (Cycle 5)  
from Day 1* to Day 84 
Tumor assessment 2 (Cycle 9) 
from Day 85 to Day 140  
Tumor assessment 3 (Cycle 13) 
from Day 141 to Day 196  
Tumor assessment 4 (Cycle 17) 
from Day 197 to Day 252 
Tumor assessment 5 (Cycle 21) 
from Day 253 to Day 308 
Tumor assessment 6 (Cycle 27) 
from Day 309 to Day 392 
… 
… 
From Cycle 28 onwards, the tumor assessments should be performed at every 12 weeks  (meaning every 84 days).  
 
*First administration of trial medication date. 
These windowing conventions will apply for reporting in the pre-switch period (See Section 6.7 for 


 
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definition). Thereafter, PFS, TTP, DOR or ORR will not be presented for the post-switch period (See 
Section 6.7 for definition).  
6.5. 
Switch Visit  
The Switch Visit is defined as the visit on which commercial Avastin® was administered for the first time.  
The assessments to be performed at the switch (prior to Avastin® administration) are specified in the 
Protocol (Flow Chart 1.2).  
6.6. 
Safety Follow Up Visit 
All subjects are required to return for a Safety Follow Up (SFU) Visit 18 weeks after their last  
administration of trial medication. For the SWS, the 18 week period will commence from the last 
administration of trial medication prior to the Switch Visit.  
If a switched subject continues to receive treatment with Avastin® beyond 18 weeks after the last dose 
of trial medication in the pre-switch period (See Section 6.7 for definition), then no SFU will be 
performed.  
After the SFU Visit or discontinuation of Avastin® (whichever occurs later) subjects will be monitored for 
survival every 3 months until death or end of trial, whichever is earlier.  
The last survival information is retrieved from the eCRF page “Survival Information” for the last visit 
performed in the Survival period.  
6.7. 
Definition of Pre-switch and Post-switch Period 
The pre-switch period is defined as the period up until the Switch Visit. For non-switched subjects, this 
corresponds to the whole trial, up until the end of the study.  


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The post-switch period is defined as the period at and after the Switch Visit (see Section 6.5) and is 
applicable to the Switched Set only (Section 5.3). The post-switch time period is defined as the Switch 
Visit until the end of the study. For this period, the Switch Visit will form the post-switch baseline, and 
treatment cycles will be renumbered post-switch Cycle 1 and so on until last cycle.  
6.8. 
Statistical Tests 
No formal hypothesis testing will be performed. However, confidence intervals (CIs) are presented and 
will be interpreted in an exploratory fashion only. 
6.9. 
Common Calculations 
For quantitative measurements, change from baseline will be calculated as: 
o 
Test Value at Visit X – Baseline Test Value. 
For quantitative measurements, percentage change from baseline will be calculated as:  
o 
(
Test Value at Visit x− Baseline Test Value
Baseline Test Value
) X 100 
6.10. 
Software Version 
All analyses will be conducted using SAS® version 9.4 or higher.  
7. STATISTICAL CONSIDERATIONS 
7.1. 
Adjustments for Covariates and Factors to be Included 
in Analyses 
No adjustments for covariates will be performed for this trial and no factors will be included in analyses. 


 
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7.2. 
Multicenter Studies 
This trial will be conducted by multiple investigators at multiple centers internationally (approximately 50 
clinical sites). Few subjects are expected to be recruited per site.  
7.3. 
Missing Data 
Missing safety data will not be imputed, unless otherwise specified in Section 16.  
 
Missing efficacy data will be handled as described in Section 15.2.2 of this analysis plan. 
7.4. 
Multiple Comparisons/ Multiplicity 
No multiplicity-adjustment will be performed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs.  
The shells provided with this TSAP describe the presentations for this trial and therefore the format and 
content of the summary tables, figures and listings to be provided by 
 Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this trial. The number of subjects 
included in each analysis set will be summarized overall.  
The following subject disposition and withdrawals will be presented for the SCR.  


 
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Relevant dispositions and withdrawals for the post-switch period will also be presented for the SWS 
 
  
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
The
 subject disposition and withdrawals will be presented by site for the SCR: 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
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The REP (Residual Effect Period) is defined as the 18 week (126 days) period after the last dose date of 
trial medication (the last date of trial medication + 18 weeks (126 days) inclusive).  
Subjects who discontinue treatment with chemotherapy or BI 695502 or both, but do not have disease 
progression and have not started a new anticancer therapy, will continue in the trial in the non-treatment 
period until disease progression, initiation of a new anti-cancer therapy, withdrawal of consent for the 
study or the end of the trial, whichever occurs first. 
The final list of important protocol violations will be confirmed at the data review meeting before the 
database lock or data snapshot, at the time of each analysis which includes the important protocol 
violations data. 
Important protocol violations, as defined in APPENDIX 6, will be presented for the treated set.  


 
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10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data, baseline disease characteristics and other baseline characteristics will be presented 
for the TS. 
 
The f
baseline disease characteristics will be reported: 


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The f
 other baseline characteristics will be reported: 
 
Accountability for missing data will be displayed in case of any missing entries. 
10.1. 
Derivations 
 
Age (years) = (date of informed consent– date of birth)/365.25. The lower integer will be used. 
For example, if age (years) = 42.68 then age will be displayed as 42. 
In the case where the date of birth is partial (only year is available), the corresponding age will be 
presented based on the imputations specified in APPENDIX 2. 
 
Grading of hypertension [the worst case (highest grade) will be used in the corresponding 
summaries] according to CTCAE v 4.03: 
o 
Grade 0: systolic blood pressure (BP) < 120 mmHg and diastolic BP < 80 mmHg 
o 
Grade 1: systolic BP 120 - 139 mm Hg or diastolic BP 80 - 89 mm Hg 
o 
Grade 2: systolic BP 140 - 159 mm Hg or diastolic BP 90 - 99 mm Hg 
o 
Grade 3: systolic BP >=160 mm Hg or diastolic BP >=100 mm Hg 


 
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In the case where the date of event is partial (only year is available), the corresponding date will be 
presented based on the imputations specified in APPENDIX 2. 
11. SURGICAL AND MEDICAL HISTORY 
Surgical and Medical History information will be presented for the TS.  
Medical History and Surgeries/Procedures will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.1 or higher if available at the time of the data cut-off. 
 
