Clinical trial NCT02448810
Conditions: Metastatic Colorectal Cancer
Sponsor: Baxalta now part of Shire
Start date: 2015-06-15; Completion date: 2017-02-15
Enrollment: 115 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of BAX69 in combination with 5-fluorouracil (5-FU)/leucovorin (LV) or panitumumab to determine the recommended phase II dose (RP2D) of each combination; and to compare the efficacy between BAX69 in combination with 5-FU/LV for subjects with KRAS or NRAS mutated tumor (mt) or panitumumab, for subjects with KRAS and NRAS wild type tumor (wt) and standard of care (SoC) per investigator choice as third or fourth treatment line in subjects with progressive measurable metastatic colorectal cancer (mCRC).

Detailed description:

Arms: arm 1: Subjects stratified according to their mutation status. arm 2: Subjects stratified according to their mutation status. arm 3: Subjects stratified according to their mutation status. arm 4: Subjects stratified according to their mutation status. arm 5: Subjects stratified according to their mutation status. arm 6: Subjects stratified according to their mutation status.Subjects stratified according to their mutation status.
Interventions: intervention 1: BAX69 + infusional 5-FU/LV intervention 2: BAX69 + panitumumab intervention 3: BAX69 + 5-FU/LV intervention 4: BAX69 + panitumumab intervention 5: Standard of Care intervention 6: Standard of Care
Intervention descriptions: intervention 1: Study Part 1: Safety Run-in

* Administered weekly as part of a 4 week treatment cycle
* Intravenous injection intervention 2: Study Part 1: Safety Run-in

* Administered weekly as part of a 4 week treatment cycle
* Intravenous injection intervention 3: Study Part 2: Administered weekly as part of a 4 week treatment cycle

•Intravenous injection intervention 4: Study Part 2: Administered weekly as part of a 4 week treatment cycle

•Intravenous injection intervention 5: * Investigator's choice
* Dose according to drug label intervention 6: * Investigator's choice
* Dose according to drug label
* Choice includes panitumumab in KRAS \&NRAS wt group only

Protocol documents:
Prot_000.pdf: 
BAXALTA CONFIDENTIAL – RESTRICTED: DO NOT DISTRIBUTE WITHOUT PRIOR APPROVAL
CLINICAL STUDY PROTOCOL
PRODUCT: BAX69 (Imalumab)
STUDY TITLE: A Phase 2a Randomized, Open-Label Study to Assess the Safety, 
Tolerability, and Efficacy of BAX69 in Combination with 5-FU/Leucovorin or 
Panitumumab versus Standard of Care in Subjects with Metastatic 
Colorectal Cancer
STUDY SHORT TITLE: Phase 2a Study of BAX69 and 5-FU/Leucovorin or 
Panitumumab versus Standard of Care in Subjects with Metastatic Colorectal 
Cancer
PROTOCOL IDENTIFIER: 391401
CLINICAL TRIAL PHASE 2a
AMENDMENT 5 (GLOBAL): 2016 MAY 09
Replaces:
AMENDMENT 2 (GLOBAL): 2015 JUL 13
ALL VERSIONS:
Amendment 4 (Germany Version): 2015 DEC 16
Amendment 3 (United Kingdom [UK] Version): 2015 OCT 02
Amendment 2 (GLOBAL): 2015 JUL 13
Amendment 1 (GLOBAL): 2015 MAR 06
Original (GLOBAL): 2014 DEC 10
OTHER ID(s)
EudraCT Number: 2015-000896-28
IND NUMBER: 112850
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA 91362
USA
Baxalta Innovations GmbH 
Industriestrasse 67 
A-1221 Vienna
AUSTRIA


B A X 6 9 ( i mal u ma b )
Pa ge 2 of 1 2 5
Cli nical St u d y Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 M A Y 0 9
B A X A L T A C O N FI D E N TI A L – R E S T RI C T E D: D O N O T D I S T RI B U T E WI T H O U T P RI O R A P P R O V A L
1. S T U D Y P E R S O N N E L
1. 1 A ut h orize d Re prese nt at i ve ( Si g n at or y) / Res p o nsi ble P art y
, M D
Cli nical De vel o p me nt
Ba xalta U S I nc.
1. 2 St u d y Or g a niz ati o n
P P D
T he na me a n d c o ntact i nf or mati o n of t he res p o nsi ble party a n d i n di vi d uals i n v ol ve d wit h 
t he st u d y (e g, i n vesti gat or(s), sp o ns or’s me dical e x pert a n d st u d y  m o nit or, s p o ns or’s 
re prese ntati ve(s), la b orat ories, steeri n g c o m mittees, a n d o versi g ht c o m mittees [i ncl u di n g 
et hics c o m mittees ( E Cs) ], as a p plica ble) will be mai ntai ne d b y t he s p o ns or a n d pr o vi de d 
t o t he i n vesti gat or.
P P D


B A X 6 9 ( i mal u ma b )
Pa ge 3 of 1 2 5
Cli nical St u d y Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 M A Y 0 9
B A X A L T A C O N FI D E N TI A L – R E S T RI C T E D: D O N O T D I S T RI B U T E WI T H O U T P RI O R A P P R O V A L
2. S E RI O U S A D V E R S E E V E N T R E P O R TI N G
T he i n vesti gat or will c o m pl y  wit h a p plica ble la ws/re q uire me nts f or re p orti n g seri o us 
a d verse e ve nts ( S A Es), i ncl u di n g s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
( S U S A Rs), t o t he E Cs.
A L L S A Es , I N C L U DI N G S U S A Rs, A R E T O B E R E P O R T E D O N T H E A D V E R S E 
E V E N T E L E C T R O NI C C A S E R E P O R T F O R M ( eC R F)
WI T HI N 2 4 H O U R S A F T E R B E C O MI N G A W A R E O F T H E E V E N T. I F T H E 
eC R F I S N O T A V AI L A B L E T H E N T H E S A E M U S T B E R E P O R T E D O N T H E 
S E RI O U S A D V E R S E E V E N T R E P O R T ( S A E R) F O R M A N D 
T R A N S MI T T E D T O T H E S P O N S O R T O M E E T T H E 2 4 H O U R TI M E LI N E 
R E Q UI R E M E N T .
Dr u g S afet y c o nt act i nf or m ati o n: see S A E R F o r m .
Refer t o S A E Pr ot oc ol Secti o ns a n d t he st u d y te a m r oster f or f urt her i nf or m ati o n.
F or defi niti o ns a n d i nf or mati o n o n t he assess me nt of t hese e ve nts, see t he f oll o wi n g: 

A d verse e ve nts ( A E s), Secti o n 1 2. 1

S A E, Secti o n 1 2. 1. 1. 1

S U S A Rs, Secti o n 1 2. 1. 1. 2

Assess me nt of A Es, Secti o n 1 2. 1. 2
Seri o us a d verse e ve nt re p ort c o nt act i nf or m ati o n b y c o u ntr y:
C o u ntr y
Tele p h o ne
F a x
Ger ma n y
S pai n
U nite d Ki n g d o m
U nite d States
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


BAX69 (imalumab)
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
BAX69 (imalumab), a fully human recombinant anti-oxidized 
macrophage migration inhibitory factor (anti-oxMIF) antibody
Name(s) of Active Ingredient(s)
BAX69 (imalumab)
CLINICAL CONDITION(S)/INDICATION(S)
Metastatic colorectal cancer (mCRC)
PROTOCOL ID
391401
PROTOCOL TITLE
A Phase 2a Randomized, Open-Label Study to Assess the Safety, Tolerability, 
and Efficacy of BAX69 in Combination with 5-FU/Leucovorin or Panitumumab 
versus Standard of Care in Subjects with Metastatic Colorectal Cancer
Short Title
Phase 2a Study of BAX69 and 5-FU/Leucovorin or Panitumumab versus 
Standard of Care in Subjects with Metastatic Colorectal Cancer
STUDY PHASE
Ph2a
PLANNED STUDY PERIOD
Initiation
Q2 2015
Primary Completion
Q4 2016
Study Completion
Estimated study completion will occur when 75% of overall survival (OS)
events are reported.
Duration
Approximately 21 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this study, in subjects with progressive measurable mCRC, is as follows:
To evaluate the safety and tolerability of imalumab in combination with 5-fluorouracil 
(5-FU)/leucovorin (LV) or panitumumab to determine the recommended phase 2 dose (RP2D) of 
each combination
To compare the efficacy of imalumab in combination with 5-FU/LV versus standard of care (SoC) 
(investigator choice) as third or fourth treatment line in subjects with KRAS mutated (mut) and/or 
NRAS mut tumors
To compare the efficacy of imalumab in combination with panitumumab versus SoC (investigator 
choice) as third or fourth treatment line in subjects with KRAS wild type (wt) and NRAS wt tumors
Furthermore, the pharmacokinetic (PK) profile of imalumab in combination with 5-FU/LV or panitumumab 
will be characterized, and limited pharmacodynamic (PD) serum markers will be explored.
Primary Objectives
1.
To determine the RP2D of imalumab in combination with 5-FU/LV or panitumumab (Part 1)
2.
To compare progression-free survival (PFS) between imalumab in combination with 5-FU/LV for 
subjects with KRAS mut and/or NRAS mut tumors or in combination with panitumumab for 
subjects with KRAS wt and NRAS wt tumors, versus SoC (investigator choice) as third or fourth 
treatment line (Part 2)


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Secondary Objectives
1.
To compare overall response rate (ORR) and clinical benefit rate (CBR) in subjects treated at 
RP2D with imalumab in combination with 5-FU/LV or panitumumab versus SoC (investigator 
choice) as third or fourth treatment line
2.
To compare overall survival (OS) of subjects who received imalumab in combination with 
5-FU/LV or panitumumab versus SoC (investigator choice) as third or fourth treatment line
3.
To assess the safety and tolerability of imalumab in combination with 5-FU/LV or panitumumab
4.
To characterize the PK of imalumab in combination with 5-FU/LV or panitumumab
5.
To compare quality of life (QoL) of subjects who received imalumab in combination with 
5-FU/LV or panitumumab versus SoC (investigator choice) as third or fourth treatment line
Exploratory Objectives
1.
To characterize oxidated macrophage migration inhibitory factor (oxMIF) and total macrophage 
migration inhibitory factor (MIF) in plasma prior to and during treatment with imalumab in 
combination with 5-FU/LV or panitumumab
2.
To characterize tumor-associated genetic alterations in blood/urine (for all subjects treated with 
imalumab in combination with 5-FU/LV or panitumumab who provide consent for exploratory 
biomarker analyses)
3.
To compare disease-specific QoL and health utility in subjects treated with imalumab in 
combination with 5-FU/LV or panitumumab versus SoC (investigator choice) as third or fourth 
treatment line
STUDY DESIGN
Study Type/ 
Classification/ 
Discipline
Interventional; 2-treatment-arm; randomized
Safety; Tolerability; PK; Exploratory Efficacy and Exploratory PD
Control Type
SoC (including best supportive care) per investigator’s choice (Part 2)
Study Indication Type
Treatment of mCRC in third or fourth line
Intervention model 
Part 1: Safety Run-in
Part 2: Randomized, controlled, parallel, 2-treatment-arm
Blinding/Masking
Open-label
Study Design
This Phase 2a study will be conducted in approximately 40 study sites in the United 
States (US) and the European Union (EU). The study will comprise 2 sequential parts 
(subjects can only participate in either Part 1 or Part 2 of the study):

Part 1: A Safety Run-in period to evaluate 2 predefined doses
(7.5 mg/kg and 10 mg/kg) of imalumab given every week (QW) in 
combination with infusional 5-FU/LV given every 2 weeks (Q2W) in 
subjects with mutated tumors (KRAS mut, and/or NRAS mut), or 
imalumab in combination with panitumumab given Q2W in subjects 
with wild type tumors (KRAS wt and NRAS wt). Prior to entry into the 
study, subjects will be stratified according to their KRAS/NRAS 
mutation status. Treatments will be administered in 4-week (28-day)
cycles.


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
Part 2: A 2-treatment-arm design using a 2:1 ratio for subjects to 
receive imalumab + 5-FU/LV or imalumab + panitumumab (Arm A) or 
SoC per investigator choice (Arm B). Prior to randomization, subjects 
will be stratified according to their mutation status. Within each 
stratum, subjects will be randomized in a 2:1 ratio to receive 
imalumab + 5-FU/LV (KRAS mut and/or NRAS mut tumors) or 
imalumab + panitumumab (KRAS wt and NRAS wt tumors) (Arm A)
or SoC per investigator choice (Arm B).
For all subjects in Parts 1 and 2, treatment will continue until disease 
progression, unacceptable toxicity, or withdrawal of consent.
Part 1: Safety Run-in
For each combination, subjects will be enrolled into 2 sequential cohorts, with a 
minimum of 3 and a maximum of 6 subjects per cohort. 
For each combination, enrollment will proceed according to the following rules 
based on the occurrence of dose-limiting toxicities (DLTs):

If zero out of 3 evaluable subjects experience a DLT during the first 
28 days after the first administration of study drug at the first dose 
level, the second dose level will be opened for enrollment after review 
of the safety data by the Data Review Committee (DRC).

If 1 out of 3 evaluable subjects experiences a DLT during the first 
28 days after administration of study drug at the first dose level, 
3 additional subjects will be enrolled at the first dose level, for a total 
of 6 evaluable subjects. After review of the safety data of all 
6 evaluable subjects, the DRC will decide if the second dose level or a 
lower dose level will be explored.

If 2 or more evaluable subjects experience a DLT during the first 
28 days after the first administration of study drug at the first dose 
level, the second dose level will not be open to enrollment and the 
DRC will decide if a lower dose level will be explored.
The DRC will meet for safety reviews after 3 subjects in a dosing cohort have 
completed the first treatment cycle. The DRC will decide either to enroll
additional subjects or open the next dose level. For each combination, based on 
all data of all evaluable subjects, the DRC will either determine the RP2D, or 
will decide to explore an intermediate dose level.
DLT Definition
A DLT is defined as any drug-related treatment-emergent adverse event (TEAE) 
(graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI CTCAE] v4.03) that occurs during the first 
28 days after treatment start and that meets any of the following criteria:

Any ≥Grade 3 non-hematologic toxicity excluding:
a.
Mucositis/stomatitis of Grade 3 that resolves to Grade 1 or less 
with supportive measures within 7 days
b.
Diarrhea of < 3 days duration following adequate and optimal 
therapy 
c.
Nausea and vomiting of < 3 days duration with adequate and 
optimal therapy


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d.
Fatigue of < 7 days duration following initiation of adequate 
supportive care
e.
Alopecia
f.
Any single laboratory value out of the normal range that has no 
clinical significance and that resolves to ≤Grade 2 with adequate 
measures within 7 days; transient Grade 3 elevations (lasting 
< 5 days) of hepatic transaminases in the absence of simultaneous 
increase in serum bilirubin

Any Grade 4 hematologic toxicity excluding:
a.
Grade 4 neutropenia lasting for ≤5 days and not accompanied by
fever
b.
Isolated Grade 4 lymphocytopenia without clinical correlate 

Grade 3 febrile neutropenia 

Grade 3 thrombocytopenia associated with bleeding 

Any life-threatening complication or abnormality not covered in the 
NCI CTCAE v4.03
Determination of RP2D
For each combination, based on all data of all evaluable subjects, the DRC will 
determine the RP2D, or decide if an intermediate dose level must be explored.
Part 2: Exploratory Phase 2a
This is a 2-treatment-arm phase using a 2:1 ratio for subjects to receive 
imalumab + 5-FU/LV or imalumab + panitumumab (Arm A) or SoC per 
investigator choice (Arm B). Prior to randomization, subjects will be stratified 
according to their KRAS/NRAS status. Within each stratum, subjects will be 
randomized in a 2:1 ratio to receive imalumab + 5-FU/LV (KRAS mut and/or 
NRAS mut tumors) or imalumab + panitumumab (KRAS wt and NRAS wt
tumors) (Arm A) or SoC per investigator choice (Arm B). Randomization will 
occur via an Interactive Response Technology (IRT) System. For each 
combination in Arm A, subjects will receive imalumab at the RP2D determined 
in Part 1 for the corresponding combination. All subjects will be treated until 
disease progression, unacceptable toxicity, or withdrawal of consent. An 
independent Data Safety Monitoring Board (DSMB) comprised of recognized 
experts in the field of oncology and biostatistics clinical care and research, will
review accumulating unblinded safety data of subjects in Part 2 on a quarterly
basis. The composition, activities, and responsibilities of the DSMB are 
described in further detail in the DSMB Charter.