 
 
11.1. 
MEDICAL HISTORY AND PREVIOUS SURGICAL PROCEDURES 
Medical History and Previous Surgical Procedures as well as Active Medical History and Concomitant 
Surgical procedures will be presented by System Organ Class (SOC) and Preferred Term (PT). 
SOCs will be sorted by internationally agreed European Medicines Agency (EMA) SOC order (refer to 
APPENDIX 4), PTs will be sorted by decreasing frequency within SOCs based on total count. 
11.2. 
PRIOR RADIOTHERAPY 
Prior radiotherapy, as reported in the eCRF, will be presented by anatomic site by decreasing frequency 
based on total count. 
 
 


 
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12. MEDICATIONS 
Medications will be presented for the TS and coded using WHO Drug Dictionary (WHO-DD) version 
SEP2016 or higher. No Anatomical Therapeutic Chemical (ATC) class coding will be performed. The 
medical terms will be summarized by WHO-DD Preferred Name. 
The WHO-DD Preferred Names will be sorted by decreasing frequency based on total count. 
   
12.1. 
PRIOR ANTI-CANCER DRUG THERAPIES 
Prior anti-cancer drug therapies, as reported in the eCRF, will be presented using WHO-DD preferred 
names. 
 
12.2. 
PREVIOUS, CONCOMITANT AND POST-TRIAL MEDICATION THERAPY 
See APPENDIX 2 for handling of partial dates for medications. In the case where it will not be possible 
to define a medication as prior, concomitant or post, the medication will be classified by the worst case; 
i.e. concomitant. Concomitant medications will also be reported separately for the SWS for the post-
switch period. 


 
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12.3. 
CONCOMITANT ANTI-HYPERTENSIVE MEDICATION 
The 
information on anti-hypertensive medications will be reported for the Pre-Switch 
Period: 


 
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Identification of these anti-hypertensive medications will be based on pre-specified WHO-DD preferred 
names according to medical input. The following process will be used by the medical advisor: 
 
13. TRIAL MEDICATION EXPOSURE 
Trial medication is defined as BI 695502. Some subjects were switched from BI 695502 to Avastin® at 
their Switch Visit. So, the post-switch period exposure to Avastin® will be presented and listed seperately 
for the SWS. 
Exposure to trial medication and exposure to Avastin® will be presented for the TS and the SWS. 
 
A descriptive table will present the dose intensity and relative dose intensity (as defined in Section 14) for 
each cycle, as well as, for the following periods of interest: 
 
Cycle 1 to Cycle 4; 
 
Cycle 1 to Cycle 8; 
 
Prior to Switch Visit (Cycle 1 to last cycle performed prior to the Switch Visit (if applicacle)). 
 
For the post-switch period, the Switch Visit is redefined as the baseline Switch Visit, and each cycle post-
switch incrementally numbered starting from Cycle 1 post-switch, regardless of the number of cycles 
performed pre-switch.   
 
All screened subjects assigned to trial medication (as defined in Section 9) who should have completed 
the pre-specified visit are considered as subjects expected to be treated at pre-specified visit. 


 
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The frequency and percentage of subjects treated compared to the number of subjects expected to be 
treated at each scheduled visit until all cycles done will be presented for trial medication, Avastin®, 
Oxaliplatin, Leucovorin and 5FU. 
 
In addition, the frequency and percentage of subjects treated at each scheduled visit, for all cycles, will 
also be presented for trial medication, Oxaliplatin, Leucovorin and 5FU. 
 
A descriptive table will present the dose intensity and relative dose intensity (as defined in Section 14). 
 
The amount of trial medication, Oxaliplatin, Leucovorin and 5FU will be calculated at site 
 
 
 
 


 
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A dose delay will be defined based on the duration between the start date/time of the infusion of trial 
medication and the start date/time of the next infusion of trial medication: (
 
 
  
  
 
 
 
 
 
 
 
 
 
14. DOSE INTENSITY AND RELATIVE DOSE INTENSITY 
The dose intensity and the relative dose intensity for the trial medication, Oxaliplatin, Leucovorin and 5FU 
will be calculated for each 2 week cycle.  
 
  
 
 


 
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14.1. 
Derivations 
 
Dose Intensity 
The dose Intensity is defined as the total dose of trial medication given in a fixed time period. 
 
Relative Dose Intensity 
The relative dose intensity (%) is defined as the dose intensity ( in mg/kg/week)  divided by the protocol 
planned dose (in mg/kg/week) X 100. 
 
 
 


 
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15. EFFICACY OUTCOMES  
15.1. 
Primary Efficacy 
No primary efficacy analysis will be performed for this trial. 
15.2. 
Secondary Efficacy 
The secondary efficacy analyses will be performed on the TS for the pre-switch period. Subjects data 
will be censored at or prior to the Switch visit. Post-switch period data will not be used in the secondary 
efficacy analyses. 
Secondary efficacy analyses will be based on the central imaging review. The imaging charter describes 
the central imaging assessment. RECIST 1.1 is the basis for the central imaging review. 
15.2.1. Secondary Efficacy Variables & Derivations 
To analyze tumor response, one may need to determine the date of tumor assessment. If there are 
more than one tumor assessment in a given  tumor assessment window, then the data for the scan with 
the most recent date, i.e., the last tumor assessment in that window will be used. 
The date of disease progression is defined as the date of radiological diagnosis of PD for subjects 
progressed according to central review assessment. 
15.2.1.1. 
PROGRESSION-FREE SURVIVAL  
Progression-free survival (PFS) time is defined as the time from first administration of trial medication  
until disease progression as assessed by central imaging review according to RECIST 1.1 or death from 
any cause for the Pre-Switch Period (as collected on ‘End of Treatment’, ‘Safety Follow-up’ and 
‘Survival Information’ pages of eCRF), whichever occurs first. 
For non-switched subjects, PFS time will be censored on the date of the last adequate tumor 
assessment for subjects who do not have an event (PD or death) or for subjects with an event after two 
or more subsequent missing response assessments. 
For the SWS, PFS time will be censored at the last tumor assessment at or prior to the Switch Visit for 
subjects who do not have an event (PD or death) for the pre-switched period. 
Subjects who do not have a baseline tumor assessment or who do not have any post-baseline tumor 
assessment will have PFS time censored at first administration of trial medication time unless death 
occurred on or before the time of the second planned tumor assessment in which case the death will be 
considered as an event. 
 


 
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15.2.1.2. 
OBJECTIVE RESPONSE RATE 
The objective response of  each subject will be classified according to the following  RECIST 1.1 
categories based on independent central review, irrespective of protocol violations or missing data: 
 
Complete response (CR), 
 
Partial response (PR), 
 
Stable disease (SD), 
 
Progressive disease (PD), 
 
Not applicable (NA), 
 
Not evaluable (NE). 
The OR rate is defined as the proportion of subjects achieving an unconfirmed CR or PR after the start 
of treatment. 
OR will be evaluated for each subject separately from the date of first administration of trial medication 
(i.e. Study Day 1) until either: 
 
Progression according to RECIST 1.1 based on independent central review,  
 
Unacceptable toxicity defined by end of treatment due to adverse event as reported in the eCRF 
 
Death as reported in the eCRF 
 
Switching treatment 
 
End of trial without switching treatment, 
whichever occurs first. 
Unscheduled assessments recorded after the first administration of trial medication will be taken into 


 
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account. 
The date of End of Treatment’ due to an adverse event corresponds to date of the last infusion.  
However, in cases where the start date of the adverse event leading to study drug discontinuation is 
after the last infusion date  the following definition will apply:  
The date of End of Treatment due to the adverse event is imputed as the date of the AE with the earliest 
start date among the subject’s AEs with start dates after the subject’s last infusion date.  The time to OR 
is considered as censored at this imputed End of Treatment Date. 
A swimmer plot of the objective response at each cycle (as assessed by central imaging review), over 
the whole treatment duration in days, will be produced on the TS. Subjects will be categorized as OR= 
Yes/No. 
15.2.1.3. 
DURATION OF RESPONSE 
Duration of response (DOR) is defined as the time from first documented CR or PR until time of 
progression as assessed by central imaging review for the Pre-Switch Period. 
This definition above applies only to subjects who experienced CR/PR. 


 
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15.2.1.4. 
TIME TO PROGRESSION 
Time of progression (TTP) is defined as the time from first administration of trial medication to the date 
of tumor progression, as assessed by central imaging review for the Pre-Switch Period. 
 
 


 
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15.2.1.5. 
OVERALL SURVIVAL 
Overall survival (OS) time is defined as the time from first administration of trial medication until death 
from any cause for the Pre-Switch Period (as collected on ‘End of Treatment’, ‘Safety Follow-up’ and 
‘Survival Information’ pages of eCRF). 
For subjects alive, the overall survival will be censored at the last date known to be alive for the Pre-
Switch Period.  
15.2.2. Missing Data Methods for Secondary Efficacy Variable(s) 
For the purpose of OR rate analysis, a secondary endpoint, subjects who do not have documented CR or 
PR at a specific time point will be considered as non-responders at this time point. Missing or non-


 
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evaluable response assessments will not be imputed and the subject will be considered as a non-
responder. 
The imaging charter (Section 6.2.2, criterion 13.D) details the criteria needed to handle missing 
assessments in the central independent review. 
If there is no post baseline assessment at all then the subject will be considered as a non responder. 
15.2.3. Analysis of Secondary Efficacy Variables 
15.2.3.1. 
ANALYSIS OF OBJECTIVE RESPONSE RATE 
The number and percent of subjects with a CR or PR and the OR rate will be summarized in a descriptive 
table, together with a Wilson score 95% CI for the OR rate. Additionally, the response categories will be 
analyzed descriptively and displayed by cycle in the same summary table. 
For unscheduled visits, the study day will be attributed to the corresponding cycle according to the rule 
defined in Section 6.4. For the subjects with progression of disease or  treatment stopped due to 
unacceptable toxicity, or death or end of trial, their study day will also be evaluated in order to determine 
the corresponding cycle according to the rule defined in Section 6.4. 
 
Number and percent of subjects with at least one lesion (nodal, non-nodal) will be presented per tumor 
assessment visit (baseline, Cycle 5, Cycle 9, …), as well as, the location of each lesion. 
The following characteristics will also be reported: 
- 
For target lesions: 
 
Response (Complete Response, Partial Response, Stable Disease, Progressive Disease, Not 
Evaluable)  
 
Sum of the diameters (mm)  
- 
For non-target lesions: 
 
Response (Complete Response, Non CR/ Non PD, Progressive Disease, Not Evaluable)  
 
Number of subjects with at least one of Absent/Normal assessment 
 
Number of subjects with at least one of Present/Stable assessment 


 
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 
Number of subjects with at least one Progressed assessment 
 
Number of subjects not assessed 
- 
For new lesions: 
 
Number of subjects with at least one new lesion  
 
15.2.3.2. 
ANALYSIS OF PROGRESSION-FREE SURVIVAL 
The PFS will be analyzed descriptively using Kaplan-Meier (KM) estimates.The 1-year PFS rate and 
median PFS time will be estimated with 95% confidence intervals and will displayed in a summary table. 
The CI for 1-year PFS rates will be determined using Greenwood’s variance estimate [2]. The CI for the 
median PFS time will be calculated according to the Brookmeyer and Crowley method [3]. 
In addition, the KM survival rate will be presented graphically.The number of subjects at risk, as well as 
the number of events, the 1-year PFS rate and median PFS time will also be provided in the same figure. 
This figure will also be provided by subgroup. 
 
15.2.3.3. 
ANALYSIS OF DURATION OF RESPONSE, TIME TO PROGRESSION AND OVERALL 
SURVIVAL 
The DOR, TTP and OS will be analyzed descriptively using KM estimates, in the same manner as for the 
PFS (see Section 15.2.3.2). The 1-year rate will not be calculated for the DOR. 
Kaplan-Meier estimates of duration of follow-up will also be presented, with the ‘event’ defined as the point 
at which the subject was censored for the original survival analysis.  For this analysis, subjects who died 
are considered to be censored at the time at which the death occurred. 
15.2.4. Sensitivity Analysis of Secondary Efficacy Variables 
No sensitivity analyses are planned. 
 