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Assessments
Safety data will be regularly monitored throughout the study. The investigator 
will evaluate the study treatment antitumor activity after completion of every 
other treatment cycle (ie, every 2 cycles) using magnetic resonance imaging 
(MRI) or computerized tomography (CT) imaging and in accordance to the 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in all subjects 
treated at RP2D. In Part 1, and in Arm A of Part 2, plasma levels of imalumab, 
oxMIF, and total MIF will be measured. The effect of imalumab in combination 
with 5-FU/LV or panitumumab on tumor-associated genetic biomarkers will be 
monitored. Blood and urine samples will be collected from those subjects who 
provide consent for this optional exploratory analysis. It is possible that 
blood/urine biomarkers may correlate with clinical outcome (safety and 
efficacy) in response to imalumab treatment.
Planned Duration of 
Subject Participation
Subject participation includes a maximum of 4 weeks for screening, and 
30 (±7) days for post-treatment safety follow-up. Subjects will receive treatment 
until disease progression, unacceptable toxicity, or withdrawal of consent. 
Subjects will be followed until progression is clinically or radiologically 
documented.
The duration of the study is estimated as a total of 21 months, inclusive of 
approximately 15 months to complete accrual, followed by approximately 
6 months for primary outcome measure. Study completion is estimated to occur 
when 75% of OS events have been reported.
Primary Safety Outcome Measure

Occurrence of DLTs (Part 1)
Primary Efficacy Outcome Measure

PFS, defined as time between treatment initiation and tumor progression (per RECIST v1.1) or death 
from any cause, with censoring of subjects who are lost to follow-up or withdraw consent (Part 2)
Secondary Outcome Measures
Immunogenicity:

Occurrence of binding and/or neutralizing anti-imalumab antibodies

Incidence and severity of infusion reactions after imalumab
Safety:

Occurrence of TEAEs and/or serious adverse events (SAEs), regardless of causality or relationship 
to study drug, using NCI CTCAE v4.03

Other safety measurements: physical or instrumental examinations, electrocardiograms (ECGs), 
vital signs, clinically relevant changes in instrumental examinations or laboratory values
Efficacy:

Response evaluation according to RECIST v1.1

OS time from randomization to death of any cause


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PK:

Imalumab plasma PK will be characterized using a population PK modeling approach, in 
combination with PK data from other studies. 
QoL:

Quality of life assessed using the EORTC QLQ-C30
Exploratory Outcome Measures
PD:

Levels of oxMIF and total MIF in plasma
Genetic biomarkers:

Tumor-associated genetic alterations in blood/urine (for subjects treated with imalumab in 
combination with 5-FU/LV or panitumumab who provide consent for exploratory biomarker 
analyses)
The sponsor will obtain available historical tumor mutational testing results for subjects.
QoL:

Quality of life assessed using the EORTC QLQ-CR29

European Quality of Life – 5 Dimensions (EQ-5D)
INVESTIGATIONAL PRODUCT, DOSE, AND MODE OF ADMINISTRATION
Active Products in 
Experimental Arms
Imalumab
Dosage form: solution, vial for infusion
Dosage frequency: QW over 4-week cycles
Mode of Administration: IV with a flow rate of 1.0 mL/min to 3.6 mL/min
Doses in Part 1: 7.5 mg/kg and 10 mg/kg
Dose in Part 2: For each combination, the dose will be the RP2D as determined 
during Part 1
Panitumumab
Dosage frequency: Q2W 
Mode of Administration: IV over 60 minutes (maximum 1000 mg; if 
> 1000 mg, infuse over 90 minutes)
Dose (Parts 1 and 2): 6 mg/kg
In case of mild-moderate infusion reaction, reduce infusion rate by 50%. In case
of a severe infusion reaction, the infusion must be immediately stopped and 
panitumumab permanently discontinued.
5-FU/LV
Dosage frequency: Q2W
Mode of Administration: IV over 48 hours
Dose (Parts 1 and 2): LV 400 mg/m² over 2 hours, followed by 5-FU 
2400 mg/m² IV over 46 hours
Control Drugs
Investigator’s choice (including best supportive care) will be done according to 
local SoC


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SUBJECT SELECTION 
Targeted Accrual
Part 1: 12 to 24 subjects; non-evaluable subjects will be replaced to meet study 
objectives.
Part 2: Maximum of 66 subjects
Number of 
Groups/Arms/Cohorts
Part 1: 2 cohorts per combination
Part 2: 2 treatment arms
Inclusion Criteria
Subjects must meet ALL of the following criteria to be eligible for this study:
1.
Provision of a signed informed consent
2.
Male and female subjects 18 years of age and older at the time of screening
3.
Subjects who progressed after receiving at least 2, but no more than 3, prior cancer drug therapy 
treatment lines including SoC in the metastatic setting
4.
Anticipated life expectancy > 3 months at the time of screening
5.
Weight between 40 kg and 180 kg
6.
Histologically or cytologically confirmed diagnosis of CRC 
7.
Metastatic CRC not amenable to surgical resection
8.
Known KRAS, NRAS mutation status (if unknown status for either of these genes, and no archival 
tissue is available, a fresh tumor biopsy will be obtained)
9.
At least 1 measurable lesion as defined by RECIST v1.1 
10. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-2
11. Adequate hematological function, defined as: 
a.
Platelet count ≥100,000/µL
b.
Prothrombin time and activated partial thromboplastin time (aPTT) < 1.5 times the upper limit 
of normal (ULN) 
c.
Absolute neutrophil count (ANC) ≥1,000/µL
d.
Hemoglobin ≥9 g/dL, without the need for transfusion in the 2 weeks prior to screening
12. Adequate renal function, defined as serum creatinine ≤2.0 times ULN and creatinine clearance 
> 50 mL/min or estimated glomerular filtration rate > 50ml/min/1.73 m2
13. Adequate liver function, defined as:
a.
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN for 
subjects without liver metastases, or ≤5 times ULN in the presence of liver metastases
b.
Bilirubin ≤2.0 times ULN, unless subject has known Gilbert’s syndrome 
14. Adequate venous access
15. For female subjects of childbearing potential, the subject presents with a negative serum 
pregnancy test at screening and agrees to employ 2 forms of adequate birth control methods, 
including at least 1 barrier method (eg, diaphragm with spermicidal jelly or foam, or [for male 
partner] condom) throughout the course of the study and for at least 90 days after the last 
administration of imalumab. In addition, these birth control methods must be continued for at least 
180 days after last administration of 5-FU in subjects who receive this treatment. Secondary
contraceptive measures could be either birth control pills, patches, or intrauterine devices


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16. For male subjects, they must agree to use adequate contraceptive measures including at least 
1 barrier method (eg, condom with spermicidal jelly or foam and [for the female partner] 
diaphragm with spermicidal jelly or foam, birth control pills/patches, or intrauterine device) and 
abstain from sperm donation throughout the course of the study and for at least 90 days after the 
last administration of imalumab. In addition, these birth control methods must be continued for at 
least 180 days after last administration of 5-FU in subjects who receive this treatment
17. Subject is willing and able to comply with the requirements of the protocol
Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for the study:
1.
Known central nervous system metastases
2.
Prior malignancy(s) within the past 3 years, with the exception of curatively treated basal or 
squamous cell carcinoma of the skin, locally advanced prostate cancer, ductal carcinoma in situ of 
breast, in situ cervical carcinoma and superficial bladder cancer
3.
Prior treatment with panitumumab for subjects with KRAS wt and NRAS wt tumors
4.
Known history of keratitis, ulcerative keratitis, or severe dry eye in subjects with KRAS wt and 
NRAS wt tumors
5.
Residual adverse event (AE) from previous treatment > Grade 1, except neuropathy and alopecia
6.
Prior intolerance to fluoropyrimidine for subjects with KRAS mut and/or NRAS mut tumors
7.
Myocardial infarction within 6 months prior to Cycle 1 Day 1 (C1D1), and/or prior diagnoses of 
congestive heart failure (New York Heart Association Class III or IV), unstable angina, unstable 
cardiac arrhythmia requiring medication; and/or the subject is at risk for polymorphic ventricular 
tachycardia (eg, hypokalemia, family history, or long QT syndrome)
8.
Uncontrolled hypertension, defined as systolic blood pressure ≥160 mmHg and/or diastolic blood 
pressure ≥100 mmHg confirmed upon repeated measures
9.
Left ventricular ejection fraction (LVEF) < 40% as determined by echocardiogram
(ECHO)/multigated acquisition scan (MUGA) performed at screening or within 90 days prior to 
C1D1
10. QT/QTc interval > 450 msec, as determined by screening ECG performed no earlier than 1 week 
before C1D1
11. Prior anti-tumor therapy (chemotherapy, radiotherapy, antibody therapy, molecular targeted 
therapy, retinoid therapy, or hormonal therapy) within 4 weeks (< 28 days) prior to C1D1
12. Major surgery within 4 weeks (< 28 days) prior to C1D1
13. Active joint inflammation or history of inflammatory arthritis or other immune disorder involving 
joints (osteoarthritis is not exclusionary)
14. Active infection involving IV antibiotics within 2 weeks prior to C1D1
15. Known history of or active hepatitis B virus (HBV) and/or hepatitis C virus (HCV), or active 
tuberculosis
16. Known history of human immunodeficiency virus (HIV) type 1/2 or other immunodeficiency 
disease
17. Subject has received a live vaccine within 4 weeks (< 28 days) prior to C1D1
18. Known hypersensitivity to any component of recombinant protein production by Chinese Hamster 
Ovary (CHO) cells 
19. Exposure to an investigational product or investigational device in another clinical study within 
4 weeks (< 28 days) prior to C1D1, or is scheduled to participate in another clinical study 
involving an investigational product or device during the course of this study 
20. Subject is breastfeeding or intends to begin breastfeeding during the course of the study 


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21. Any disorder or disease, or clinically significant abnormality on laboratory or other clinical test(s) 
(eg, blood tests, ECG), that in medical judgment of the investigator may impede the subject’s 
participation in the study, pose increased risk to the subject, and/or confound the results of the 
study 
22. Subject is a family member or employee of the investigator 
STATISTICAL ANALYSIS
Sample Size Calculations
Part 1: The final sample size in the Safety Run-in phase is dependent on the pre-stated rules of the dose 
escalation study design (see Section 8.1). In Part 1, the sample size for each dosing regimen (ie, 
imalumab + 5-FU/LV and imalumab + panitumumab) is expected to be between 6 and 12 subjects (ie, 3 to 
6 subjects at each imalumab dose level). Non-evaluable subjects will be replaced to meet study objectives.
Part 2: The primary exploratory efficacy endpoint will be PFS. Assuming that the median PFS is 
2.4 months in the control arm and 4.25 months in the experimental arm (hazard ratio 0.565), and using a 
one-sided α of 0.15 and β of 0.20 with a drop-out rate of 20% at 6 months, 48 PFS events are needed. With 
an enrollment ratio of 2:1, and taking into account the time for accrual of 1 year and an additional 
follow-up period of 6 months after the last subject is enrolled, the sample size needed is a total of 
44 subjects in the imalumab-containing treatment arms and 22 subjects in the control arm (SoC), for a total 
of 66 subjects.
Planned Statistical Analysis
In general, descriptive summaries will be presented for the safety and immunogenicity variables collected. 
Continuous variables will be summarized using mean, standard deviation, minimum, median, and 
maximum. Categorical variables will be summarized using frequency counts and percentages. For time-to-
event variables, Kaplan-Meier (KM) plots, median time-to-event, and other percentiles will be presented. 
For the primary efficacy endpoint PFS, the one-sided p-value from log rank test will be presented. AEs will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will be summarized by 
system organ class and preferred term. In addition, summaries of AEs by severity and relationship to study 
drug will be presented.
Where appropriate, some measures will be summarized by both point estimates and estimation of 
95% confidence intervals (CIs). 
An interim analysis will be implemented for planning purposes when 33 PFS events have been observed. 
The interim analysis will primarily include a summary of safety (as measured by incidence of TEAEs) and 
PFS by treatment arm. The DSMB will be included in review of the interim analysis data.
More detailed information about estimation of treatment effects, summarization of data, graphical 
representations, and analysis conventions will be provided in the imalumab Statistical Analysis Plan.


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4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 13
5. LIST OF ABBREVIATIONS .................................................................................... 19
6. BACKGROUND INFORMATION .......................................................................... 23
6.1 Description of Investigational Product ............................................................... 23
6.1.1 Macrophage Migration Inhibitory Factor (MIF) ....................................... 23
6.1.2 The Role of MIF in Cancer........................................................................... 23
6.1.3 Imalumab, Anti-Macrophage Migration Inhibitory Factor Antibody..... 24
6.1.4 Genetic Biomarkers Analysis........................................................................ 25
6.1.5 Rationale for Dose, Treatment Period, and Dosing Frequency................. 26
6.1.5.1 Dose Rationale......................................................................................... 26
6.1.5.2 Treatment Duration Rationale.............................................................. 26
6.1.5.3 Rationale for Dosing Frequency............................................................ 26
6.1.5.4 Rationale for Selection of Combination Therapies ............................. 27
6.2 Clinical Condition/Indication .............................................................................. 27
6.3 Population to be Studied ...................................................................................... 28
6.4 Findings from Nonclinical and Clinical Studies................................................. 28
6.4.1 Non-Clinical Summary.................................................................................. 28
6.4.2 Clinical Summary .......................................................................................... 30
6.4.2.1 Clinical Protocol 391101......................................................................... 30
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 33
6.6 Compliance Statement.......................................................................................... 33
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 34
7.1 Study Purpose ....................................................................................................... 34
7.2 Primary Objectives............................................................................................... 34
7.3 Secondary Objectives ........................................................................................... 34
7.3.1 Efficacy ........................................................................................................... 34
7.3.2 Safety............................................................................................................... 35


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7.3.3 Pharmacokinetics........................................................................................... 35
7.3.4 Quality of Life ................................................................................................ 35
7.4 Exploratory Objectives......................................................................................... 35
7.4.1 Pharmacodynamics........................................................................................ 35
7.4.2 Genetic Biomarkers....................................................................................... 35
7.4.3 Quality of Life ................................................................................................ 35
8. STUDY DESIGN......................................................................................................... 36
8.1 Brief Summary...................................................................................................... 36
8.2 Overall Study Design............................................................................................ 36
8.2.1 Part I: Safety Run-In..................................................................................... 36
8.2.1.1 Stopping Criteria for Dose Escalation.................................................. 37
8.2.2 Part 2: Exploratory Phase 2a........................................................................ 38
8.2.3 Definition of Dose-Limiting Toxicity ........................................................... 38
8.3 Duration of Study Period(s) and Subject Participation .................................... 39
8.4 Outcome Measures ............................................................................................... 39
8.4.1 Primary Outcome Measure .......................................................................... 39
8.4.2 Secondary Outcome Measures ..................................................................... 40
8.4.2.1 Immunogenicity Outcome Measures .................................................... 40
8.4.2.2 Safety Outcome Measures...................................................................... 40
8.4.2.3 Efficacy Outcome Measures .................................................................. 40
8.4.2.4 Pharmacokinetic Outcome Measures ................................................... 40
8.4.2.5 Quality of Life Outcome Measures ....................................................... 40
8.4.3 Exploratory Outcomes Measure .................................................................. 40
8.5 Randomization and Blinding............................................................................... 41
8.6 Study Stopping Rules............................................................................................ 41
8.7 Investigational Product and Standard Drugs .................................................... 41
8.7.1 Packaging, Labeling, and Storage................................................................ 41
8.7.1.1 Imalumab ................................................................................................ 41
8.7.1.2 Leucovorin............................................................................................... 42
8.7.1.3 5-Fluorouracil ......................................................................................... 42
8.7.1.4 Panitumumab.......................................................................................... 42
8.7.1.5 Standard of Care (Investigator Choice) ............................................... 42
8.7.2 Preparation and Storage of Pooled Product ............................................... 43
8.7.2.1 Imalumab ................................................................................................ 43
8.7.2.2 5-Fluorouracil, Leucovorin, and Panitumumab.................................. 44
8.7.2.3 Standard of Care Drugs......................................................................... 44
8.7.3 Administration ............................................................................................... 44
8.7.3.1 Imalumab ................................................................................................ 44
8.7.3.2 5-Fluorouracil, Leucovorin, and Panitumumab.................................. 44
8.7.3.3 Standard of Care Drugs......................................................................... 45
8.7.4 Description of Treatment.............................................................................. 45
8.7.4.1 Part 1: Safety Run-In ............................................................................. 45
8.7.4.2 Part 2: Exploratory Phase 2a................................................................. 45


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8.7.5 Investigational Product Accountability ....................................................... 46
8.8 Source Data ........................................................................................................... 46
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 47
9.1 Inclusion Criteria.................................................................................................. 47
9.2 Exclusion Criteria................................................................................................. 48
9.3 Withdrawal and Discontinuation ........................................................................ 50
10. STUDY PROCEDURES .......................................................................................... 51
10.1 Informed Consent and Enrollment ................................................................... 51
10.2 Subject Identification Code................................................................................ 51
10.3 Screening and Study Visits................................................................................. 51
10.3.1 Screening Assessments ................................................................................ 51
10.3.2 Baseline Assessments (Cycle 1 Day 1, Predose) ........................................ 53
10.3.3 Treatment Cycles......................................................................................... 53
10.3.3.1 Study Drug Administration ................................................................. 54
10.3.3.2 Day 1 of Each Cycle.............................................................................. 56
10.3.3.3 Day 8 of Each Cycle.............................................................................. 57
10.3.3.4 Day 15 of Each Cycle............................................................................ 58
10.3.3.5 Day 22 of Each Cycle............................................................................ 60
10.3.3.6 Day 28 (Cycle 1 and then Every Other Cycle) ................................... 60
10.3.3.7 Day 28 (Cycle 2 and then Every Other Cycle) ................................... 61
10.3.3.8 End of Study/Early Termination Visit................................................ 61
10.3.3.9 Safety Follow-Up Visit.......................................................................... 62
10.3.3.10 Survival Follow-Up (Post Therapy) .................................................. 63
10.4 Medications and Non-Drug Therapies.............................................................. 63
10.5 Subject Completion/Discontinuation ................................................................ 63
10.6 Procedures for Monitoring Subject Compliance............................................. 64
11. ASSESSMENT OF EFFICACY, PHARMACOKINETICS, 
PHARMACODYNAMICS, AND GENETIC TESTING........................................ 64
11.1 Plasma Imalumab, oxMIF, and Total MIF...................................................... 64
11.2 Antitumor Effect – Solid Tumors...................................................................... 65
11.3 Genetic Testing.................................................................................................... 65
11.4 Tumor-Associated Biomarkers.......................................................................... 66
12. ASSESSMENT OF SAFETY................................................................................... 66
12.1 Adverse Events.................................................................................................... 66
12.1.1 Definitions..................................................................................................... 66
12.1.1.1 Serious Adverse Event.......................................................................... 67
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 68
12.1.1.3 Non-Serious Adverse Event ................................................................. 68