 
 
 
 
 
 
 


 
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16. SAFETY OUTCOMES 
For the pre-switch period, all outputs for safety outcomes will be based on the TS.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise 
specified with the relevant section. Limited safety outcomes will be presented for the  post-switch period 
as noted in the relevant sections below.  Unless specified, safety outcomes will be presented tabulated 
for the pre-switch period only. All post-switch safety outcomes will be listed.For the post-switch period, a 
limited group of SWS safety outcomes (Anaphylactic reactions/hypersensitivity reactions/infusion-
related reactions and occurrence of anti-drug antibodies) will be analyzed. 
Safety endpoints in this trial are: 
Primary endpoint: 
 The primary safety endpoint of the trial is subjects with any of the following selected AEs: 
1. Anaphylactic reactions/hypersensitivity reactions/infusion-related reactions, 
2. Arterial and venous thromboembolic events 
3. GI perforations, 
4. Hypertension, 
5. Proteinuria, 
6. Pulmonary hemorrhage, 
7. All haemorrhages including pulmonary haemorrhages, 
8. Wound-healing complications including abscess and fistulas, 
9. Posterior reversible encephalopathy syndrome, 
10. Ovarian failure. 
Other Endpoints: 
 
Subjects with other haemorrhages. 
 All AEs including AEs related to trial treatment, assessed according to National Cancer Institute-
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, with a focus on those 
AEs of Grade 3 or 4. 
 All AEs potentially related to immunogenicity. 
 All protocol-specified adverse events of special interest (AESIs). 
 ADAs/nADAs at Weeks 0, 4, 8, 16, 24, 32, 40, 52 and 30-day FU and long-term SFU Visit. 
 
16.1. 
Adverse Events 
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, Version 19.1 or higher if 


 
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available at the time of the data cut-off. 
Non-switched subjects: 
- 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in 
severity on or after the first dose of trial medication and prior to the last date of trial medication + 
18 weeks inclusive (126 days) (REP). 
- 
Post-treatment AEs are defined as AEs that started after treatment stop + 18 weeks (126 days). 
Switched subjects (SWS): 
For the pre-switch period,  
- 
TEAEs are defined as AEs that started or worsened in severity on or after the first dose of trial 
medication up to (and not including) the date of first Avastin®. 
For the post-switch period,  
The REP of the initial treatment needs to be re-considered. Every AE that occurred on or after the 
switching date and up to (and including) the 30-days follow-up visit will be analysed as “(BI 695502 to 
Avastin)” in order to take the initial treatment into consideration and to distinguish pre-switch and post-
switch events. So for switched subjects, TEAE will be defined as all AEs that started up to the 30-days 
follow-up visit. Note that a 30-days follow-up visit is scheduled 30 days after last Avastin administration. 
Figure below provides an overview of the relationship between pre- and post-switch and TEAE and Post 
TEAE for those that switched (SWS) and those that did not switch (non-SWS).  
 
Figure – Treatment Emergent Adverse Events, Pre-Switch and Post-Switch period 
 
 
 
 
 
 
 
 
 
 
Note: Post TEAEs are not tabulated for the post-switch period.  
 
 
First dose of trial medication 
Pre-switch 
TEAE 
Post-switch 
TEAE 
Post TEAE 
Day of switch to Avastin 
TEAE 
Post TEAE 
SWS 
Non-SWS


 
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See APPENDIX 2 for handling of partial dates for AEs. In the case where it is not possible to define an 
AE as treatment emergent or not, then the AE will be classified by the worst case; i.e. treatment 
emergent.  


 
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An overall summary of number and percent of subjects within each of the categories described in the 
sub-sections below, will be provided as specified in the PTs, the SOCs will be sorted by internationally 
agreed EMA SOC order (refer to APPENDIX 4), PTs will be sorted by decreasing frequencies (within 
SOC).  
An overall summary of number and percent of subjects within relevant sub-sections below will be also 
presented for the post-switch period. 
A combined listing will be produced of all AEs (including TEAEs and Non-TEAEs) for the pre and post-
switch periods. Unless otherwise stated, other AE listings below will i) include only TEAEs and ii) be 
combined for the pre and post-switch periods.. 
16.1.1. Post-Treatment AEs  
Frequency and percentage of post-treatment AEs will be presented by SOC and PT for the pre-switch 
period. All post treatment AEs will be listed 
16.1.2. TEAEs Specific Derivation 
16.1.2.1. 
PATIENT-YEARS INCIDENCE RATE 
Patient-years incidence rate per 1000 years for AEs meeting the specific criterion for the analysis (see 
Sections 16.1.3 ,16.1.7,16.1.9, and 16.1.9) will be calculated as follows: 
(Number of subjects with AE meeting the specific criterion) / (Patient-Years) * 1000 
Where Patient-Years is the cumulative time at risk for all subject (calculated in days) in the treatment 
group divided by 365.25. 
The time at risk (in days) per subject for the pre-switch period is derived as following: 
If the subject : 
Time at risk (days) 
Had at least one AE with specific 
criterion 
start date of first AE meeting the specific criterion – 
first trial medication date +1 
Without AE with specific criterion 
Completed REP 
(last trial medication date + 126 – first trial 
medication date +1 
Without AE with specific criterion 
Ongoing, not yet completed REP 
(Snapshot date) – first trial medication date +1 
Without AE with specific criterion 
deaths 
(Death date) – first trial medication date +1 
 


 
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For the post-switch period, the time at risk (in days) per subject will be deriving as following:  
If the subject : 
Time at risk (days) 
Had at least one AE with specific 
criterion 
start date of first AE meeting the specific criterion – 
first Avastin administration date +1 
Without AE with specific criterion 
and attended 30-days follow-up 
visit 
(last Avastin administration date + 30 – first Avastin 
administration date +1 
Without AE with specific criterion 
Ongoing, not yet attended 30-
days follow-up visit 
(Snapshot date) – first Avastin administration date 
+1 
Without AE with specific criterion 
deaths 
(Death date) – first Avastin administration date +1 
16.1.2.2. 
WILSON SCORE CONFIDENCE LIMITS 
PROC FREQ with option BINOMIAL will be used for programming purpose, for the Wilson 
score CI (Wilson, 1927 [4]). 
 
16.1.3. All TEAEs  
Frequency and percentage of TEAEs will be presented by SOC and PT and also broken down further 
by maximum severity and relationship to trial medication. Patient-year incidence rate (as defined in 
Section 16.1.2.1) will also be displayed. Patient-years incidence rate will be reported only for pre-switch 
period. For the post-switch period, it will also be reported only for the SWS. 
In addition, a summary of frequencies, percentages and number of events by SOC, PT and by NCI-
CTCAE grade will be displayed.  
All TEAEs will be listed separately for the pre-switch and post-switch period. 


 
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16.1.3.1. 
INTENSITY 
TEAE intensity is classified from Grade 1 to Grade 5, according to the NCI-CTCAE v4.03 or later. If a 
subject reports a TEAE more than once within a SOC/ PT, then the AE with the worst case intensity will 
be used in the corresponding intensity summaries. Intensity categories collected in the “Adverse Event” 
page of the eCRF are: 
 
“Grade 1 – Mild Adverse Event”, 
 
“Grade 2 – Moderate Adverse Event”, 
 
“Grade 3 – Severe Adverse Event”, 
 
“Grade 4 – Life threatening or disabling”, 
 
“Grade 5 – Death”. 
The categories “Any grade”, “Grade 1”, “Grade 2”, “Grade 3”, “Grade 4”, “Grade 5” and “Missing grade” 
will be displayed in the outputs. 
16.1.3.2. 
RELATIONSHIP TO TRIAL MEDICATION 
A related TEAE is defined as a TEAE with a relationship to trial medication ticked “yes” in the eCRF 
according to the investigator. TEAEs with a missing relationship to trial medication will be regarded as 
related to trial medication. If a subject reports the same AE more than once within a SOC/ PT, then the 
AE with the worst case relationship to trial medication will be used in the corresponding relationship 
tables. “Related” will be considered as the worst case relationship to trial medication compared to “Not 
Related”. 
For TEAEs with a relationship to trial medication (as defined in Section 16.1.3.2), a summary of 
frequencies, percentages and number of events by SOC and PT, as well as, a by subject listing will be 
prepared. Patient-years incidence rate (as defined in Section 16.1.2.1) will also be displayed. 
In addition, a summary of frequencies, percentages and number of events by SOC, PT and by NCI-
CTCAE grade will be displayed. 
 
16.1.4. TEAEs Leading to Temporary Interruption of Trial Medication, Oxaliplatin, 
Leucovorin or 5FU 
TEAEs leading to temporary interruption of trial medication, Oxaliplatin, Leucovorin or 5FU will be 
identified by using the “Drug interrupted” category on the “Adverse Events” page of the eCRF.  
For TEAEs leading to temporary interruption of trial medication, Oxaliplatin, Leucovorin or 5FU, 
separate summaries of frequencies, percentages and number of events by SOC and PT, as well as, a 
by subject listing will be prepared. 
In addition, the same summary table will also be prepared for TEAEs leading to temporary interruption 
of any of the chemotherapy components (either Oxaliplatin, Leucovorin or 5FU). 


 
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In this context ‘temporary interruption’ refers to any interruption during the administration of the trial 
medication. 
 
16.1.5. TEAEs Leading to Discontinuation of Trial Medication, Oxaliplatin, Leucovorin  
or 5FU 
TEAEs leading to permanent discontinuation of trial medication, Oxaliplatin, Leucovorin or 5FU will be 
identified by using the “Drug Withdrawn” category on the “Adverse Events” page of the eCRF. 
For TEAEs leading to permanent discontinuation of trial medication, Oxaliplatin, Leucovorin or 5FU, 
separate summaries of frequencies, percentages and number of events by SOC and PT will be 
prepared. 
In addition, the same summary table will also be prepared for TEAEs leading to permanent 
discontinuation of any of the chemotherapy components (either Oxaliplatin, Leucovorin or 5FU). 
TEAEs leading to permanent discontinuation of trial medication due to progression disease will be 
identified by using the “Progressive disease” category on the “End of Treatment” page of the eCRF. 
For TEAEs leading to permanent discontinuation of trial medication due to progression of disease a listing 
will be prepared.  
TEAEs leading to treatment drug discontinuation will be listed, for trial medication, Oxaliplatin, Leucovorin 
and 5FU.  
16.1.6. TEAEs Leading to Reduction of Chemotherapy 
TEAEs leading to reduction of Oxaliplatin, Leucovorin or 5FU will be identified by using the “Dose 
reduced” category on the “Adverse Events” page of the eCRF.  
For TEAEs leading to reduction of Oxaliplatin, Leucovorin or 5FU, separate summaries of frequencies, 
percentages and number of events by SOC and PT will be prepared. 
In addition, the same summary table will also be prepared for TEAEs leading to reduction of any of the 
chemotherapy components (either Oxaliplatin, Leucovorin or 5FU). 
TEAEs leading to Oxaliplatin reduction, as well as TEAEs leading to Leucovorin reduction and TEAEs 
leading to 5FU reduction, will be listed. 
16.1.7. Serious TEAEs 
Serious adverse events (SAEs) are those events which the investigator ticked “Yes, specify” to the item 
“Is this a serious adverse event?” on the “Adverse Events” page of the eCRF. 
A table with the number of subjects, percentages and number of Treatment Emergent SAEs by SOC 
and PT will be prepared. Patient-years incidence rate (as defined in Section 16.1.2.1) will also be 
displayed. A comparable table regarding the post-switch period will be performed for the SWS.  


 
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In addition, separate summaries of frequencies, percentages and number of events by SOC and PT will 
be displayed for serious TEAEs leading to death, serious TEAEs related to trial medication and serious 
TEAEs related to trial medication and leading to death. 
Serious TEAEs will be listed and also be presented for the post-switch period for the SWS. 
16.1.8. Non-Serious TEAEs 
Non-serious TEAEs are those events for which the investigator ticked “No” to the item “Is this a serious 
adverse event?” on the AEs page of the eCRF. 
Frequency of subjects, number of events and incidence of subject with non-serious TEAEs, as well as 
number of events, will be presented by SOC and PT, if PT incidence is >5%. 
16.1.9. TEAEs Leading to Death 
TEAEs leading to Death are those events which are recorded as “Fatal” on the “Adverse Events” page 
of the eCRF.  
For TEAEs leading to death, a summary of frequencies, percentages and number of events by SOC 
and PT will be prepared. Patient-years incidence rate (as defined in Section 16.1.2.1) will also be 
displayed. 
TEAEs leading to Death will also be listed. 
16.1.10. 
AEs Selected 
16.1.10.1. 
AES SELECTED FOR PRIMARY ENDPOINT ASSESSMENT (PRIMARY ENDPOINT) 
The number and percentage of subjects with at least one AE selected for primary endpoint assessment 
will be summarized. Percentage will be reported with associated 95% Wilson score confidence interval (as 
defined in Section 16.1.2.2). The patient-years incidence rate (as defined in Section 16.1.2.1) will also be 
reported in the same summary. This  table will  be produced by AE category. 
In addition, a summary of frequencies, percentages and number of events by category and by PT will be 
displayed. A comparable summary description regarding the post-switch period will be performed for the 
SWS. 
 