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12.1.1.4 Unexpected Adverse Events................................................................. 68
12.1.1.5 Preexisting Diseases.............................................................................. 69
12.1.2 Assessment of Adverse Events.................................................................... 69
12.1.2.1 Severity .................................................................................................. 70
12.1.2.2 Causality................................................................................................ 71
12.1.2.3 Safety Reporting ................................................................................... 72
12.2 Urgent Safety Measures ..................................................................................... 73
12.3 Untoward Medical Occurrences........................................................................ 74
12.4 Non-Medical Complaints ................................................................................... 74
12.5 Medical, Medication, and Non-Drug Therapy History................................... 75
12.6 Physical Examinations........................................................................................ 75
12.7 Clinical Laboratory Parameters........................................................................ 75
12.7.1 Hematology and Clinical Chemistry.......................................................... 75
12.7.2 Urinalysis...................................................................................................... 76
12.7.2.1 Assessment of Laboratory Values....................................................... 76
12.8 Vital Signs............................................................................................................ 77
12.9 Electrocardiograms ............................................................................................ 77
13. STATISTICS............................................................................................................. 78
13.1 Sample Size and Power Calculations ................................................................ 78
13.2 Datasets and Analysis Cohorts .......................................................................... 78
13.3 Handling of Missing, Unused, and Spurious Data........................................... 78
13.4 Methods of Analysis............................................................................................ 78
13.4.1 General Considerations............................................................................... 78
13.4.2 Demographics and Other Subject Characteristics ................................... 79
13.4.3 Primary Outcome Measure......................................................................... 80
13.4.3.1 Primary Safety Outcome Measure...................................................... 80
13.4.3.2 Primary Efficacy Outcome Measure .................................................. 80
13.4.4 Secondary Outcome Measures ................................................................... 80
13.4.4.1 Immunogenicity Outcome Measures .................................................. 80
13.4.4.2 Safety Outcome Measures.................................................................... 81
13.4.4.3 Secondary Efficacy Outcome Measures ............................................. 82
13.4.4.4 Secondary Pharmacokinetic Outcome Measure................................ 82
13.4.4.5 Secondary Quality of Life Outcome Measures .................................. 82
13.4.5 Exploratory Outcome Measures ................................................................ 82
13.5 Planned Interim Analysis of the Study ............................................................. 83
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 83
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 83
15.1 Investigator’s Responsibility.............................................................................. 83
15.1.1 Final Clinical Study Report........................................................................ 84
15.2 Training ............................................................................................................... 84


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15.3 Monitoring........................................................................................................... 84
15.4 Safety Monitoring ............................................................................................... 84
15.4.1 Data Safety Monitoring (Part 1)................................................................. 84
15.4.2 Data Safety Monitoring Board (Part 2)..................................................... 85
15.5 Auditing ............................................................................................................... 85
15.6 Non-Compliance with the Protocol ................................................................... 85
15.7 Laboratory and Reader Standardization ......................................................... 85
16. ETHICS ..................................................................................................................... 86
16.1 Subject Privacy ................................................................................................... 86
16.2 Ethics Committee and Regulatory Authorities................................................ 86
16.3 Informed Consent ............................................................................................... 86
17. DATA HANDLING AND RECORD KEEPING................................................... 87
17.1 Confidentiality Policy ......................................................................................... 87
17.2 Study Documentation and Case Report Forms ............................................... 87
17.3 Document and Data Retention........................................................................... 88
18. FINANCING AND INSURANCE........................................................................... 88
19. PUBLICATION POLICY........................................................................................ 88
20. SUPPLEMENTS....................................................................................................... 89
20.1 Study 391401 Schematic..................................................................................... 89
20.2 Schedule of Study Procedures and Assessments.............................................. 90
21. REFERENCES........................................................................................................ 106
22. SUMMARY OF CHANGES.................................................................................. 110
Tables
Table 1 Study 391401: Management of Imalumab Injection-Related Reactions............ 55
Table 2 Mapping Conventions for AE Severity (For AEs Not Described Within NCI 
CTCAE).................................................................................................................... 70
Table 3 Schedule of Study Procedures and Assessments: Parts 1 and 2 ......................... 90
Table 4 Schedule of Study Procedures and Assessments: SoC Following Randomization 
(4-Week Cycles or if Subject is on Best Supportive Care)....................................... 95
Table 5 Schedule of Study Procedures and Assessments: SoC Following Randomization 
(3-Week Cycles) ....................................................................................................... 99


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Table 6 Schedule of Pharmacokinetic and Pharmacodynamic Sample Collections (Parts 
1 and 2) for Subjects Receiving Imalumab Treatment ........................................... 103
Table 7 Blood Volumes (Parts 1 and 2) for Lab Tests and PK/PD for Subjects Receiving 
Imalumab Treatment............................................................................................... 104
Table 8 Blood and Urine Volumes (Parts 1 and 2) for Optional Genetic Biomarkers 
cfDNA Analysis for Subjects Receiving Imalumab Treatment.............................. 105
Figures
Figure 1 Protocol 391401 Dose Escalation Scheme........................................................ 37
Figure 2 Study 391401 Schematic................................................................................... 89


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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
5-FU
5-fluorouracil
ADA
anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase
anti-MIF
anti-macrophage migration inhibitory factor
anti-oxMIF
anti-oxidized macrophage migration inhibitory factor
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration vs time curve
AUC0-336
area under the concentration vs time-curve from time zero to 
336 hours
AUC0-inf
area under the concentration vs time-curve from time zero to 
infinity
AUC0-tau
area under the concentration vs time-curve from time zero to time 
tau over a dosing interval at steady state
BRAF
B-Raf proto-oncogene, serine/threonine kinase
C1D1
Cycle 1 Day 1
C2D15
Cycle 2 Day 15
CBR
clinical benefit rate
cfDNA
cell-free DNA
CHO
Chinese Hamster Ovary
CI
confidence interval
CL
clearance
Cmax
maximum observed concentration
Cmin
minimum observed concentration
CRC
colorectal cancer
CRF
case report form
CRP
C-reactive protein
CT
computerized tomography
CTA
Clinical Trial Agreement
CXCR
C-X-C chemokine receptor
DLT
dose-limiting toxicity
DRC
Data Review Committee


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Abbreviation
Definition
DSMB
Data Safety Monitoring Board
EC
ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
Electronic Data Capture
EGFR
epidermal growth factor receptor
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30
EORTC QLQ-CR29
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire for colorectal cancer 29
EQ-5D
European Quality of Life – 5 Dimensions
ERK1
extracellular signal-regulated kinase 1
ERK2
extracellular signal-regulated kinase 2
FAS
Full Analysis Set
GCP
Good Clinical Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus 
HR
hazard ratio
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IL
interleukin
INR
International Normalized Ratio
IP
investigational product
IRT
Interactive Response Technology
IV
intravenous(ly)
KM
Kaplan-Meier
KRAS
Kirsten rat sarcoma viral oncogene homolog
KRAS mut
mutated Kirsten rat sarcoma viraloncogene homolog
KRAS wt
wild type Kirsten rat sarcoma viral oncogene homolog
LV
leucovorin
LVEF
left ventricular ejection fraction
mCRC
metastatic colorectal cancer


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Abbreviation
Definition
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines & Healthcare products Regulatory Agency (UK)
MIF
macrophage migration inhibitory factor
MRI
magnetic resonance imaging
MRT
mean residence time
MTD
maximum tolerated dose
mut
mutated
NADA
neutralizing anti-drug antibody
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NGS
next generation sequencing
NMC
non-medical complaint
NOAEL
no observed adverse effect level
NRAS
neuroblastoma RAS viral (v-ras) oncogene homolog
ORR
overall response rate
OS
overall survival
oxMIF
oxidated macrophage migration inhibitory factor
PD
pharmacodynamic
PEI
Paul-Ehrlich-Institute
PFS
progression-free survival
PK
pharmacokinetic
PS
performance status
QoL
quality of life
qPCR
quantitative polymerase chain reaction
QTc
corrected QT interval
Q2W
every 2 weeks
QW
every week
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
RSI
Reference safety information
SAE
serious adverse event
SAER
serious adverse event report
SIC
subject identification code
SmPC
Summary of Product Characteristics


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Abbreviation
Definition
SoC
standard of care
SUSAR
suspected unexpected serious adverse reaction
t½
half-life
TEAE
treatment-emergent adverse event
UK
United Kingdom
ULN
upper limit of normal
US
United States
US CFR
US Code of Federal Regulations
Vdss
volume of distribution at steady state
wt
wild type


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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
6.1.1 Macrophage Migration Inhibitory Factor (MIF)
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that acts as 
a critical upstream regulator of the inflammatory cascade, influences adaptive immune 
responses, and is a pivotal regulator of innate immunity.1; 2 MIF is secreted by the 
anterior pituitary gland and from pre-formed stores in immune cells in response to injury, 
infection, and cellular stress.2; 3 MIF promotes the release of other cytokines (such as 
tumor necrosis factor-α, INF-γ, interleukin [IL]-1β, IL-6, IL-8) and plays a central role in 
autocrine/paracrine activation of macrophages.2; 4 MIF is implicated in the pathogenesis 
of inflammatory and autoimmune diseases, which have been associated with certain 
allelic variants of the human MIF gene5 as well as with elevated levels of MIF in 
serum.6; 7; 8
MIF displays also a number of functions that promote tumor progression: (i) MIF acts 
directly on tumor cells by activating signaling pathways that promote cell proliferation 
and cell survival. (ii) MIF facilitates invasion of the extracellular matrix and induces 
angiogenesis and tumor vascularization. (iii) As a pro-inflammatory cytokine, MIF is one 
of the mediators of tumor micro-inflammation. Inflammatory-mediated events such as the 
production of reactive, cytotoxic molecules and growth factors as well as the activation of 
signal-transduction pathways that promote cell survival and proliferation, are proposed to 
be important factors in cancer progression.9 MIF has been shown to be up-regulated in a 
large variety of human neoplasms (eg, pancreatic, breast, prostate, colon, brain, skin, and 
lung-derived tumors),10; 11; 12 where it is thought to contribute to tumor growth, 
angiogenesis, invasiveness, and metastases spread. Indeed, anti-MIF antibodies have 
been shown to effectively inhibit tumorigenesis and angiogenesis in a variety of animal 
models.13; 14; 15
6.1.2 The Role of MIF in Cancer
MIF is involved in the regulation of tumor-suppressor genes, angiogenesis, and cell 
senescence. Tumor progression is supported by several MIF activation responses 
including sustained extracellular signal-regulated kinase (extracellular signal-regulated 
kinase 1 [ERK1] and extracellular signal-regulated kinase 2 [ERK2]) activation,
inhibition of p53-mediated growth arrest and apoptosis, increased hypoxia-inducible 
factor-1α, and delayed tumor cell senescence. Increased angiogenic factor production 
(eg, vascular endothelial growth factor) and increased matrix metalloproteinase secretion 
facilitate tumor invasion. Additionally MIF dependent activation of CD44 enhances the 


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metastatic process.9 MIF binds to CD74 surface protein that leads to CD44-dependent 
activation of Src-family receptor tyrosine kinases. MIF can also bind and signal through 
G-protein coupled chemokine receptors (C-X-C chemokine receptor [CXCR] 2 and 
CXCR4). However, the precise expression and functional profile of the MIF-receptor 
complexes have not yet been resolved.16
Several studies also report that MIF expression closely correlates with tumor 
aggressiveness and metastatic potential, suggesting that MIF may play an important role 
in disease severity and cell survival.17 Recent data suggest that extracellular MIF may 
contribute to a more aggressive tumor phenotype as compared to intracellular MIF,18
which is not accessible to neutralization by antibodies. Neutralizing anti-MIF antibodies 
have been shown to effectively inhibit tumorigenesis in animal models of B cell 
lymphoma, prostate cancer and colon cancer.13; 14; 15
MIF has been shown to be up-regulated in a large variety of human neoplasms, including 
colorectal cancer (CRC).19 The concentration of serum MIF was positively correlated 
with an increased risk of hepatic metastasis in subjects with CRC. MIF was also 
dramatically up-regulated in human colorectal tissue, with 20–40 times as many 
MIF-positive cells found in the mucosa of subjects with CRC than in normal tissues.19
Given the association between MIF and CRC, various animal studies have examined MIF 
as a potential therapeutic target in this disease. Mice bearing CT26 colon carcinoma cell 
transplants were treated with neutralizing anti-MIF antibodies and a significant reduction 
in tumor burden and tumor-associated angiogenesis was observed relative to 
vehicle-treated animals.15; 19 Furthermore, studies demonstrated that tumor growth rate 
was significantly lower in MIF knockout (MIF-/-) mice than in wild-type (MIF+/+) 
mice.20 In summary, there is mounting evidence to suggest that MIF may play a key role 
in CRC.
6.1.3 Imalumab, Anti-Macrophage Migration Inhibitory Factor Antibody
Imalumab is a recombinant, fully human antibody specific for the active form of the 
MIF molecule. Imalumab is expressed in a Chinese Hamster Ovary (CHO) cell line using 
plasma protein-free production process. The antibody consists of two heavy chains of the 
gamma-1 isotype, and 2 kappa light chains and shows structural features typical for 
human IgG-1/kappa. Each heavy chain carries 1 N-glycan. Imalumab, formulated as a 
sterile, nonpyrogenic, liquid preparation in 250 mM glycine buffer pH 5.0, is stable 
within a protein concentration range of 50 – 100 mg anti-oxidated macrophage migration 
inhibitory factor (anti-oxMIF)/mL. During formulation development, imalumab stability 
in a liquid formulation was demonstrated. Results showed constant functional activity 


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(demonstrated by anti-oxMIF enzyme-linked immunosorbent assay) and no increase of 
aggregates (confirmed by dynamic light scattering) when stored at 4°C. There was only a 
modest increase in dimers by 0.03% per month with a corresponding decrease for 
monomers (size exclusion high performance liquid chromatography data confirmed by 
asymmetric flow field fractionation) (Imalumab Formulation Development Report 
RD_PPD_120902).21
6.1.4 Genetic Biomarkers Analysis
Studies of metastatic colorectal cancer (mCRC) demonstrated that KRAS/NRAS-status 
can change during therapy and that KRAS/NRAS-mutation can be found by cell-free 
DNA (cfDNA) interrogation in patients originally KRAS/NRAS-wild type (wt).22
Molecular alterations (in most instances point mutations) of KRAS are causally 
associated with the onset of acquired resistance to anti-epidermal growth factor receptor 
(EGFR) treatment in colorectal cancers. Analysis of metastases from patients who 
developed resistance to cetuximab or panitumumab showed the emergence of KRAS 
amplification in one sample and acquisition of secondary KRAS mutations in 60% (6/10) 
of cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients 
as early as 10 months prior to radiographic documentation of disease progression.23 It has 
been demonstrated that the primary tumor – identified by conventional tumor-tissue 
KRAS tests – is not consistently representative of the related metastasis, especially when 
considering treatment of mCRC. This suggests the need for re-biopsy of metastases or, 
preferably, for an efficient blood test to adjust the predictive value of KRAS status in 
response to anti-EGFR therapy in patients with mCRC at the time of decision making. In 
addition, cfDNA analysis enables the noninvasive detection of the emergence of KRAS 
mutations as drivers of acquired resistance to panitumumab in mCRC.
Therefore, subjects with mCRC in this study will be monitored using cfDNA 
methodologies for a change in KRAS/NRAS status from KRAS/NRAS-wt to 
KRAS/NRAS-mutated (mut).
Numerous studies have shown that patients treated with an anti-EGFR tyrosine kinase 
inhibitor (erlotinib or gefitinib) can acquire resistance to these therapies, which is 
associated with the development of T790M mutations. Several studies have also shown 
that cfDNA can be used to identify B-Raf proto-oncogene, serine/threonine kinase 
(BRAF) mutations in patients receiving BRAF inhibitors.24; 25; 26; 27
Thus, in addition to the KRAS gene, a larger cancer gene panel will be tested by either 
targeted next generation sequencing (NGS) or quantitative polymerase chain reaction 
(qPCR) using tumor-derived cfDNA in order to identify imalumab-specific patterns of 


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genetic tumor adaption/mechanisms resistance. Results from the cfDNA analyses might 
also be used to verify tumor burden.28
6.1.5 Rationale for Dose, Treatment Period, and Dosing Frequency
6.1.5.1 Dose Rationale
As of 2015 JUL 01, preliminary Phase 1 data indicate that imalumab was generally well 
tolerated up to a dose of 37.5 mg/kg every 2 weeks (Q2W) and 25 mg/kg every week 
(QW). The observed dose-limiting toxicity (DLT) occurred in a subject treated with 
50 mg/kg Q2W. Pharmacokinetic (PK) assessment generally showed a linear increase 
over the imalumab dose range.
The 7.5 mg/kg and 10 mg/kg starting doses in Part 1 of this study were selected as a 
result of the preliminary Phase 1 data and represent at least an approximate of 2.5-fold 
safety factor (based on area under the concentration vs time-curve from time zero to time 
tau over a dosing interval at steady state [AUC0-tau]) in comparison to the dose at which 
the observed DLT occurred in a subject in Study 391101 treated with 50 mg/kg Q2W.
During Arm 2 of the Phase 1 study in mCRC subjects, biopsies from liver metastases 
were collected from subjects treated with 10 or 25 mg/kg QW to study drug penetration 
and target saturation. Preliminary results show an accumulation over time of treatment of 
imalumab within the tumor cells and the surrounding stroma, with a mean of 
approximately 100% target occupancy after the first cycle of treatment (n=3 subjects at 
10 mg/kg QW). At 25 mg/kg QW (n=1), a comparable target occupancy was detected in 
the tumor after the first treatment cycle, but imalumab was also detected in adjacent 
normal liver tissue. Thus, these data support the rationale for 10 mg/kg QW dose as a 
treatment regimen for the Phase 2a study.
6.1.5.2 Treatment Duration Rationale
Subjects will be treated until disease progression, unacceptable toxicity, death or subject
withdrawal of consent, whichever occurs first (see Section 9.3).
6.1.5.3 Rationale for Dosing Frequency
The QW dosing frequency was selected using preliminary Phase 1 PK data
(Study 391101) showing that optimal tissue saturation could be obtained with the QW
dosing relative to the Q2W dosing. The half-life of imalumab ranged from 3.3 to 10.8 
days (ie, around a range of approximately 1 week), indicating that QW dosing is 
preferable to Q2W dosing for maintaining more stable concentrations of imalumab. For 