The selected AEs for primary analysis are the following: 
1. 
Anaphylactic reactions/hypersensitivity reactions/infusion-related reactions 
2. 
Arterial and venous thromboembolic events 


 
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3. 
GI perforations 
4. 
Hypertension 
5. 
Proteinuria 
6. 
Pulmonary hemorrhage 
7. 
All haemorrhages including pulmonary haemorrhages 
8. 
Wound-healing complications including abscess and fistulas 
9. 
Posterior reversible encephalopathy syndrome 
10. 
Ovarian failure 
Identification of these categories will be based on pre-specified MedDRA terms according to medical input 
– see APPENDIX 7. 
AEs selected for primary endpoint assessment will be listed separately for the pre and post-switch period. 
Frequency and percentage of subjects with at least one AE selected for primary endpoint assessment, 
overall and by AE category, will be analyzed for each of the levels of the subgroups as defined in Section 
7.5. The Wilson score method will be used to determine the 95% CIs for the proportions of subjects with 
selected AEs. These estimates will be produced by subsetting the data to the individual levels within the 
subgroup. 
16.1.10.2. 
AES SELECTED FOR EXPLORATORY ANALYSIS 
Other haemorrhages is selected for the exploratory analysis. 
Identification of this category will be based on pre-specified MedDRA terms according to medical input – 
see APPENDIX 7. 
The number and percentage of subjects with at least one “Other haemorrhages” AE will be summarized. 
Percentage will be reported with associated 95% Wilson score confidence interval (as defined in 
Section 16.1.2.2). The patient-years incidence rate (as defined in Section 16.1.2.1) will also be reported 
in the same summary. 
In addition, a summary of frequencies, percentages and number of events by PT will be displayed. 
16.1.11. 
TEAEs Of Special Interest 
AESIs reported by investigators are those events recorded as “Adverse Event of Special Interest” equal to 
“Yes” on the “Adverse Events” page of the eCRF. 
A table with the number of subjects, percentages and number of Treatment Emergent AESIs reported by 
investigators, by the categories described in the sub-sections below and by PT, will be provided for the 
Pre-Switch Period. A comparable table regarding the post-switch period will be presented for the SWS. 
Treatment Emergent AESIs reported by investigator will be listed. A comparable listing regarding the post-
switch period will be performed for the SWS. 


 
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16.1.11.1. 
 HEPATIC INJURY 
Hepatic injuries events are those events identified by medical advisor on the subset of AEs for subjects 
presenting laboratory potential Hepatic injury findings (refer to Section16.4.1.1) as follows. 
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
Subjects showing the following laboratory abnormalities need to be followed up according to Section  
 
Hepatic injury defined by the following alterations of liver parameters for subjects with normal 
liver function at baseline: an elevation of AST and/or ALT ≥3 x ULN combined with an elevation 
of total bilirubin ≥2 x ULN measured in the same blood draw sample. 
 
Hepatic injury defined by the following alterations of liver parameters for subjects with impaired 
liver function at baseline: an elevation of AST and/or ALT ≥5 x the baseline value combined with 
an elevation of total bilirubin ≥2 x the baseline value measured in the same blood draw sample. 
 
Marked peak aminotransferase (ALT and/or AST) elevations >10 x ULN. 
 
Hepatic injury considered to be AESIs are those events identified as both hepatic injury adverse events 
related to trial medication and recorded as “Adverse Event of Special Interest” equal to “Yes” on the 
Adverse Events page of the eCRF. 
Hepatic injury TEAEs related to trial medication will also be listed. The listing will include the “Adverse 
Event of Special Interest” equal to “Yes” information from the “Adverse Events” page of the eCRF as a 
flag. 
16.1.11.2. 
GASTROINTESTINAL PERFORATIONS 
GI perforations are those events recorded as MedDRA code in the pre-defined SMQ = “Gastrointestinal 
perforation”. 
GI perforations considered to be AESIs are those events identified as both GI perforations and recorded 
as “Adverse Event of Special Interest” equal to “Yes” on the “Adverse Events” page of the eCRF. 
Treatment emergent GI perforations will also be listed. The listing will include the “Adverse Event of 
Special Interest” equal to “Yes” information from the “Adverse Events” page of the eCRF as a flag. 
16.1.11.3. 
ANAPHYLACTIC REACTIONS 
Anaphylactic reactions are those events recorded as MedDRA code in the pre-defined Standardized 
MedDRA Queries (SMQ) = “Anaphylactic reactions” (narrow). 
Anaphylactic reactions considered to be AESIs are those events identified as both anaphylactic 
reactions and recorded as “Adverse Event of Special Interest” equal to “Yes” on the “Adverse Events” 
page of the eCRF, that occurred within 24 hours of trial medication infusion and the casualty is related 
to trial medication. Treatment emergent anaphylactic reactions will also be listed. The listing will include 
the “Adverse Event of Special Interest” equal to “Yes” information from the “Adverse Events” page of the 
eCRF as a flag. 


 
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16.1.11.4. 
PULMONARY HAEMORRHAGES  
Pulmonary haemorrhages are those events recorded in BIcMQ “Pulmonary haemorrhage” (refer to 
APPENDIX 7). 
Pulmonary haemorrhage AEs considered to be AESIs are those events identified as both Pulmonary 
haemorrhage and recorded as “Adverse Event of Special Interest” equal to “Yes” on the “Adverse Events” 
page of the eCRF. 
Treatment emergent pulmonary haemorrhages will also be listed. The listing will include the “Adverse 
Event of Special Interest” equal to “Yes” information from the Adverse Events page of the eCRF as a flag. 
16.1.11.5. 
OTHER AESIS 
Other AESIs are those not falling into any of the above mentioned MedDRA categories and recorded as 
“Adverse Event of Special Interest” equal to “Yes” on the Adverse Events page of the eCRF. 
Other AESIs will be listed. The listing will include the “Adverse Event of Special Interest” equal to “Yes” 
information from the Adverse Events page of the eCRF as a flag. 
16.1.12. 
TEAEs Potentially Related to Immunogenicity 
A table with the number of subjects, percentages and number of TEAEs potentially related to 
immunogenicity will be prepared by SOC and PT. A comparable table regarding the post-switch period will 
be performed for the SWS. 
Identification of these TEAEs potentially related to immunogenicity will be based on PTs according to 
medical input.  


 
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16.1.13. 
Local Tolerability 
Injection site reactions are those events which are recorded as “infusion reaction” on the Adverse 
Events page of the eCRF. A table with the number of subjects, percentages and number of TEAEs 
injection site reactions by SOC and PT will be prepared. 
16.1.14. 
Grade 3 or 4 TEAEs  
Grade 3 or 4 TEAEs are those events with a Grade 3 or a Grade 4 intensity according to NCI-CTCAE 
v4.03. 
Note that if a subject reports a TEAE more than once within a SOC/ PT, then the worst case intensity 
won’t be used and in case of Grade 3 or a Grade 4 intensity at least once, the AE will be counted in the 
Grade 3 or 4 TEAEs summaries. 
For Grade 3 or 4 TEAEs, a summary of frequencies, percentages and number of events by SOC and 
PT will be prepared. A similar summary will also be prepared for Grade 3 or 4 TEAEs with a relationship 
to trial medication. 
 
16.2. 
Exempted Events of Disease Progression 
Progression of disease and death due to progression are considered as disease outcome and therefore, 
are exempted from reporting as a (S)AE. Frequency and percentage of these will be summarized by 
cycle.  
16.3. 
Deaths 
If any subject dies during the trial, 
 


 
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will be presented in a summary table and listed. 
The SWS will be noted on the associated listing, so that any deaths occurring to the SWS will be 
attributed to the post-switch period. 
 
16.4. 
Laboratory Evaluations 
All laboratory analyses will be done on the TS. All laboratory evaluations (16.4.1-16.4.2) will be 
assessed for the pre-switch period. Combined listings of laboratory evaluations for the pre and post-
switch period will be provided. 
Laboratory values taken after the first dose of trial medication up to a period of 18 weeks after the last 
dose of the trial medication will be assigned to the treatment phase for evaluation. Baseline and 
treatment phase assessments will be used in summary tables. All assessments will be presented in 
listings. 
Results from the central laboratory will be included in the reporting of this trial for Serum Chemistry, 
Hematology, Urinalysis and Coagulation. A list of laboratory assessments to be included in the outputs 
is included in APPENDIX 3.  
In general, laboratory evaluations will be summarized in SI units. Additionally, the data will be summarized 
in US units, if applicable. Listings will present both SI and US units in case of differences, otherwise only 
SI units will be presented.   
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification 
(BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose 
of quantitative summaries. 
The handling of retests, unscheduled and early termination data are described in Section 6.3. 
16.4.1. Regular Safety Laboratory Evaluations 
 summaries and listings will be provided for laboratory data: 


 
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16.4.1.1. 
LABORATORY SPECIFIC DERIVATIONS 


 
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 
Potential Hy’s law categories : 
o 
Category 1: ALT or AST >=3xULN and TBL >=2xULN within the same sample 
o 
Category 2: TBL >=2xULN within 30 days after transaminase peak (ALT or AST >=3 
ULN) 
Potential Hy’s Law subjects are defined as subjects with laboratory data in at least one Potential 
Hy’s law category at any time point of the trial. 
16.4.1.2. 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in 
SI units and categorized as: 
 
Low: Below the lower limit of the laboratory reference range.  
 
Normal: Within the laboratory reference range (upper and lower limit included). 
 
High: Above the upper limit of the laboratory reference range. 
16.4.1.3. 
CTC GRADING FOR LABORATORY DATA 
Laboratory results will be classified according to the NCI-CTCAE v.4.03 or later. Only programmable parts 
of definitions will be performed. The “Grade 0” will be introduced to indicate that a certain laboratory value 
can be seen as “normal” and does not fulfill the criteria of NCI-CTCAE grading, either within the reference 
range or elevated in the other direction than defined in the NCI-CTCAE document. For uncertain cases 
(for example when the values can be assigned to Grade 0 based on the normal range and Grade 1 or 2 
based on the toxicity criteria), a medical check will be performed, to determine the correct grade. 
16.4.2. Other Safety Laboratory Evaluations  
16.4.2.1. 
INFECTION SCREEN 
Descriptive table will present hepatitis B and hepatitis C results and the results will also be listed. 
16.4.2.2. 
HUMAN IMMUNODEFICIENCY VIRUS TEST 
Descriptive table will present human immunodeficiency virus (HIV) test results and the results will also be 
listed. 
16.4.2.3. 
TUBERCULOSIS TEST 
Descriptive table will present Tuberculosis (TB) test results and the results will also be listed. 


 
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16.4.2.4. 
PREGNANCY TEST 
Descriptive table will present pregnancy results for females and the results will also be listed. 
16.5. 
Hypertension 
All hypertension analyses will be performed on the TS for the pre-switch period. 
 
  
 
 
 
16.6. 
Brain Lesions 
If any subject has a brain lesion during the trial, as recorded on the “Non Target Lesion” and “New 
Lesion” pages of the eCRF, the information will be listed.  
16.7. 
ECG Evaluations 
Results from ECGs will be summarized by visit and listed using the categories as recorded in the eCRF 
page “12-Lead-ECG” (“normal”, “abnormal, not clinically significant” and “abnormal, clinically 
significant”). Changes from baseline category, by visit, will be reported in a separate summary. Results 
from ECGs will be assessed for the pre-switch period. 
16.8. 
Vital Signs 
The following Vital Signs measurements will be reported for this trial for the pre-switch period: 
 
Sitting Systolic BP (mmHg) 
 
Sitting Diastolic BP (mmHg) 
 
Sitting Pulse Rate (bpm) 
 
Respiratory Rate (breaths/min) 
 
Temperature (⁰C) 
 
Weight (kg) 
 
BSA (m²) 
The following summaries will be provided for vital signs data on the TS and for the pre-switch period: 


 
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 
Actual and change from baseline by visit  
 
A combined listing of Vital Signs for the pre and post-switch periods will be provided.   
16.9. 
Physical Examination  
Incidence of evaluation categories (normal, abnormal) at baseline and post-baseline visits will be 
provided and listed for physical examination data for the pre-switch period. Changes from baseline 
category, by visit, will be reported in a separate summary. 
16.10. 
ECOG 
ECOG performance status at baseline and post-baseline visits will be listed. 
16.11. 
Other Safety Assessments 
16.11.1. 
Immunogenicity Evaluation 
Pre-switch period Immunogenicity data will be displayed for all treated subjects, and the post-switch 
period for Immunogenicity data will be displayed for only the SWS. 
The following summaries tables will be provided for Immunogenicity data: 
 
Number and frequency of subjects with ADA / nADA sampling results by visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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17. REFERENCES  
[1]  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. 
[2] Kalbfleisch JD and Prentice RL. The Statistical Analysis of Failure Time Data, New York: 2nd ed. 
Hoboken: John Wiley & Sons (2002). 
[3] Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 
1982;38:29-41. 
[4] Brown LD, Cai TT, DasGupta A. Interval estimation for a binomial proportion. Statistical Science. 
2001;16:101-133. 
 