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the 10 mg/kg dose, Cmax/Cmin ratios (peak/trough fluctuation) on Day 15 of Cycle 2 were 
approximately 4-fold for QW dosing compared with 7.5-fold for Q2W dosing.
6.1.5.4 Rationale for Selection of Combination Therapies
5-Fluorouracil and Leucovorin
The options for third- or fourth-line treatment are few, and 5-fluorouracil 
(5-FU)/leucovorin (LV) is part of standard of care (SoC). This regimen can be given 
regardless of Kirsten rat sarcoma viral oncogene homolog (KRAS) status and is well 
tolerated in this late-line setting when quality of life becomes an important parameter.
Panitumumab
Panitumumab is an approved option for third or fourth line monotherapy for subjects with 
KRAS wt tumors. Recently, using the novel technique of massively parallel multigene 
sequencing (also known as NGS), it has been shown that patients who benefit from
panitumumab are those with all-RAS wt tumors, ie, those with no mutation in KRAS and 
neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) exons 2, 3, 4 at codons 12, 
13, 61, 117, 141.29; 30; 31 The role of BRAF mutation as predictive of responsiveness to 
anti-EGFR monoclonal antibodies remains to be further validated. On the other hand, 
panitumumab is better tolerated than cetuximab because it is a fully humanized 
monoclonal antibody and it is better tolerated than another approved targeted agent, 
regorafenib, which yields severe toxicity in the majority of subjects. In this study, 
subjects will be tested for KRAS and NRAS mutation status, and only those with 
all-RAS wt tumor will be eligible for treatment with panitumumab.
Panitumumab has been approved in several countries including the United States (US) 
and Germany as standard therapy. The sponsor feels it is justified to administer 
panitumumab to subjects in this study with Eastern Cooperative Oncology Group 
(ECOG) Performance Status (PS) of 0-2. Panitumumab has been shown to be well 
tolerated in frail elderly patients (ECOG ≤3) with KRAS wt mCRC and poor prognostic 
factors in a Phase 2 study of the Spanish Cooperative Group for the Treatment of 
Digestive Tumours.32 In addition, panitumumab and cetuximab were compared in a 
randomized Phase 3 study in patients with chemotherapy-refractory KRAS wt mCRC 
(ECOG ≤2).33 The incidence of adverse events (AEs) of any grade and grade 3-4 AEs 
was similar across treatment groups.
6.2 Clinical Condition/Indication 
In this study, imalumab is intended for treatment of mCRC as third- or fourth-line
therapy.


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6.3 Population to be Studied
Male and female subjects aged 18 years or older with a confirmed diagnosis of mCRC 
are eligible if they have progressed after receiving at least 2, but no more than 3, prior 
treatment lines including SoC, and have an ECOG PS of 0-2. Adjuvant therapy in the 
metastatic setting (administered following a surgical procedure) and investigational 
products are included in the definition of a prior line of treatment for the purposes of this 
study.
6.4 Findings from Nonclinical and Clinical Studies
6.4.1 Non-Clinical Summary
A summary of non-clinical toxicology findings is provided below. Refer to the imalumab
Investigator’s Brochure (IB) for additional details.
In a single-dose cardiovascular safety pharmacology study (Study 8240906), telemetered 
cynomolgus monkeys were administered a single dose of imalumab at 25, 50, or 
200 mg/kg (Day 1). No adverse effects on cardiovascular or respiratory parameters were 
detected at doses of 25 and 50 mg/kg. Increased blood pressure (mean change of ~10%) 
and heart rate (mean change of ~30%) with corresponding shortened corrected QT 
interval (QTc) (mean change of ~10%) was measured by telemetry at the highest dose 
(200 mg/kg).
In the same study, full necropsy and histopathological evaluation of the large and small 
joints were performed at study termination (Day 6). Treatment with imalumab was 
associated with adverse clinical signs from Day 1 to 4 in one animal of the high dose 
group (200 mg/kg) including abnormal movement, hypoactivity, prostration, and tremor. 
Inflammation of the joints of the knee, elbow, tarsus, and phalanges (hand and foot) of 
animals treated at 50 or 200 mg/kg were considered to be test-item related. This 
inflammation consisted of acute to subacute inflammation of the synovia, ligaments, and 
muscle, villous hyperplasia of the synovia and hemorrhage in the joints of knee, elbow 
and tarsus. In the phalanges of the hands and feet, acute to subacute inflammation of the 
tendons and tendon sheath, as well as subcutaneous inflammation with scab and ulcer, 
were obvious. Test-item related histopathological findings in the elbow joint of 
2/4 animals of the low dose group (25 mg/kg) consisted of bilateral moderate hemorrhage 
(in 1 animal) and slight inflammation of the synovial and ligaments. A dose-related 
increase in incidence and severity was observed with inflammation. Based on these 
findings, a no observed adverse effect level (NOAEL) could not be determined under the 
conditions of this study.


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In cynomolgus monkeys, no adverse effects were detected at 25 mg/kg in the 1-month 
repeated toxicity study. However, dose-dependent, test-item-related events were evident 
at doses ≥ 100 mg/kg as transient clinical signs (transient waddling gait, squatted posture 
and reduced activity) with onset 2 to 3 days post first dose. These observations resolved 
spontaneously, within 7 days of test-item administration. No clinical signs were observed 
following subsequent (second to fifth) doses. At the end of the 1-month dosing regimen, 
animals were sacrificed for histopathology either immediately, or following a 4-week 
recovery period (high dose and control animals only). Of the animals sacrificed 
immediately, monkeys of the 50, 100 and 200 mg/kg imalumab dose groups 
demonstrated histopathological changes in knee joints, which were likely responsible for 
the clinical signs observed following the first dose. These changes were characterized as 
acute or subacute inflammation of the synovial membrane and the cruciate and patellar 
ligament and villous hyperplasia of the synovial membrane. Partial recovery of these 
histopathological changes was evident in the monkeys of the high dose group sacrificed 
after a 4-week treatment-free period (lower severity and incidence). In addition, ligament 
lesions were not detected following the recovery period. No deaths occurred during either 
the dosing or the recovery phases.
Cynomolgus monkeys were injected intravenously over a 6-month period with weekly 
doses of imalumab at dose levels of 10, 25, or 50 mg/kg, in a repeated dose chronic 
toxicity study with full fertility assessment (Study 8275958). Recovery groups (for all 
groups) for a period of 8 weeks were included. Administration with imalumab over 
26 weeks had no toxicologically relevant effects on body weight, clinical observations, 
body temperature, serum chemistry, hematology, coagulation, urine, menstrual cycle, 
testicular size, semen evaluation, spermatogenesis, or hormone parameters. Additionally, 
no ophthalmic findings were recorded. Cytokine analyses indicated there was a slight to 
moderate IL-6 response after the first, second, and last dose administered at the end of the 
dosing phase in the high-dose and intermediate-dose groups (up to 56.3 pg/ml). Group 
differences were statistically significant for male animals of the high-dose group and the 
intermediate-dose group (only after administration of the last dose). Elevations of serum 
IL-6 levels were transient in all individuals and returned to baseline values (or were 
below detectable limit) at 168 hours after imalumab administration. The timing of these 
transient changes in IL-6 serum levels, which reached statistical significance at 4 hours
and 24 hours post dose, in combination with the histopathological findings discussed 
below, suggest that these effects are likely to be related to imalumab administration. 
Highest C-reactive protein (CRP) values were detected for 2 high-dose group animals, 
showing histopathologically adverse effects for multiple joints; however, no clear dose 
dependency or correlation between CRP and histopathological results were apparent. At 


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the end of the dosing phase, microscopic findings were confined to the synovial 
membrane and adjacent ligaments and/or tendons in single or multiple joints, including 
the knee, elbow, tarsus, and phalanges of 3 intermediate-dose group and 6 high-dose 
group animals. These lesions were attributed to administration of imalumab. Findings 
consisted of subacute inflammation and villous hyperplasia of the synovial membrane (in 
the knee, elbow, and tarsus joints), subacute inflammation of the ligament (in the knee) 
and subacute inflammation of the ligament and of the tendon sheath (in the tarsus). In the 
phalanges of the hand and foot, subacute inflammation of the tendons and tendon sheath 
and/or subacute inflammation and villous hyperplasia of the synovial membrane and/or 
sub-acute inflammation of the ligament were also noted. The severity and incidence of 
the findings were more prominent in male animals. After the recovery phase, 
histopathological findings in 1 intermediate-dose group and 2 high-dose group animals 
were present in the larger joints (knee, elbow, and tarsus), as well as in the middle finger 
and little toe. These consisted of villous hyperplasia and inflammation of the synovial 
membranes and inflammation of the ligament and tendon, which was also seen in 
terminal killed animals. In addition to the above findings, ossification of the tendon 
sheath (tarsus) and ligament (elbow) was restricted to 1 high-dose group female of the 
recovery phase.
In rats, no adverse effects were detected following 5 consecutive weekly doses of up to 
250 mg/kg imalumab over a period of 1 month.
In summary, while no NOAEL was observed during the single-dose studies, repeat-dose 
toxicity studies in rats and cynomolgus monkeys demonstrated a NOAEL of 250 mg/kg 
in rats and 25 mg/kg (1 month) and 10 mg/kg (6 months) in cynomolgus monkeys.
6.4.2 Clinical Summary
6.4.2.1 Clinical Protocol 391101
As of the date of this protocol, imalumab is being evaluated in subjects with malignant 
solid tumors including metastatic adenocarcinoma of the colon or rectum, metastatic 
non-small cell lung cancer and metastatic ovarian cancer. Study 391101 is a Phase 1, 
multicenter open-label dose-escalation study to assess the safety, tolerability, PK, 
pharmacodynamics (PD), tumor penetration, and target binding of imalumab as a single 
agent in approximately 36 to 60 evaluable subjects. The 2-treatment-arm study design 
includes dose escalation with imalumab administered intravenously (IV) over a 28-day 
treatment cycle, as a single agent Q2W (Arm 1) and QW (Arm 2). The imalumab
maximum administered dose (MAD) of single agent imalumab was 50 mg/kg in the Q2W 


B A X 6 9 ( i mal u ma b )
Pa ge 3 1 of 1 2 5
Cli nical St u d y Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 M A Y 0 9
B A X A L T A C O N FI D E N TI A L – R E S T RI C T E D: D O N O T D I S T RI B U T E WI T H O U T P RI O R A P P R O V A L
sc he d ule. T he e x pa nsi o n p hase is o n g oi n g wit h t he Q W sc he d ule ( m C R C, n o n -s mall cell 
l u n g ca ncer, a n d o varia n ca ncer).
As of 2 0 1 5 J U L  0 1, a t otal of 4 8 s u bjects ( 2 8 s u bjects i n t he d ose escalati o n p hase a n d 
2 0 s u bjects i n t he e xpa nsi o n c o h ort) ha ve recei ve d d oses ra n gi n g fr o m 1 m g/ k g t o 
5 0 m g/ k g I V Q 2 W, a n d a t otal of 1 8 s u bjects i n t he d ose escalati o n p hase ha ve recei ve d 
d oses ra n gi n g fr o m 1 0 t o 2 5 m g/ k g I V Q W.
6. 4. 2. 1. 1 S afet y S u m m ar y
P P D
I mal u ma b a p pears t o be safe a n d well t olerate d u p t o a d ose of 3 7. 5 m g/ k g Q 2 W
a n d 
2 5 m g/ k g Q W. As of t he 2 0 1 5 J U L  0 1 c ut-off date, o ne s us pecte d u ne x pecte d seri o us 
a d verse reacti o n ( S U S A R) was re p orte d. F oll o wi n g a d mi nistrati o n of i mal u ma b, a 
 male wit h m C R C e x perie nce d a n u ns pecifie d i nf usi o n reacti o n. Se ve nt y-t w o 
h o urs later, t he s u bject prese nte d s y m pt o ms of s h ort ness of breat h wit h ple uritic c hest 
pai n. T he s u bject’s dia g n ostic a n d cli nical e val uati o n was c o nsiste nt wit h h y perse nsiti vit y  
p ne u m o nitis wit h o ut e vi de nce of i nfecti o n or he m orr ha ge. T his seri o us a d verse reacti o n 
of h y perse nsiti vit y  p ne u m o nitis ( Me dical Dicti o nar y f or Re g ulat or y Acti vities 
[Me d D R A ] preferre d ter m: al ve olitis aller gic), w hic h als o met t he pr ot oc ol-defi ne d 
criteria f or d ose-li miti n g t o xicit y, occ urre d after a d mi nistrati on of t he ma xi m u m 
a d mi nistere d d ose of 5 0 m g/ k g Q 2 W of i mal u ma b. C o nse q ue ntl y, e nr oll me nt i n t he 
5 0 m g/ k g Q 2 W c o h ort was disc o nti n ue d, a n d 3 a d diti o nal s u bjects were e nr olle d at t he 
d ose le vel i m me diatel y bel o w 5 0 m g/ k g Q 2 W (ie, 2 5 m g/ k g Q 2 W ) t o c ollect a d diti o nal 
safety data. Data fr o m t hese 3 a d diti o nal s u bjects were re vie we d b y t he Data Re vie w 
C o m mittee ( D R C) a n d i n vesti gat ors . Beca use n o safet y iss ues or c o ncer ns were n ote d , it 
was deci de d t o d ose escalate t o 3 7. 5 m g/ k g Q 2 W ( C o h ort 5a) rat her t ha n t o 5 0 m g/ k g
Q 2 W . All 3 s u bjects i n C o h ort 5a c o m plete d at least 1 treat me nt c ycle a n d n o D LTs we re 
re p orte d at d oses u p t o 3 7. 5 m g/ k g Q 2 W .
S u bse q ue ntl y, Ar m 2 was i nitiate d. I n C o h ort 7, a t otal of 6 s u bjec ts wit h m C R C recei ve d 
i mal u ma b 1 0 m g/ k g Q W. T he a d diti o nal 3 s u bjects at t he 1 0 m g/ k g Q W d ose le vel i n 
C o h ort 7 were e nr olle d t o f urt her c ollect P D mar kers. I n C o h ort 8, 3 s u bjects wit h m C R C 
recei ve d i mal u ma b 2 5 m g/ k g Q W. I n C o h ort 1 0, a t otal of 2 0 s u bjects recei ve d i mal u ma b
1 0 m g/ k g Q W, i ncl u di n g 8 wit h m C R C, 8 wit h o varia n ca ncer, a n d 4 wit h N S C L C. As of 
2 0 1 5 J U L  0 1, n o D L Ts were re p orte d f or a n y s u bjects treate d wit h i mal u ma b Q W 
( Ar m 2) ( preli mi nar y  data).
O ne a d diti o nal S U S A R of Gra de 3 na usea, v o miti n g, a n d c o nsti pati o n was re p orte d i n t he 
3 9 1 1 0 1 P hase 1 s t u d y after t he data c ut-off date ( 2 0 1 5 J U L  0 1) o n 2 0 1 5 S E P 1 6, w hic h 
occ urre d after 1 c y cle of i mal u ma b 1 0 m g/ k g Q W. T he I n vesti gat or assesse d t hat t his 


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serious adverse reaction was possibly related to imalumab, with constipation more likely 
to be related to the underlying disease. The most frequent related AEs experienced by the 
subjects were fatigue (8.4%), constipation (6.3%), dysgeusia (4.2%), and rash (4.2%) (as 
of 2015 JUL 01 data cut-off). The majority of related AEs were determined by the 
investigator to be mild or moderate, and many of these events were confounded by the 
underlying ailment; however, the events were evaluated taking a conservative approach, 
and the events were considered related. Overall, 15 (31.3%) subjects reported a total of 
22 serious adverse events (SAEs) (preliminary data as of 2015 JUL 01). Please refer to 
the IB for additional information.
6.4.2.1.2 Pharmacokinetic Summary
Imalumab concentration-time profiles in Arms 1 and 2 showed a bi-exponential decline 
following single and multiple dose administration. In Arm 1 (Q2W), trough (predose) 
concentrations indicated that some subjects achieved steady state by treatment Cycle 2 
Day 15 (C2D15), while others continued to show an increase in concentration up until the 
end of Cycle 3 (ie, 84 days after the start of treatment).
Across both Arms 1 (Q2W) and 2 (QW), geometric mean half-life (t1/2) ranged from 
3.3 to 8.1 days on Cycle 1 Day 1 (C1D1) and 4.1 to 10.8 days on C2D15; estimates of t1/2
appeared to be generally independent of dose over the dose range evaluated. Estimates of 
t1/2 may be underestimated for longer estimates of t1/2 and in Arm 2.
Imalumab exposure in Arm 1 (maximum observed concentration [Cmax], area under the 
concentration vs time-curve from time zero to infinity [AUC0-inf], and area under the 
concentration vs time-curve from time zero to 336 hours [AUC0-336] on C1D1, and Cmax
and AUC0-336 on C2D15) showed a generally linear increase over the dose range. A 
similar linear increase was observed for Cmax, AUC0-inf, and AUC0-336 on C1D1 in Arm 2. 
There was a larger degree of variability in exposure at the higher doses in Arm 1, which 
made it difficult to draw conclusions regarding any potential nonlinearities. These 
preliminary findings supported the conclusion that imalumab exposure at the 25 mg/kg 
dose in Arm 2 is comparable to the 37.5 mg/kg dose in Arm 1 on C1D1.


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6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
There is limited experience with imalumab administration in humans. Although the 
repeat-dose toxicology study showed acute or subacute inflammation of the joints of 
animals, which was deemed related to the administration of imalumab, there were no 
cases of drug related joint inflammation in the 48 human subjects who had received 
imalumab doses ranging from 1 to 50 mg/kg IV in the ongoing Phase 1 study as of 
2015 JUL 01. In light of these nonclinical and clinical findings, and to proactively assess 
potential joint toxicity in humans, a physical examination of the joints will be performed 
at screening and then at regular bimonthly intervals. The DRC will review all safety data 
with particular attention to pertinent AEs such as allergic reactions and joint pain on a 
monthly basis.
In general, AEs associated with the administration of monoclonal antibody agents include 
allergic reactions (eg, hives or itching), influenza-like symptoms, nausea, diarrhea, and 
skin rashes. 
As with any IV protein product, allergic type hypersensitivity reactions are possible. 
Subjects must be closely monitored and carefully observed for any symptoms throughout 
the infusion period. Subjects should be informed of the early signs of hypersensitivity 
reactions and anaphylaxis, including hives, generalized urticaria, tightness of the chest, 
shortness of breath, wheezing, and hypotension. If any of these symptoms occur, 
investigational drug administration should be discontinued immediately. In case of shock, 
standard medical treatment for shock should be implemented. Other rare SAEs may 
include low blood cell counts, coronary complications, and serious infections (including 
skin infections).
6.6 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives
2001/20/EC and 2005/28/EC, and applicable national and local regulatory requirements.


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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this study, in subjects with progressive measurable mCRC, is as follows:

To evaluate the safety and tolerability of imalumab in combination with 5-FU/LV 
or panitumumab to determine the recommended phase 2 dose (RP2D) of each 
combination

To compare the efficacy of imalumab in combination with 5-FU/LV versus SoC 
(investigator choice) as third or fourth treatment line in subjects with KRAS mut
and/or NRAS mut tumors

To compare the efficacy of imalumab in combination with panitumumab versus 
SoC (investigator choice) as third or fourth treatment line in subjects with KRAS 
wt and NRAS wt tumors
Furthermore, the pharmacokinetic (PK) profile of imalumab in combination with 
5-FU/LV or panitumumab will be characterized, and limited pharmacodynamic (PD) 
serum markers will be explored.
7.2 Primary Objectives
The primary objectives of the study are: 

To determine the RP2D of imalumab in combination with 5-FU/LV or 
panitumumab (Part 1)

To compare PFS between imalumab in combination with 5-FU/LV for subjects 
with KRAS mut and/or NRAS mut tumors or in combination with panitumumab 
for subjects with KRAS wt and NRAS wt tumors, versus SoC (investigator 
choice), as third or fourth treatment line (Part 2)
7.3 Secondary Objectives
7.3.1 Efficacy
The secondary efficacy objectives of the study are:

To compare overall response rate (ORR) and clinical benefit rate (CBR) in 
subjects treated at RP2D with imalumab in combination with 5-FU/LV or 
panitumumab versus SoC (investigator choice) as third or fourth treatment line

To compare OS of subjects who received imalumab in combination with 
5-FU/LV or panitumumab versus SoC (investigator choice) as third or fourth 
treatment line


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7.3.2 Safety
The secondary safety objective of the study is:

To assess the safety and tolerability of imalumab in combination with 5-FU/LV or 
panitumumab
7.3.3 Pharmacokinetics
The secondary PK objective of the study is:

To characterize the PK of imalumab in combination with 5-FU/LV or 
panitumumab
7.3.4 Quality of Life
The secondary QoL objective of the study is:

To compare QoL of subjects who received imalumab in combination with 
5-FU/LV or panitumumab versus SoC (investigator choice) as third or fourth 
treatment line
7.4 Exploratory Objectives
7.4.1 Pharmacodynamics
The exploratory PD objective of the study is:

To characterize oxidated macrophage migration inhibitory factor (oxMIF) and 
total MIF in plasma prior to and during treatment with imalumab in combination 
with 5-FU/LV or panitumumab
7.4.2 Genetic Biomarkers
The exploratory genetic biomarker objective of the study is:

To characterize tumor-associated genetic alterations in blood/urine (for all 
subjects treated with imalumab in combination with 5-FU/LV or panitumumab
who provide consent for exploratory biomarker analyses)
The sponsor will obtain available historical tumor mutational testing results for subjects.
7.4.3 Quality of Life
The exploratory QoL objective of the study is:

To compare disease-specific QoL and health utility in subjects treated with 
imalumab in combination with 5-FU/LV or panitumumab versus SoC 
(investigator choice) as third or fourth treatment line


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8. STUDY DESIGN
8.1 Brief Summary
This open-label, randomized study to be conducted in approximately 40 study sites in the 
US and EU. The study comprises a Safety Run-in phase (Part 1) with 2 ascending doses 
of imalumab; and an exploratory phase (Phase 2a, ie, [Part 2]) with a 2-treatment-arm 
design. Approximately 78 to 90 subjects (approximately 12 to 24 subjects in Part 1 and 
66 subjects in Part 2) with measurable mCRC, who have progressed after receiving at 
least 2, but no more than 3, prior treatment lines including SoC, will be enrolled in the 
study. Subjects can only participate in either Part 1 or Part 2 of the study. Adjuvant 
therapy in the metastatic setting (administered following a surgical procedure) and 
investigational products are included in the definition of a prior line of treatment for the 
purposes of this study.
In both parts, imalumab will be administered IV QW as part of a 4-week treatment cycle. 
Antitumor activity will be evaluated by the investigator after completion of every other 
treatment cycle (ie, every 2 cycles) using magnetic resonance imaging (MRI) or 
computerized tomography (CT) imaging and in accordance to Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1. Treatment will be continued until disease 
progression, unacceptable toxicity, withdrawal of consent, or for any other reason as 
detailed in Section 9.3. 
8.2 Overall Study Design
8.2.1 Part I: Safety Run-In
Subjects will be enrolled into 2 sequential cohorts, with a minimum of 3 and a maximum 
of 6 subjects per cohort. Subjects will receive imalumab at 7.5 and 10 mg/kg QW in 
combination with infusional 5-FU/LV given Q2W in subjects with KRAS mut and/or 
NRAS mut tumors, or in combination with panitumumab given Q2W in subjects with 
KRAS wt and NRAS wt tumors. Treatment will be administered in 4-week cycles and 
will continue until disease progression, unacceptable toxicity, withdrawal of consent, or 
for any other reason as detailed in Section 9.3.
The DRC will meet for safety reviews after 3 subjects in a dosing cohort have completed 
the first treatment cycle (ie, after 28 days) to decide if additional subjects must be 
enrolled or if the next dose level can be opened. For each combination, based on all data 
of all evaluable subjects, the DRC will determine the RP2D, or decide if an intermediate 
dose level must be explored. The RP2D will be used as the dose for Part 2.
See Section 15.4.1 for additional details on the DRC.


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8.2.1.1 Stopping Criteria for Dose Escalation
For each combination, enrollment will proceed according to the following rules based on 
the occurrence of DLTs:

If zero out of 3 evaluable subjects experience a DLT during the first 28 days after 
the first administration of study drug at the first dose level, the second dose level 
will be opened for enrollment after review of the safety data by the DRC

If 1 out of 3 evaluable subjects experiences a DLT during the first 28 days after 
administration of study drug at the first dose level, 3 additional subjects will be 
enrolled at the first dose level, for a total of 6 evaluable subjects. After review of 
the safety data of all 6 evaluable subjects, the DRC will decide if the second dose 
level or a lower dose level will be explored

If 2 or more evaluable subjects experience a DLT during the first 28 days after the 
first administration of study drug at the first dose level, the second dose level will 
not be open to enrollment, and the DRC will decide if a lower dose level will be
explored
See Section 8.2.3 for DLT definition. See Figure 1 for a schematic of the dose escalation.
Figure 1
Protocol 391401 Dose Escalation Scheme
Abbreviation: DLT=dose-limiting toxicity.
a A subject is considered evaluable if he/she can be evaluated for adverse events during the first 
28 days after first study drug administration, or is withdrawn from the study due to a DLT. 


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8.2.2 Part 2: Exploratory Phase 2a
This is a 2-treatment-arm phase using a 2:1 ratio for subjects to receive 
imalumab + 5-FU/LV or imalumab + panitumumab (Arm A) or SoC per investigator 
choice (Arm B). Within each stratum, subjects will be randomized in a 2:1 ratio to 
receive imalumab + 5-FU/LV (KRAS mut and/or NRAS mut tumors) or 
imalumab + panitumumab (KRAS wt and NRAS wt tumors) (Arm A) or SoC per 
investigator choice (Arm B). Randomization will occur via an Interactive Response 
Technology (IRT) System until the targeted number of subjects in each treatment arm is 
achieved. For each combination in Arm A, subjects will receive imalumab at the RP2D 
determined in Part 1 for the corresponding combination. Subjects in Arm A with KRAS 
mut and/or NRAS mut tumors will receive 5-FU/LV in addition to imalumab at the RP2D 
dose determined in Part 1. Subjects in Arm A with KRAS wt and NRAS wt tumors will 
receive panitumumab in addition to imalumab at the RP2D dose determined in Part 1.
Subjects in Arm B with KRAS/NRAS mut or wt tumors will receive investigator’s choice 
(SoC, including best supportive care). If investigator’s choice is to give panitumumab, 
subjects must have KRAS wt and NRAS wt tumors. All subjects will be treated until 
disease progression, unacceptable toxicity, or withdrawal of consent.
An independent Data Safety Monitoring Board (DSMB) will review accumulating 
unblinded safety data of subjects in Part 2 on a quarterly basis. See Section 15.4.2 for 
additional details.
The effect of imalumab in combination with 5-FU/LV or panitumumab on 
tumor-associated genetic biomarkers will be monitored. Blood and urine samples will be 
collected from those subjects treated with imalumab in combination with 5-FU/LV or 
panitumumab who provide consent for this optional exploratory analysis. It is possible 
that blood/urine biomarkers may correlate with clinical outcome (safety and efficacy) in 
response to imalumab treatment.
8.2.3 Definition of Dose-Limiting Toxicity
A DLT is defined as any drug-related treatment-emergent adverse event (TEAE) (graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events [NCI CTCAE] v4.03) that occurs during the first 28 days after treatment start and 
that meets any of the following criteria:

Any ≥Grade 3 non-hematologic toxicity excluding:
a.
Mucositis/stomatitis of Grade 3 that resolves to Grade 1 or less with 
supportive measures within 7 days
b. Diarrhea of < 3 days duration following adequate and optimal therapy 


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c.
Nausea and vomiting of < 3 days duration with adequate and optimal therapy
d. Fatigue of < 7 days duration following initiation of adequate supportive care
e.
Alopecia
f.
Any single laboratory value out of the normal range that has no clinical 
significance and that resolves to ≤Grade 2 with adequate measures within 
7 days; transient Grade 3 elevations (lasting < 5 days) of hepatic 
transaminases in the absence of simultaneous increase in serum bilirubin

Any Grade 4 hematologic toxicity excluding:
a.
Grade 4 neutropenia lasting for ≤5 days and not associated with fever
b. Isolated Grade 4 lymphocytopenia without clinical correlate 

Grade 3 febrile neutropenia 

Grade 3 thrombocytopenia associated with bleeding 

Any life-threatening complication or abnormality not covered in the NCI 
CTCAE v4.03 
In subjects treated with panitumumab, if a dermatologic reaction develops that is Grade 3 
(NCI CTCAE v.4.03) or higher (or is considered intolerable), the dose modifications 
recommended in the product label will be implemented.34
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is anticipated to be approximately 21 months from study 
initiation (ie, first subject enrolled) to study completion (ie, last subject last visit). The 
recruitment period is expected to be 15 months. Study completion is estimated to occur 
when 75% of OS events have been reported.
Subject participation includes a maximum of 4 weeks for screening, and 30 (±7) days for 
post-treatment safety follow-up. Subjects will receive treatment until disease progression, 
unacceptable toxicity, or withdrawal of consent. For subjects who have stopped study 
drug or have documented disease progression, post-study telephone calls to assess OS 
will be made by site staff every 3 months.
8.4 Outcome Measures
8.4.1 Primary Outcome Measure
The primary safety outcome measure is the occurrence of DLTs (Part 1).
The primary efficacy outcome measure is PFS defined as time between treatment 
initiation and tumor progression (per RECIST v1.1 criteria) or death from any cause, with 
censoring of subjects who are lost to follow-up or withdraw consent (Part 2).


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8.4.2 Secondary Outcome Measures
8.4.2.1 Immunogenicity Outcome Measures

Occurrence of binding and/or neutralizing anti-imalumab antibodies

Incidence and severity of infusion reactions after imalumab
8.4.2.2 Safety Outcome Measures

Occurrence of SAEs and/or TEAEs, regardless of causality or relationship to 
study drug and coded according to NCI CTCAE v4.03

Other safety measurements: physical or instrumental examinations,
electrocardiograms (ECGs), vital signs, and clinically relevant changes in 
instrumental examinations or laboratory values
8.4.2.3 Efficacy Outcome Measures

Response evaluation according to RECIST v1.1

OS, defined as time from randomization to death of any cause
8.4.2.4 Pharmacokinetic Outcome Measures
Imalumab plasma PK will be characterized using a population PK modeling approach, in 
combination with data from other studies. Results of population PK modeling will be 
reported in a separate report.
8.4.2.5 Quality of Life Outcome Measures
The QoL outcome measure uses the EORTC QLQ-C30.
8.4.3 Exploratory Outcomes Measure
The exploratory PD outcome measures include plasma levels of oxMIF and total MIF.
Genetic biomarkers will also be investigated as an optional exploratory outcome.
Exploratory genetic biomarker outcome measures include tumor-associated genetic 
alterations of cfDNA in blood/urine, for subjects treated with imalumab in combination 
with 5-FU/LV or panitumumab who provide consent for these analyses. The sponsor will 
obtain available historical tumor mutational testing results for subjects.
The exploratory QoL outcome measures use the EORTC QLQ for colorectal cancer 29 
(EORTC QLQ-CR29) and the European Quality of Life – 5 Dimensions questionnaire 
(EQ-5D). The EORTC QLQ-CR29 will be used as a supplement to the EORTC 
QLQ-C30 to assess the disease-specific aspects of colorectal cancer. The EQ-5D is a 
health utility measure.


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8.5 Randomization and Blinding
This is an open-label study. In Part 2, randomization will occur to minimize bias and 
fulfill a 2:1 ratio between Arm A and Arm B. Prior to randomization, subjects will be 
stratified according to their KRAS and NRAS mutation status. Randomization will occur 
via an IRT System until the targeted number of subjects in each treatment-arm is 
achieved.
8.6 Study Stopping Rules
This study will be stopped if 1 or more of the following criteria are met:

Excessive toxicity or clinically meaningful SAE that may pose significant health 
risks

Decision by the sponsor to interrupt or terminate the study at any time for reasons 
including, but not limited to, safety or ethical issues or insufficient non-
compliance
When feasible, the sponsor will provide advance notification to the investigator of the 
impending action prior to its taking effect. The sponsor will promptly inform all other 
investigators and/or institutions conducting the study if the study is interrupted or 
terminated for safety reasons, and will also inform the regulatory authorities of the 
interruption or termination of the study and the reason(s) for the action. If required by 
applicable regulations, the investigator must inform the IEC/IRB promptly and provide 
the reason for the interruption or termination.
8.7 Investigational Product and Standard Drugs
8.7.1 Packaging, Labeling, and Storage
8.7.1.1 Imalumab
Dosage Form: Injection, solution
Packaging: Imalumab (50 mg/mL) will be supplied as a ready-for-use, sterile, 
non-pyrogenic liquid preparation in single-dose glass vials of 5 mL (with acceptable fill 
variance from 5.45 to 5.85 grams).
Labeling: The product will be labeled according to the valid regulatory requirements for 
clinical studies.
Storage: Imalumab must be stored under refrigerated conditions (2° to 8°C or 36° to 
46°F) in the original package to protect from light. Do not freeze the product. Do not use 
if expiration date is exceeded or carton is damaged.


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8.7.1.2 Leucovorin
Dosage Form: Injection, solution
Packaging: LV will be obtained from a local pharmacy by the study site.
Labeling: LV will be labeled by the manufacturer, and additional labels will be provided 
by the sponsor to denote investigational usage, if applicable.
Storage: LV must be stored in accordance to the package label.
8.7.1.3 5-Fluorouracil
Dosage Form: Injection, solution
Packaging: 5-FU will be obtained from a local pharmacy by the study site.
Labeling: 5-FU will be labeled by the manufacturer, and additional labels will be 
provided by the sponsor to denote investigational usage, if applicable.
Storage: 5-FU must be stored in accordance to the package label.
8.7.1.4 Panitumumab
Dosage Form: Injection, solution
Packaging: Commercially available panitumumab will be required for the study and will 
be sourced locally by the study site. If obtaining supplies is prohibitive, sponsor 
facilitation may be provided.
Labeling: Panitumumab will bear the label as provided by the manufacturer; however,
additional labels will be provided by the sponsor to denote investigational usage, if 
applicable.
Storage: Panitumumab must be stored in accordance to the package label.
8.7.1.5 Standard of Care (Investigator Choice)
Standard of care drugs will be obtained from a local pharmacy by the study site. The SoC 
drugs will bear the label as provided by the manufacturer and will not be re-labeled at the 
study site.