 
 


 
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APPENDIX 3. LABORATORY ASSESSMENTS 
Laboratory parameter 
Gradable with NCI-CTCAE 
SI unit 
US unit 
Serum chemistry 
 
 
 
Creatinine 
X 
umol/L 
mg/dL 
Alkaline phosphatase 
X 
IU/L 
AST 
X 
IU/L 
ALT 
X 
IU/L 
Gamma glutamyl transpeptidase (g-GT) 
X 
IU/L 
Bilirubin 
X 
umol/L 
mg/dL 
Glucose 
X (Hypoglycemia/Hyperglycemia) 
mmol/L 
mg/dL 
Total cholesterol 
X (Cholesterol high) 
mmol/L 
mg/dL 
Total protein 
 
mmol/L 
mg/dL 
Albumin 
X  
(Hypoalbuminemia) 
g/L 
g/dL 
Sodium  
X (Hyponatremia/Hypernatremia) 
mmol/L 
mEq/L 
Potassium  
X 
 (Hypokalemia/Hyperkalemia) 
mmol/L 
mEq/L 
Chloride 
 
mmol/L 
mEq/L 
Calcium  
X (Hypocalcemia/Hypercalcemia) 
mmol/L 
mg/dL 
Creatinine clearance 
 
mL/s 
mL/min 
Hematology 
 
 
 
Hemoglobin 
X 
(Anemia/ Hemoglobin increased) 
g/L 
g/dL 
Hematocrit 
 
V/V 
% 
Platelets  
X 
10^9/L 
10^3/uL 
White blood cells 
X 
(White blood cell 
decreased/Leukocytosis) 
10^9/L 
10^3/uL 
Lymphocytes 
X 
(Lymphocyte count 
decreased/Lymphocyte count 
increased) 
10^9/L 
10^3/uL 
Neutrophils (abs) 
X 
10^9/L 
10^3/uL 
Neutrophils (%) 
 
% of white blood cells 
Monocytes (abs) 
 
10^9/L 
10^3/uL 
Monocytes (%) 
 
% of white blood cells 
Eosinophils (abs) 
 
10^9/L 
10^3/uL 
Eosinophils (%) 
 
% of white blood cells 
Basophils (abs) 
 
10^9/L 
10^3/uL 


 
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Laboratory parameter 
Gradable with NCI-CTCAE 
SI unit 
US unit 
Basophils (%) 
 
% of white blood cells 
Reticulocyte count 
 
10^12/L 
10^6/uL 
Reticulocyte (%) 
 
% of white blood cells 
Urinalysis  
 
 
 
Protein 
Gradable proteinuria is only reported 
at screening which is not reported (as 
per section 16.4) 
g/L 
mg/dL 
Glucose 
 
mmol/L 
mg/dL 
Blood 
 
N/A 
Coagulation 
 
 
 
INR (International Normalized Ratio,) 
 
N/A 
aPTT (activated Partial Thromboplastin 
Time) 
X 
second 
PT (Prothrombin Time) 
 
second 
 
 
 
 


 
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APPENDIX 4. EMA SOC ORDER FOR PRESENTATION OF THE AE IN THE TABLES 
Order System Organ Class                                                                    
0 Uncoded                   
1 Infections and infestations                                            
2 Neoplasms benign, malignant and unspecified (incl cysts and polyps)    
3 Blood and lymphatic system disorders                                   
4 Immune system disorders                                                
5 Endocrine disorders                                                    
6 Metabolism and nutrition disorders                                     
7 Psychiatric disorders                                                  
8 Nervous system disorders                                                
9 Eye disorders                                                          
10 Ear and labyrinth disorders                                            
11 Cardiac disorders                                                      
12 Vascular disorders                                                     
13 Respiratory, thoracic and mediastinal disorders                        
14 Gastrointestinal disorders                                             
15 Hepatobiliary disorders                                                
16 Skin and subcutaneous tissue disorders                                 
17 Musculoskeletal and connective tissue disorders                        
18 Renal and urinary disorders                                            
19 Pregnancy, puerperium and perinatal conditions                         
20 Reproductive system and breast disorders                               
21 Congenital, familial and genetic disorders                             
22 General disorders and administration site conditions                   
23 Investigations                                                         
24 Injury, poisoning and procedural complications                         
25 Surgical and medical procedures                                        
26 Social circumstances                                                   
27 Product issues 
 


 
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APPENDIX 5. CUT-OFF APPLICATION RULES 
Cut-off rules are detailed in a separate document named “BI1302.3_SDTM_cut_off_ v3.0 04May2018”. 
 
 
 


 
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APPENDIX 6. IMPORTANT PROTOCOL VIOLATIONS 
Important protocol violations are detailed in a separate document named “BI1302.3_Important protocol 
violations_v3.0_04May2018”. 
 
 


 
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APPENDIX 7. BICMQS, SMQS AND SELECTED PTS 
Each of the safety concerns listed in the table below can be difined  by one or more MedDRA 
preferred terms defined  per SMQ or  BIcMQ which are part of the medical concept of the safety 
concern. 
 
Safety concern 
 
Anaphylactic 
reactions/hypersensitivity 
reactions/infusion-related 
reactions 
 
 
 
 
Arterial and venous 
thromboembolic events 
 
 
 
 
 
 GI perforations 
 
 Hypertension 
 
 
 Proteinuria 
 
 
 Pulmonary haemorrhage 
 
 
 
 
 Other haemorrhages 
 
Other haemorrhages 
excluding Pulmonary 
haemorrhage 
 
 
 
 
 


 
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Note: all external files are based on MedDRA version 21.0. Files will be upgraded to the higher MedDRA 
version available at the time of each data cut-off. 
 
Wound-healing 
complications including 
abscess and fistulas 
MedDRA PT selection by medical reviewer and BIcMQ 
‘Wound-healing complications’ 
Posterior reversible 
encephalopathy syndrome 
MedDRA PT selection by medical reviewer 
 
Ovarian failure 
Narrow and Broad SMQ ‘Fertility disorders’ 
(20000210)