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8.7.2 Preparation and Storage of Pooled Product
8.7.2.1 Imalumab
Imalumab solution for injection must be prepared on the day of administration. The initial 
dose (in mg) will be prepared based on the subject’s body weight at screening/baseline. 
Dose (in mg) will be adjusted when a ≥10% change in the subject’s weight is observed 
(compared to the body weight currently being used for the basis of dose preparation).
Volume (ml) = [Dose (mg/kg)/Concentration (mg/mL)] x Subject Weight (kg)
Concentration (mg/mL) = 50 mg/mL
Depending on the amount of imalumab to be administered, the content of multiple vials 
of imalumab may be pooled into a syringe of appropriate size (maximum of 50 mL), and 
may require more than one syringe to be filled with imalumab.
The vials will be brought to room temperature. The flip cap is then removed from the 
study drug vial, and the exposed stopper wiped with alcohol. All imalumab preparations 
for IV injection must be prepared aseptically under a laminar flow hood and should be 
inspected visually for particulate matter and discoloration. Only clear or slightly 
opalescent, colorless to yellow to pink solutions without visible particles are to be 
administered. No dilution of imalumab is permitted. Further details regarding the 
preparation of imalumab are provided in the Pharmacy Manual.
Once prepared, the imalumab solution for injection will be kept at room temperature or, if 
not used immediately, at 2° to 8°C (36° to 46˚F). For the latter, the imalumab solution 
must be allowed sufficient time to equilibrate to room temperature prior to 
administration, noting that infusion of imalumab shall begin within 7 hours (4 hours prior 
to aspiration and 3 hours after aspiration) from when the vials are removed from storage.
Vials removed from storage to equilibrate to room temperature must not be removed 
from secondary packaging (original outer box), in order to protect product from light 
until administration.
Administration of imalumab should be performed in accordance with Section 8.7.3.1.
Do not dilute the imalumab solution with any other solutions or IV fluids unless 
agreed upon by the sponsor.


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8.7.2.2 5-Fluorouracil, Leucovorin, and Panitumumab
Fluorouracil, LV, and panitumumab will be reconstituted according to the package label 
provided by the manufacturers and according to local pharmaceutical regulations.
8.7.2.3 Standard of Care Drugs
Standard of care drugs will be reconstituted according to the package label provided by 
the manufacturers and according to local pharmaceutical regulations. Investigators will 
also respect the contraindications in the Summaries of Product Characteristics (SmPCs) 
of the comparators and give consideration to the special warnings and precautions in the 
SmPCs of comparators.
8.7.3 Administration
8.7.3.1 Imalumab
For Parts 1 and 2, once the required volume of imalumab is aspirated into a suitably sized 
syringe, the study drug will be administered via IV infusion at a flow rate between 
1.0 and 3.6 mL/min. The syringe may be hand-pushed for IV administration; 
alternatively, a syringe-driver pump may be used to actuate the syringe depending on the 
user/administrator’s comfort and/or preference. Considerations include: the amount of 
product to be infused, the size of the syringe used, the length of time to administer the 
product, and the user’s ability to deliver the product as indicated. Parameters, including 
flow rate, shall be programmed into the pump, after which infusion can begin. While a 
50 mL syringe is generally the maximum syringe size that can be loaded into a syringe 
driver pump, if additional volume is required for the administration, the emptied syringe 
can be replaced in the pump with a new syringe filled with the additionally required study
drug.
8.7.3.2 5-Fluorouracil, Leucovorin, and Panitumumab
For Parts 1 and 2, LV will be administered via IV infusion at a dose of 400 mg/m2 over 
2 hours. Immediately following LV administration, 5-FU will be administered via IV 
infusion pump at a dose of 2400 mg/m2 over 46 hours.
For Parts 1 and 2, panitumumab will be administered via IV infusion pump at a dose of 
6 mg/kg over 60 minutes (maximum of 1000 mg; if >1000 mg, infusion will occur over 
90 minutes).


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8.7.3.3 Standard of Care Drugs
Standard of care drugs will be selected by the investigator based on individual subjects’ 
needs and clinical disease course. If panitumumab is the selected SoC for subjects in 
Arm B (control arm), the subjects must not have failed prior therapy with panitumumab
or have a known history of keratitis, ulcerative keratitis or severe dry eye. Administration 
of all SoC drugs should be performed in accordance with the respective product label.
Investigators will also respect the contraindications in the SmPCs of the comparators, and 
give consideration to the special warnings and precautions in the SmPCs of comparators.
8.7.4 Description of Treatment
In both Parts 1 and 2, imalumab administration will occur QW, and 5FU/LV or 
panitumumab administration will occur Q2W in 4-week cycles. Treatment schedule for 
SoC drugs will be in accordance with the respective product label.
For all subjects in Parts 1 and 2, treatment will continue until disease progression, 
excessive toxicity, withdrawal of consent, or for any other reason as detailed in 
Section 9.3.
8.7.4.1 Part 1: Safety Run-In
Regimen 1:
Imalumab (7.5 or 10 mg/kg) will be administered (as per Section 8.7.3.1) 1 hour before
5-FU/LV (administered as per Section 8.7.3.2).
Regimen 2:
Imalumab (7.5 or 10 mg/kg) will be administered (as per Section 8.7.3.1) 1 hour before 
panitumumab (administered as per Section 8.7.3.2).
8.7.4.2 Part 2: Exploratory Phase 2a
8.7.4.2.1 Arm A
Imalumab (at the RP2D, as determined in Part 1) will be administered (as per 
Section 8.7.3.1) 1 hour before 5-FU/LV (administered as per Section 8.7.3.2) in subjects 
with KRAS mut and/or NRAS mut tumors.
Imalumab (at the RP2D, as determined in Part 1) will be administered (as per 
Section 8.7.3.1) 1 hour before panitumumab (administered as per Section 8.7.3.2) in 
subjects with KRAS wt and NRAS wt tumors.


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8.7.4.2.2 Arm B (Investigator Choice)
Standard of care will be chosen by the investigator and will be administered according to 
product label(s) and in accordance to local pharmaceutical regulations. If panitumumab is 
chosen, it will be administered as described in Section 8.7.3.2 and only in subjects with 
KRAS wt and NRAS wt tumors and in subjects who have not had prior therapy with 
panitumumab, or have a known history of keratitis, ulcerative keratitis or severe dry eye.
8.7.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the protocol and that 
the storage area is secured, with access limited to authorized study personnel. The 
investigator will maintain records that the IP(s) was received, including the date received, 
drug identity code, date of manufacture or expiration date, amount received and 
disposition. The IP(s) must be dispensed only at the study site or other suitable location 
(eg, infusion center or home, as applicable per study design). Records will be maintained 
that includes the subject identification code (SIC), dispensation date, and amount 
dispensed. All remaining partially used and/or unused IP(s) will be returned to the 
sponsor or sponsor’s representative after study completion/termination, or destroyed with 
the permission of the sponsor in accordance with applicable laws and study site 
procedures. If IP(s) is to be destroyed, the investigator will provide documentation in 
accordance with sponsor’s specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise the following: 
hospital records, medical records, clinical and office charts, laboratory notes, 
memoranda, subjects' diaries or evaluation checklists, outcomes reported by subjects, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories and at medico-technical departments involved in 
the clinical study.
In this trial, no source data will be entered directly onto the case report forms (CRFs).
For additional information on study documentation and CRFs, see Section 17.2.


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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Provision of a signed informed consent
2. Male and female subjects 18 years of age and older at the time of screening
3. Subjects who progressed after receiving at least 2, but no more than 3, prior cancer 
drug therapy treatment lines including SoC in the metastatic setting
4. Anticipated life expectancy >3 months at the time of screening
5. Weight between 40 kg and 180 kg
6. Histologically or cytologically confirmed diagnosis of CRC 
7. Metastatic CRC not amenable to surgical resection
8. Known KRAS, NRAS mutation status (if unknown status for either of these genes,
and no archival tissue is available, a fresh tumor biopsy will be obtained)
9. At least 1 measurable lesion as defined by RECIST v1.1 
10. ECOG PS of 0-2
11. Adequate hematological function, defined as: 
a.
Platelet count ≥100,000/µL
b.
Prothrombin time and activated partial thromboplastin time (aPTT) 
< 1.5 times the upper limit of normal (ULN) 
c.
Absolute neutrophil count (ANC) ≥1000/µL
d.
Hemoglobin ≥9 g/dL, without the need for transfusion in the 2 weeks prior 
to screening
12. Adequate renal function, defined as serum creatinine ≤2.0 times ULN and 
creatinine clearance > 50 mL/min or estimated glomerular filtration rate
> 50 ml/min/1.73 m2
13. Adequate liver function, defined as:
a.
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 times ULN for subjects without liver metastases, or ≤5 times ULN in 
the presence of liver metastases
b.
Bilirubin ≤2.0 times ULN, unless subject has known Gilbert’s syndrome 
14. Adequate venous access


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15. For female subjects of childbearing potential, the subject presents with a negative 
serum pregnancy test at screening and agrees to employ 2 forms of adequate birth 
control measures, including at least 1 barrier method (eg, diaphragm with 
spermicidal jelly or foam, or [for male partner] condom) throughout the course of 
the study and for at least 90 days after the last administration of imalumab. In 
addition, these birth control methods must be continued for at least 180 days after 
last administration of 5-FU in subjects who receive this treatment. Secondary
contraceptive measures could be either birth control pills, patches, or intrauterine 
devices
16. For male subjects, they must agree to use adequate contraceptive measures 
including at least 1 barrier method (eg, condom with spermicidal jelly or foam 
and [for the female partner] diaphragm with spermicidal jelly or foam, birth 
control pills/patches, or intrauterine device) and abstain from sperm donation 
throughout the course of the study and for at least 90 days after the last 
administration of imalumab. In addition, these birth control methods must be 
continued for at least 180 days after last administration of 5-FU in subjects who 
receive this treatment
17. Subject is willing and able to comply with the requirements of the protocol.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. Known central nervous system metastases
2.Prior malignancy(s) within the past 3 years, with the exception of curatively treated 
basal or squamous cell carcinoma of the skin, locally advanced prostate cancer, 
ductal carcinoma in situ of breast, in situ cervical carcinoma and superficial bladder 
cancer
3.Prior treatment with panitumumab for subjects with KRAS wt and NRAS wt 
tumors
4. Known history of keratitis, ulcerative keratitis, or severe dry eye in subjects with 
KRAS wt and NRAS wt tumors
5. Residual AE from previous treatment > Grade 1, except neuropathy and alopecia
6. Prior intolerance to fluoropyrimidine for subjects with KRAS mut and/or 
NRAS mut tumors


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7. Myocardial infarction within 6 months prior to C1D1, and/or prior diagnoses of 
congestive heart failure (New York Heart Association Class III or IV), unstable 
angina, unstable cardiac arrhythmia requiring medication; and/or the subject is at 
risk for polymorphic ventricular tachycardia (eg, hypokalemia, family history, or 
long QT syndrome)
8. Uncontrolled hypertension, defined as systolic blood pressure ≥160 mmHg and/or 
diastolic blood pressure ≥100 mmHg confirmed upon repeated measures
9. LVEF < 40% as determined by echocardiogram (ECHO)/multigated acquisition 
scan (MUGA) performed at screening or within 90 days prior to C1D1
10. QT/QTc interval > 450 msec, as determined by screening ECG performed no 
earlier than 1 week before C1D1
11. Prior anti-tumor therapy (chemotherapy, radiotherapy, antibody therapy, 
molecular targeted therapy, retinoid therapy or hormonal therapy) within 4 weeks
(< 28 days) prior to C1D1
12. Major surgery within 4 weeks (< 28 days) prior to C1D1
13. Active joint inflammation or history of inflammatory arthritis or other immune 
disorder involving joints (osteoarthritis is not exclusionary)
14. Active infection involving IV antibiotics within 2 weeks prior to C1D1
15. Known history of or active hepatitis B virus (HBV) and/or hepatitis C virus 
(HCV), or active tuberculosis
16. Known history of human immunodeficiency virus (HIV) type 1/2 or other 
immunodeficiency disease
17. Subject has received a live vaccine within 4 weeks (< 28 days) prior to C1D1
18. Known hypersensitivity to any component of recombinant protein production by 
CHO cells 
19. Exposure to an investigational product or investigational device in another clinical 
study within 4 weeks (< 28 days) prior to C1D1, or is scheduled to participate in 
another clinical study involving an investigational product or device during the 
course of this study 
20. Subject is breastfeeding or intends to begin breastfeeding during the course of the 
study 
21. Any disorder or disease, or clinically significant abnormality on laboratory or 
other clinical test(s) (eg, blood tests, ECG), that in medical judgment of the 
investigator may impede the subject’s participation in the study, pose increased 
risk to the subject, and/or confound the results of the study 
22. Subject is a family member or employee of the investigator


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9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (ie, reduce the degree of participation in the study) 
consent for continued participation and data collection. The reason for withdrawal will be 
recorded on the End of Study CRF. Assessments to be performed at the termination visit 
(including in cases of withdraw or discontinuation) are described in Section 10.3.3.8 and 
Section 20.2.
Discontinuation (ie, complete withdrawal from study participation) may be due to 
dropout (ie, active discontinuation by subject) or loss to follow-up (ie, discontinuation by 
subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject. 
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:

Disease progression according to RECIST v1.1

Clinical progression due to the subject’s underlying malignancy

Excessive toxicity

Intercurrent illness unrelated to the subject’s underlying malignancy that prevents 
further participation

The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post-delivery, if feasible. The investigator will record a narrative description of 
the course of the pregnancy and its outcome.

The subject begins lactating. IP exposure will be discontinued. The investigator 
will record a narrative description of the course of the baby’s development. 

Participation in another clinical study involving an investigational product during 
the course of the study.

Protocol non-compliance

Subject withdrawal of consent

Study closure or termination by the sponsor

Use of prohibited therapies (see protocol Section 10.4)


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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any subject who provides informed consent (ie, signs and dates the informed consent 
form and assent form, if applicable) is considered enrolled in the study.
10.2 Subject Identification Code
The SIC will comprise the following series of numbers: protocol identifier (eg, 391401) 
to be provided by the sponsor, 2- or 3-digit number study site number (eg, 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (eg, 0003) reflecting the order 
of enrollment (ie, signing the informed consent form). For example, the third subject who 
signed an informed consent form at study site 02 will be identified as 
Subject 391401-020003. All study documents (eg, CRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) will be permitted as long as it does not contain a combination of 
information that allows identification of a subject (eg, collection of a subject’s initials and 
birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining an enrollment/screening log that includes all 
subjects enrolled. The log also will serve to document the reason for screening failure. 
All screening data will be collected and reported in CRFs, regardless of screening 
outcome. If a subject is re-screened, the End of Study CRF should be completed, and a 
new ICF, new SIC, and new CRF will be required for that subject. At re-screening, 
results from assessments that were conducted within the previous 21 days can be reused, 
to avoid repetition of numerous Screening assessments.
The overall study design is illustrated in Figure 2. Details on the procedures to be 
performed at each study visit, including screening, can be found in Supplement 20.2,
Schedule of Study Procedures and Assessments.
10.3.1 Screening Assessments
After informed consent has been obtained, subjects will be screened on-site for eligibility 
based on the inclusion and exclusion criteria defined in Section 9.1 and Section 9.2, 
respectively. Screening procedures must be performed within 28 days prior to first 
imalumab administration (C1D1).


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Screening assessments include the following:

Eligibility evaluation (review of inclusion/exclusion criteria and completion of the 
required eligibility form)

Demographics (date of birth, gender, race, and ethnicity)

Relevant medical and surgical history

Vital signs (body temperature, heart rate, blood pressure, respiratory rate, and 
weight)

Physical examination

ECOG PS

12-lead ECG

ECHO/MUGA

Clinical laboratory assessments (hematology, serum chemistry, and coagulation)

Urinalysis

Serum pregnancy test for women of childbearing potential

Genetic testing (for KRAS and NRAS tumor status)

CT or MRI scans for tumor measurement (as assessed by RECIST v1.1), unless 
results from CT or MRI scans performed within 28 days prior to first imalumab 
administration (C1D1), are available

Blood sample for immunogenicity (anti-drug antibody [ADA] and neutralizing 
anti-drug antibody [NADA])

Blood sample for PK assessment

Blood sample for PD biomarkers (oxMIF and total MIF)

Blood sample for cfDNA (genetic biomarkers)

Urine sample for cfDNA (genetic biomarkers)

Collection of AEs

Review of concomitant medications/non-drug therapies

Entry into IRT System
See the Schedule of Study Procedures and Assessments (Table 3) for additional details on 
screening assessments.


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10.3.2 Baseline Assessments (Cycle 1 Day 1, Predose)
At the baseline visit (C1D1), subject eligibility will be confirmed and all questionnaires 
will be completed prior to the start of any assessments. The following baseline 
assessments will be performed for all subjects prior to dosing:

EORTC QLQ-C30

EORTC QLQ-CR29

EQ-5D

Vital signs (body temperature, heart rate, blood pressure, respiratory rate, weight, 
and height; recorded within 30 minutes prior to start of treatment)

Physical examination

ECOG PS

12-lead ECG

Clinical laboratory assessments (hematology, serum chemistry, and coagulation). 
Immediately prior to Cycle 1, laboratory assessments can be performed either on 
Day -1 or on Day 1 predose

Urine dipstick test for women of childbearing potential

Urinalysis

For subjects receiving imalumab treatment, blood samples for PK (imalumab 
plasma levels) and PD biomarkers (oxMIF and total MIF) are to be collected at 
any time on Day 1 prior to infusion (see Table 6).

Collection of AEs

Review of concomitant medications/non-drug therapies

Entry into IRT System for randomization
See the Schedules of Study Procedures and Assessments (Table 3, Table 4, and Table 5) 
for additional details on baseline (Day 1, predose) assessments.
10.3.3 Treatment Cycles
After all baseline assessments have been completed, subjects will begin treatment 
Cycle 1 with administration of their first dose of imalumab. Subjects will receive 
imalumab QW on Days 1, 8, 15, and 22 as part of a 4-week/28-day treatment cycle. A 
new cycle should begin after every 28-day period (ie, 4 weeks). For all subjects, 
treatment will continue until disease progression, unacceptable toxicity, withdrawal of 
consent, or for any other reason as detailed in Section 9.3.


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10.3.3.1 Study Drug Administration
All study drug administrations will take place at the study site or a qualified facility with 
medical supervision (such as an infusion center) where a subject’s safety can be 
monitored during and following administration. All study drugs must be administered by 
a qualified healthcare professional (see Section 8.7.3 for additional details).
At any time during the study, any of the study drugs may be interrupted or discontinued 
at the discretion of the investigator based on his/her evaluation of the subject’s condition 
or safety. If treatment with 5-FU/LV or panitumumab is interrupted due to an AE, and 
there are no concurrent safety concerns regarding imalumab, treatment with imalumab 
may be continued while treatment with 5-FU/LV or panitumumab is interrupted.
No dose modification is planned for this study, with the exception of the dose 
modifications referred to in Section 8.2.3 for subjects treated with panitumumab who 
develop dermatologic reactions Grade 3 (CTCAE v.4.03) or higher, or considered 
intolerable.
Any injection site reactions, regardless of causality, will be recorded on the AE CRF. 
Any concomitant medications, including those used to treat AE(s), will be recorded on 
the appropriate CRF.
The use of an indwelling catheter to withdraw blood samples is permitted, in particular 
on the days of intensive blood sampling. When blood sample collection occurs within 
24 hours following study drug administration, the blood sample should not be collected 
from the same side used for study drug injection.
All study drugs should be prepared on the day of administration, as described in 
Section 8.7.2 and Section 8.7.3.
For each study drug administration, the following information will be captured in the 
appropriate CRF(s):

Planned dose

Date and start and end times of imalumab injection

Actual volume injected

Time of interruption, restart, or discontinuation, as applicable

Volume injected at the time of interruption or discontinuation, as applicable

Reason(s) for interruption or discontinuation, if applicable

Any AE(s), if applicable


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
Use of any medications/non-drug therapies including those used to treat AE(s), if 
applicable.
10.3.3.1.1 Imalumab Administration
Considering the limited experience of imalumab in humans at the time of this study’s 
commencement, subjects should remain on-site for at least 8 hours following the first 
imalumab administration, for safety monitoring with medical supervision. During the 
Safety Run-in, subjects should remain on-site for safety monitoring for at least 2 hours 
following imalumab administration on Day 8 and Day 15 of Cycle 1 (applicable to all 
subjects).
Injection-related reactions that have been observed with other monoclonal antibodies 
administered by IV injection include: allergic reactions (eg, hives or itching), 
influenza-like symptoms, nausea, diarrhea, and skin rashes. Injection-related reactions 
should be managed according to guidance provided in Table 1.
Table 1
Study 391401: Management of Imalumab Injection-Related Reactions
NCI CTCAE Grade
Guidance for Management of Reaction
Grade 1 (Mild, transient reactions not requiring 
treatment with medication)
The injection may be interrupted until resolution of 
symptoms at the discretion of the investigator. If the 
injection is interrupted, upon symptom resolution 
the injection may be resumed as tolerated. 
Grade 2 (Prolonged response or recurrence after 
symptomatic medication)
The injection is to be interrupted, and treatment 
with symptomatic medications initiated (eg, 
antihistamines, antipyretics, narcotics, IV fluids). 
Upon resolution of symptoms, the injection may be 
resumed at the discretion of the investigator.
Grade 3 (Not rapidly responsive to symptomatic 
medications; subject is hospitalized)
Imalumab administration is to be discontinued, and 
the subject should be administered best supportive 
care. In addition, the investigator should contact the 
sponsor to discuss appropriate follow-up testing.
Grade 4 (Life-threatening consequences; urgent 
intervention indicated)
Abbreviations: IV=intravenous; NCI CTCAE=National Cancer Institute Common Terminology Criteria 
for Adverse Events.
A kit containing supplies suitable for emergency treatment of anaphylactic reactions and 
personnel with appropriate expertise/training in administering basic life support and in 
the management of hypersensitivity reactions must be readily accessible on-site during all 
imalumab administrations.


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10.3.3.1.2 5-Fluorouracil, Leucovorin, Panitumumab, and Standard of Care 
Administration
Treatments will be administered in accordance with the respective drug’s product label. If 
panitumumab is the selected SoC for subjects in Arm B (control arm), the subjects must 
not have had prior therapy with panitumumab or have a known history of keratitis, 
ulcerative keratitis or severe dry eye. Investigators should advise subjects to minimize 
their exposure to ultraviolet light (sunlight) following treatment with 5-FU or 
panitumumab.
10.3.3.2 Day 1 of Each Cycle
On Day 1 of each treatment cycle in both Parts 1 and 2 of the study (unless otherwise 
depicted below), the assessments/treatment administrations listed below will occur. At 
baseline, ie, C1D1, the predose assessments described in Section 10.3.2 should be 
conducted before proceeding with the first administration of study drug.
Prior to administration of study drug:

Vital signs (including body temperature, heart rate, blood pressure, respiratory 
rate, and weight; recorded within 30 minutes prior to start of treatment)

Physical examination

ECOG PS

12-lead ECG

Clinical laboratory assessments (hematology, serum chemistry, and coagulation)

Urine dipstick test for women of childbearing potential

Urinalysis

For subjects receiving imalumab treatment, blood samples for PK (imalumab
plasma levels) and PD biomarkers (oxMIF and total MIF) are to be collected -2 to 
0 h predose (see Table 6).

Collection of AEs

Review of concomitant medications/non-drug therapies

Entry into IRT System (Part 1: all subject visits; Part 2: Arm A subject visits 
only)
Administration of study treatment(s):

Imalumab administration:

Part 1: all subjects

Part 2: subjects in Arm A


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
5-FU/LV or panitumumab administration:

Part 1: Subjects with KRAS mut and/or NRAS mut tumors will receive 
5-FU/LV, and subjects with KRAS wt and NRAS wt tumors will receive 
panitumumab.

Part 2: In Arm A (5-FU/LV), subjects with KRAS mut and/or NRAS mut 
tumors will receive 5-FU/LV, and subjects with KRAS wt and NRAS wt 
tumors will receive panitumumab.

SoC administration:

Part 2, Arm B: For SoC, drug dose and schedule to be given in 
accordance with product label.
Following administration of study treatment:

On Day 1 of each cycle:

Vital signs measurement should be recorded within 30 minutes of 
completion of the imalumab injection

On Day 1 of first cycle only:

For subjects receiving imalumab treatment, blood samples for PK 
(imalumab plasma levels) and PD biomarkers (oxMIF and total MIF) are 
collected at 0 to 2 h postdose and 6 to 8 h postdose (see Table 6).

12-lead ECG, 2 (± 1) h postdose

Following the first imalumab administration, subjects should remain at 
the study site for at least 8 hours, for safety monitoring with medical 
supervision. Upon leaving the site following the first imalumab
administration, subjects should remain in close proximity to medical care 
until completion of the Day 2 study visit.

On Day 1 of each subsequent treatment cycle:

For subjects receiving imalumab treatment, blood samples for PK 
(imalumab plasma levels) and PD biomarkers (oxMIF and total MIF) are 
collected at 0 to 2 h postdose (see Table 6).

On Day 2 or Day 4 of first cycle only:

On Day 2 (24 ± 4 h post first dose) OR Day 4 (72 ± 8 h post first dose):
blood draw for the determination of levels of free oxMIF and free total 
MIF (see Table 6)
10.3.3.3 Day 8 of Each Cycle
On Day 8 of each treatment cycle in both Parts 1 and 2 of the study (unless otherwise 
depicted below), the following assessments/treatment administrations will occur:


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Prior to administration of study drug:

Vital signs (including body temperature, heart rate, blood pressure, respiratory 
rate, and weight; recorded within 30 minutes prior to start of treatment)

Clinical laboratory assessments:

Cycle 1 only: hematology, serum chemistry, and coagulation

All subsequent cycles: hematology

Collection of AEs

Review of concomitant medications/ non-drug therapies

Entry into IRT System (Part 1: all subject visits; Part 2: Arm A subject visits 
only)

On Day 8 of Cycle 1 only:

For subjects receiving imalumab treatment, blood samples for PK 
(imalumab plasma levels) and PD biomarkers (oxMIF and total MIF) are 
collected -2 to 0 h predose (see Table 6).
Administration of study treatment(s):

Imalumab administration:

Part 1: all subjects

Part 2: subjects in Arm A

SoC administration (if applicable):

Part 2, Arm B: For SoC, drug dose and schedule to be given in 
accordance with product label.
Following administration of study treatment:

Vital signs measurement should be recorded within 30 minutes of completion of 
the imalumab injection

On Day 8 of Cycle 1 only:

For subjects receiving imalumab treatment, blood samples for PK 
(imalumab plasma levels) and PD biomarkers (oxMIF and total MIF) are 
collected 0 to 2 h postdose (see Table 6).
10.3.3.4 Day 15 of Each Cycle
On Day 15 of each treatment cycle in both Parts 1 and 2 of the study (unless otherwise 
depicted below), the following assessments/treatment administrations will occur:


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Prior to administration of study drug:

Vital signs (including body temperature, heart rate, blood pressure, respiratory 
rate, and weight; recorded within 30 minutes prior to start of treatment)

Physical examination

Clinical laboratory assessments (hematology, serum chemistry, and coagulation)

Collection of AEs

Review of concomitant medications/ non-drug therapies

Entry into IRT System (Part 1: all subject visits; Part 2: Arm A subject visits 
only)

On Day 15 of Cycle 1 only:

For subjects receiving imalumab treatment, blood samples for PK 
(imalumab plasma levels) and PD biomarkers (oxMIF and total MIF) are 
collected -2 to 0 h predose (see Table 6).
Administration of study treatment(s):

Imalumab administration:

Part 1: all subjects

Part 2: subjects in Arm A

5-FU/LV or panitumumab administration:

Part 1: Subjects with KRAS mut and/or NRAS mut tumors will receive 
5--FU/LV, and subjects with KRAS wt and NRAS wt tumors will receive 
panitumumab.

Part 2: In Arm A (5-FU/LV), subjects with KRAS mut and/or NRAS mut 
tumors will receive 5-FU/LV, and subjects with KRAS wt and NRAS wt 
tumors will receive panitumumab

SoC administration (if applicable)

Part 2, Arm B: For SoC, drug dose and schedule to be given in 
accordance with product label.
Following administration of study treatment:

Vital sign measurements should be recorded within 30 minutes of completion of 
the imalumab injection

On Day 15 of Cycle 1 only:

For subjects receiving imalumab treatment, blood samples for PK 
(imalumab plasma levels) and PD biomarkers (oxMIF and total MIF) are 
collected 0 to 2 h postdose (see Table 6).


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10.3.3.5 Day 22 of Each Cycle
On Day 22 of each treatment cycle in both Parts 1 and 2 of the study (unless otherwise 
depicted below), the following assessments/treatment administrations will occur:
Prior to administration of study drug:

Vital signs (including body temperature, heart rate, blood pressure, respiratory 
rate, and weight; recorded within 30 minutes prior to start of treatment)

Clinical laboratory assessments (hematology only)

Collection of AEs

Review of concomitant medications/ non-drug therapies

Entry into IRT System (Part 1: all subject visits; Part 2: Arm A subject visits 
only)

On Day 22 of Cycle 1 only:

For subjects receiving imalumab treatment, blood samples for PK 
(imalumab plasma levels) and PD biomarkers (oxMIF and total MIF) are 
collected -2 to 0 h predose (see Table 6).
Administration of study treatment(s):

Imalumab administration:

Part 1: all subjects

Part 2: subjects in Arm A

SoC administration (if applicable, for subjects receiving 4-week treatment cycles 
only):

Part 2, Arm B: For SoC, drug dose and schedule to be given in 
accordance with product label.
Following administration of study treatment:

Vital sign measurements should be recorded within 30 minutes of completion of 
the imalumab injection

On Day 22 of Cycle 1 only:

For subjects receiving imalumab treatment, blood samples for PK 
(imalumab plasma levels) and PD biomarkers (oxMIF and total MIF) are 
collected 0 to 2 h postdose (see Table 6).
10.3.3.6 Day 28 (Cycle 1 and then Every Other Cycle)

Blood sample for cfDNA (genetic biomarkers)

Urine sample for cfDNA (genetic biomarkers)


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Blood/urine samples will be collected according to the schedule outlined in Table 3, from 
those subjects treated with imalumab in combination with 5-FU/LV or panitumumab who
provide consent for this optional exploratory analysis. This sampling will start on in 
Cycle 1 (Day 28) and will then be repeated every other cycle, ie, Cycle 3 (Day 28), 
Cycle 5 (Day 28), Cycle 7 (Day 28), etc.
10.3.3.7 Day 28 (Cycle 2 and then Every Other Cycle)

CT or MRI scans for tumor measurement (as assessed by RECIST v1.1)
During treatment, scans will be conducted from Cycle 2 (Day 28) and then be repeated 
every other cycle, ie, Cycle 4 (Day 28), Cycle 6 (Day 28), etc. Tumor measurements by 
CT or MRI scans will be conducted every 8 weeks in subjects receiving SoC in 3-weekly 
treatment cycles (the study day of this assessment will vary from cycle to cycle; see 
Table 5).
10.3.3.8 End of Study/Early Termination Visit
Subjects who experience disease progression or who discontinue early from the study 
will be asked to undergo an End of Study/Early Termination visit. All questionnaires will 
be completed prior to the start of any assessments.
The following assessments will be performed at this visit:

EORTC QLQ-C30

EORTC QLQ-CR29

EQ-5D

Vital signs (body temperature, heart rate, blood pressure, respiratory rate, and 
weight)

Physical examination

ECOG PS

12-lead ECG

Clinical laboratory assessments (hematology, serum chemistry, and coagulation)

Urine dipstick test for women of childbearing potential

Urinalysis

CT or MRI scans for tumor measurement (as assessed by RECIST v1.1), if no 
disease progression was confirmed previously and this visit occurs > 4 weeks 
after the last scan; no additional scans will be required if disease progression is 
confirmed at this visit.


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
For subjects treated with imalumab, blood sample for immunogenicity (ADA 
and NADA)

For subjects treated with imalumab, blood sample for cfDNA (genetic 
biomarkers)

For subjects treated with imalumab, urine sample for cfDNA (genetic 
biomarkers)

Collection of AEs

Review of concomitant medications/non-drug therapies

Entry into IRT System
10.3.3.9 Safety Follow-Up Visit
Following the End of Study/Early Termination visit, subjects will undergo a Safety 
Follow-up visit within 30 (±7) days after the last dose of study treatment. All 
questionnaires will be completed prior to the start of any assessments. The following 
assessments will be performed at this visit:

EORTC QLQ-C30

EORTC QLQ-CR29

EQ-5D

Vital signs (body temperature, heart rate, blood pressure, respiratory rate, and 
weight)

Physical examination

ECOG PS

12-lead ECG

Clinical laboratory assessments (hematology, serum chemistry, and coagulation)

Urine dipstick test for women of childbearing potential

Urinalysis

If no disease progression was confirmed previously and this visit occurs 
> 4 weeks after the last scan, CT or MRI scan for tumor measurement as 
assessed by RECIST v1.1

For subjects treated with imalumab, blood sample for immunogenicity (ADA 
and NADA)

Collection of AEs

Review of concomitant medications/non-drug therapies


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10.3.3.10 Survival Follow-Up (Post Therapy)
For subjects who have stopped study drug or have documented disease progression, 
post-study telephone calls to assess OS will be made by site staff every 3 months.
10.4 Medications and Non-Drug Therapies
During the study, subjects are expected to be on concomitant medication(s) if they are
given treatment for any underlying medical conditions, provided the medications are not 
anticancer therapies. Subjects may take additional concomitant medication(s) as needed 
for medical management during this study. If growth factor medications are to be 
administered, they should be used in accordance with local best practice. All concomitant 
medication use should be recorded.
The following medications and non-drug therapies are not permitted within 4 weeks
(< 28 days) prior to study drug administration and during the course of the study:

Medications:

Antitumor therapy, including chemotherapy, radiotherapy, antibody therapy, 
molecular targeted therapy, retinoid therapy, or hormonal therapy

Brivudin, sorivudine, and other nucleoside analogues must be avoided in 
subjects who receive treatment with 5-FU

Live vaccines must be avoided for 6 weeks following last dose of imalumab

Other investigational product

Non-drug therapies:

Major surgery

Investigational device
The following medications are not permitted within 4 weeks (< 28 days) prior to C1D1
and during the course of the study:

Live vaccines
A subject who has taken any of these medications or received any of these non-drug 
therapies must be discontinued.
10.5 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have, completed all 
study procedures according with the protocol (with or without protocol deviations).


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Reasons for completion or discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (eg, death), 
discontinuation by subject (eg, lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (eg, pregnancy, progressive 
disease, non-compliance with IP/protocol violation(s), recovery), study terminated by 
sponsor, or other (reason to be specified by the investigator, eg, technical problems). 
Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study 
completion/termination visit. If the completion/termination visit is done as an additional, 
unscheduled visit, the assessment results shall be recorded with the 
completion/termination visit. If a subject terminates participation in the study and does 
not return for the completion/termination visit, their last recorded assessments shall 
remain recorded with their last visit. The reason for discontinuation will be recorded, and 
the data collected up to the time of discontinuation will be used in the analysis and 
included in the clinical study report. If additional assessments are required, the 
assessments shall be recorded separately. Assessments to be performed at the termination 
visit (including in cases of withdraw or discontinuation) can be found in Section 20.2
Schedule of Study Procedures and Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.6 Procedures for Monitoring Subject Compliance
All study procedures are to be performed under the direct supervision of the 
investigator/a licensed healthcare professional at the study site, and thus, no separate 
procedures will be used to monitor subject compliance.
11. ASSESSMENT OF EFFICACY, PHARMACOKINETICS, 
PHARMACODYNAMICS, AND GENETIC TESTING
11.1 Plasma Imalumab, oxMIF, and Total MIF
Blood samples (8 mL per sample) for the assessment of plasma imalumab concentrations, 
oxMIF levels, and total MIF levels in systemic circulation will be prepared from blood 


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collected into tubes containing sodium citrate (anticoagulant) according to the schedule 
detailed in Section 10.3 and Table 3. A total of 10 samples (80 mL of blood in total) will 
be collected in Cycle 1, and 2 samples (16 mL of blood in total) will be collected in each 
subsequent cycle, from each subject for these measurements. When blood sample 
collection occurs within 24 hours following imalumab administration, the blood sample 
should not be collected from the same arm used for imalumab injection. Blood samples 
are to be processed according to directions provided in the laboratory manual. Each 
plasma sample (approximately 1 mL each for imalumab PK, oxMIF, and total MIF) will 
be split into duplicate aliquots.
The exact date and clock time of collection of each blood sample should be collected on 
the electronic case report form (eCRF). Additionally, the exact date and time, and 
relevant dosing details of each imalumab dose administered during Cycle 1 should be 
collected on the eCRF.
11.2 Antitumor Effect – Solid Tumors
In this study, tumor response will be evaluated using RECIST v1.1. Tumor measurements 
are to be obtained for objective tumor assessment at baseline and on Day 28 of every 
second treatment cycle (ie, every 8 weeks), as detailed in Section 10.3, Table 3 and 
Table 4. Tumor measurements by CT or MRI scans will be conducted every 8 weeks in 
subjects receiving SoC in 3-weekly treatment cycles (the study day of this assessment 
will vary from cycle to cycle; see Table 5). A tumor measurement should be obtained at 
the End of Study/Early Termination visit, if no disease progression was confirmed 
previously and this visit occurs > 4 weeks after the last scan; no additional scans will be 
required if disease progression is confirmed at this visit. A tumor measurement should be 
obtained at the Safety Follow-up visit, if no disease progression was confirmed 
previously and this visit occurs > 4 weeks after the last scan.
For an individual subject, the method (CT and/or MRI scan) used to measure tumor 
burden at baseline should be used for each subsequent tumor assessment. Baseline tumor 
measurements and identification of target lesions may be based on imaging obtained 
within 28 days prior to first imalumab administration (C1D1). Scheduled tumor response 
assessments must be interpreted prior to the start of the next treatment cycle. A subject’s 
best overall response will be determined at the End of Study/Early Termination Visit.
11.3 Genetic Testing
Genetic testing for KRAS/NRAS mutation status will be performed at screening. If not 
readily available, genetic testing for KRAS/NRAS mutation status needs to be done early 


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enough to allow randomization within 4 weeks. If KRAS mutation status is known, the 
subject can start treatment while NRAS testing is pending.
Dosing regimen for Part 1 is dependent on KRAS/NRAS mutation status. Subjects who 
are determined to have tumors with KRAS mut, NRAS mut, or both mutations will be 
assigned to the combination therapy of 5-FU/LV and imalumab. Subjects who are 
determined to have KRAS wt and NRAS wt tumors will be assigned to the combination 
therapy of panitumumab and imalumab.
In Part 2 of the trial, subjects will be stratified according to their KRAS/NRAS mutation 
status and then randomized to Arms A or B in a 2:1 ratio.
11.4 Tumor-Associated Biomarkers
Tumor-associated genetic alterations in blood and urine (for subjects treated with 
imalumab in combination with 5-FU/LV or panitumumab who provide consent for 
optional exploratory biomarker analyses) will be assessed. Genetic changes of cfDNA 
using whole exome sequencing, targeted NGS strategy or qPCR on a bi-monthly basis 
will at least cover the genes, such as but not limited to, KRAS, NRAS, APC, p53, BRAF, 
PIK3CA, since mutations in these genes have been identified as driver mutations in 
mCRC and/or are responsible for resistance to anti-EGFR therapy. However, in order to 
identify imalumab-specific patterns of genetic tumor adaption, a larger panel of cancer-
related genes will be analyzed.
Blood samples (10 mL) and urine samples (30 mL) for the assessment of genetic 
biomarkers (cfDNA) will be collected according to the schedule presented in Table 3. 
Blood and urine samples are to be processed and frozen according to directions provided 
in the separate laboratory manual. The exact date and clock time of collection of each 
blood and urine sample should be collected on the eCRF.
The sponsor will obtain available historical tumor mutational testing results for subjects.
12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered an IP 
that does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and unintended sign (eg, an abnormal laboratory finding), 
symptom (eg, rash, pain, discomfort, fever, dizziness, etc.), intercurrent disease (eg, 


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peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of 
an IP, whether or not considered causally related to the IP.
Each Grade 3 or Grade 4 abnormal laboratory value will be reported as an AE, unless the 
abnormal value relates to a diagnosis that is itself recorded as an AE or has no clinical 
correlate. 
Events relating to clinical deterioration due to disease progression as a result of the 
underlying malignancy are not to be considered or analyzed as AEs (or SAEs), but will 
be recorded on the CRF.
A TEAE is defined as any event not present prior to the initiation of the treatments or any 
event already present that worsens in either intensity or frequency following exposure to 
the treatments.
12.1.1.1 Serious Adverse Event
A serious adverse event (SAE) is defined as an untoward medical occurrence that at any 
dose meets one or more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the 
judgment of the investigator, at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death had it been more 
severe

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay

Results in persistent or significant disability/incapacity (ie, a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the definitions above


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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 drug dependence or drug abuse

Reviewed and confirmed seroconversion for HIV, hepatitis A virus (HAV), HBV, 
HCV, hepatitis E virus (HEV), or parvovirus B19 (B19V)

Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an (S)AE; however, any pregnancy complication or pregnancy 
termination by therapeutic, elective, or spontaneous abortion shall be considered 
an SAE
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment (ie, including active comparators) that 
is both serious and unexpected.
The event(s) must meet all of the following

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
Once determined to meet the criteria for a SUSAR, an SAE should be submitted to 
regulatory agencies expeditiously.
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (RSI) (eg, IB, package insert). The expectedness of AEs will be determined 
by the sponsor using the IB as the RSI. This determination will include considerations 
such as the number of AEs previously observed, but not on the basis of what might be 
anticipated from the pharmacological properties of a medicinal product.
For the purposes of this study, all AEs experienced by a subject, including unexpected 
AEs, will be recorded on the AE CRF.


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12.1.1.5 Preexisting Diseases
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure, will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described on 
the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, each non-serious untoward medical occurrence 
experienced by a subject undergoing study-related procedure(s) before first exposure to 
IP will be recorded on the AE CRF; however, these events will not be considered as AEs 
and will not be included in the analysis of AEs.
Each TEAE (non-serious AE or SAE) from the first IP exposure until study 
completion/discontinuation or 30 days (±7 days) following the last IP treatment will be 
described on the AE CRF using the medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
expressions (see definition in Section 12.1). Each AE will be evaluated by the 
investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2.
For each AE, the outcome (ie, recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (ie, dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, or unknown) will also be recorded on the AE 
CRF. Recovering/resolving AEs will be followed until resolution, medically stabilized, or 
30 days after the last IP administration, whichever comes first. If the severity rating for 
an ongoing AE changes before the event resolves, the original AE report will be revised 
(ie, the event will not be reported as separate AE). During the course of any AE, the 
highest severity rating will be reported.
Deviations from the protocol-specified dosage (including overdosing [any dose that is at 
least 20% higher than the highest explored dose level], underdosing [any dose that is 
lower than the intended explored dose level by 10%], abuse, and withdrawal [see 


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Section 9.3]), treatment errors (including incorrect route of administration, use of an 
incorrect product, and deviations from the protocol-defined dosing schedule), failures of 
expected pharmacological actions, and unexpected therapeutic or clinical benefits will be 
followed with regard to occurrence of AEs, lack of efficacy, and/or other observations 
because these events may be reportable to regulatory authorities.
Any pregnancy of the subject or partner that is confirmed within 90 days after 
administration of imalumab will be reported on a Pregnancy Form and followed up at 
estimated date of delivery and 1 year postdelivery, if feasible.
If an investigator becomes aware of an SAE occurring in a subject after study 
completion, the SAE must be reported on the provided Serious Adverse Event Report 
(SAER) Form within 24 hours after awareness; no additional reporting on CRFs is 
necessary.
12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the NCI CTCAE v4.03. In the event an AE is not described in the 
NCI CTCAE v4.03, the severity grades will be mapped to the following terms:
Table 2
Mapping Conventions for AE Severity (For AEs Not Described Within NCI CTCAE)
NCI CTCAE Grade
Corresponding AE Severity
(if Not Provided in NCI CTCAE)
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated
Grade 2
Moderate; minimal, local, or noninvasive 
intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)
Grade 3
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-
care ADL
Grade 4 
Life-threatening consequences; urgent intervention 
indicated
Grade 5 
Death related to AE
Abbreviations: AE=adverse event; NCI CTCAE=National Cancer Institute Common Terminology 
Criteria for Adverse Events.


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12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, eg, 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not associated with the IP (ie, does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely 
alternative etiology)

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which 
may include but is not limited to the following: 
o Reappearance of a similar reaction upon re-administration (positive 
rechallenge)
o Positive results in a drug sensitivity test (skin test, etc.)
o Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid

Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 5 days, the 
investigator shall provide the alternative etiology. These causality definitions will also be 
used to assess the relationship of an AE with a study-related procedure(s), if necessary.


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12.1.2.3 Safety Reporting
Adverse events/SAEs will be assessed at all study visits as outlined in the Schedules of 
Study Procedures and Assessments (see Table 3, Table 4, and Table 5) and 
Section 12.1.2.
Adverse events/SAEs are to be recorded on the AE page of the eCRF. Each event should 
be recorded separately.
Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the investigational product, must be reported immediately (within 24 hours 
of the study center’s first knowledge of the event). All SAEs must be reported via the 
Electronic Data Capture (EDC) system by completing the relevant eCRF page(s) in 
English. Once the SAE has been recorded in the EDC system, the sponsor and other 
designated recipients will be informed of the event automatically. For instances in which 
the EDC may become unavailable, SAEs must be reported using the back-up paper 
SAER Form to meet the 24 hour timeline requirement (for contacts and instructions refer 
to the SAER Form). Once the EDC becomes available, the site must enter all SAE data as 
reported on the back-up paper SAER Form on the applicable eCRF pages.
The reported event will contain as much available information concerning the SAE to 
enable the sponsor or designee to file a report, which satisfies regulatory reporting 
requirements. The initial SAE information reported on the applicable eCRF pages (or 
back-up SAER Form, if applicable) must at least include the following:

Protocol Number

Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)

Investigational product exposure

Medical Term for Event (Diagnosis preferably) 

Description of the (S)AE, including:
Date of onset
(S)AE treatment (drug, dose, route of administration)
Causal relationship by the Investigator
Measures taken (ie, action taken regarding investigational product in 
direct relationship to the AE)
Outcome

Seriousness criteria (ie, death, life-threatening, or other criterion)


B A X 6 9 ( i mal u ma b )
Pa ge 7 3 of 1 2 5
Cli nical St u d y Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 M A Y 0 9
B A X A L T A C O N FI D E N TI A L – R E S T RI C T E D: D O N O T D I S T RI B U T E WI T H O U T P RI O R A P P R O V A L

Ca use of deat h

A ut o ps y fi n di n gs (if a vaila ble)

Na me, a d dress, fa x n u m ber, e mail, a n d tele p h o ne n u m ber of t he re p orti n g 
I n vesti gat or (f or pa per S A E R F or ms)
T he seri o us a d verse e ve nt re p ort i n g c o ntact i n f or mati o n is pr o vi de d bel o w b y c o u ntr y:
C o u ntr y
Tele p h o ne
F a x
Ger ma n y
S pai n
U nite d Ki n g d o m
U nite d States
Criteria f or d oc u me nti n g t he relati o ns hi p t o t he i n vesti gati o nal pr o d uct, se verit y , a n d 
o utc o me will be as descri be d i n Secti o n 1 2. 1 .
All S A Es t hat are s p o nta ne o usl y  re p orte d wit hi n 3 0 da ys of a s u bject’s last visit are t o be 
c ollected a n d re p orte d as pre vi o usl y  descri be d.
I n me dical e mer ge ncies, t he i n vesti gat or s h o ul d use me dical j u d g me nt a n d re m o ve t he 
s u bject fr o m t he i m me diate hazar d. T he s p o ns or or desi g nee will be n otifie d re gar di n g 
t he t ype of e mer ge nc y  a n d c o urse of acti o n ta ke n a n d t he pr oce d ures f or S A E re p orti n g 
will be f oll o we d, if necessar y .
D uri n g a s u bject’s partici pati o n i n t he st u d y , t he i n vesti gat or or i nstit uti o n will pr o vi de 
a de q uate me dical care f or a n y A Es, i ncl u di n g cli nicall y si g nifica nt la b orat or y val ues 
related t o t he st u d y . T he i n vesti gat or or i nstit uti o n s h o ul d i nf or m a s u bject w he n me dical 
care is nee de d f or a n i nterc urre nt ill ness (cli nic, la b orat or y  res ults, or ot her wise) t hat i n 
t he o pi ni o n of t he i n vesti gat or s h o ul d recei ve me dical f oll o w- u p.
1 2. 2 Ur ge nt S afe t y Me as ures
P P D
A n ur ge nt safet y meas ure is a n i m me diate acti o n ta ke n, w hic h is n ot defi ne d b y t he 
pr ot oc ol, i n or der t o pr otect s u bjects partici pati n g i n a cli nical trial fr o m i m me diate har m. 
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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Urgent safety measures may be taken by the sponsor or clinical investigator and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical trial or trials

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. In the 
event(s) of an apparent immediate hazard to the subject, the investigator will notify the 
sponsor immediately by phone and confirm notification to the sponsor in writing as soon 
as possible, but within 1 calendar day after the change is implemented. The sponsor will 
also ensure the responsible ethics committee (EC) and the relevant competent authorities 
are notified (in writing, if applicable) of the urgent safety measures taken in such cases 
according to local regulations.
12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (ie, from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the AE CRF (and SAER Form if eCRF is not available). These events will 
not be considered as SAEs and will not be included in the analysis of SAEs. 
For the purposes of this study, each non-serious untoward medical occurrence 
experienced by a subject undergoing study-related procedure(s) before the first IP 
exposure will be recorded on the AE CRF; these events will not be considered as AEs 
and will not be included in the analysis of AEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety, and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, eg, reconstitution difficulty

Missing components


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
Damage to the product or unit carton

A mislabeled product (eg, potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems, including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary.
All medications taken and non-drug therapies received from enrollment until 
completion/termination will be recorded on the concomitant medications and non-drug 
therapies CRFs.
12.6 Physical Examinations
At screening and subsequent study visits (as described in Table 3, Table 4, and Table 5), 
a physical examination will be performed on the following body systems: general 
appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, skin, and neurological. An examination of all major 
joints will also be performed. At screening, if an abnormal condition is detected, the 
condition will be described on the medical history CRF. At study visits, if a new 
abnormal or worsened abnormal pre-existing condition is detected, the condition will be 
described on the AE CRF. If the abnormal value was not deemed an AE because it was 
due to an error, due to a preexisting disease (described in Section 12.1.1.5), not clinically 
significant, a symptom of a new/worsened condition already recorded as an AE, or due to 
another issue that will be specified, the investigator will record the justification on the 
source record.
12.7 Clinical Laboratory Parameters
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count [hemoglobin, hematocrit, 
erythrocytes (ie, red blood cell count), and leukocytes (ie, white blood cell count)] with 


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differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet 
counts. 
In addition, a serum pregnancy test will be performed on women of childbearing potential 
at screening.
The clinical chemistry panel will consist of sodium, potassium, calcium, magnesium,
albumin, ALT, AST, total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, 
creatinine clearance according to Cockcroft-Gault, C-reactive protein, and glucose. 
The coagulation panel will include International Normalized Ratio (INR) and aPTT.
Blood will be obtained for assessment of hematology and clinical chemistry parameters 
according to the schedule detailed in Section 10.3 (see Table 3, Table 4, and Table 5). 
Blood volumes obtained are detailed in Table 7. Hematology and clinical chemistry 
assessments will be performed on EDTA-anticoagulated whole blood and serum, 
respectively, at a local laboratory. 
12.7.2 Urinalysis
The urinalysis panel will consist of protein, glucose, and blood.
In addition, pregnancy urine dipstick tests for females of childbearing potential will be 
performed on Day 1 of each treatment cycle (prior to dosing) and at the End of 
Study/Early Termination visit and Safety Follow-up visit.
Urine will be collected according to the schedule detailed in Section 10.3 (see Table 3, 
Table 4, and Table 5).
12.7.2.1 Assessment of Laboratory Values
12.7.2.1.1 Toxicity Grading Scale
Laboratory values will be evaluated according to the NCI CTCAE v4.03.
12.7.2.1.2 Assessment of Abnormal Laboratory Values
Each Grade 3 or Grade 4 abnormal laboratory value will be reported as an AE, unless the 
abnormal value is a symptom of, or relates to, a diagnosis that is itself recorded as an AE.
For each other abnormal laboratory value, clinically significant values that are treatment-
emergent or that are present at baseline and significantly worsen during the study, in the 
judgment of the investigator, will be reported as AEs. However, clinically significant 


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abnormal laboratory values will not be reported as AEs if they meet either or both of the 
following criteria:
1. Value is associated with the disease being studied, unless judged by the investigator 
as more severe than expected for the subject’s condition.
2. Value is associated with a preexisting condition that has not worsened.
Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal result or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator.
12.8 Vital Signs
Vital signs will include body temperature (°C or °F), respiratory rate (breaths/min), pulse 
rate (beats/min), and systolic and diastolic blood pressure (mmHg). Height (inches or cm)
will be measured once at baseline. Weight (lb or kg) will also be collected once at each 
visit, prior to study drug administration.
Vital signs are to be measured after a 5-minute rest. Sitting position is recommended for 
blood pressure measurement. Vital signs will be measured according to the schedule 
described in Section 10.3 (see Table 3, Table 4, and Table 5).
Vital sign values are to be recorded on the CRF. For each abnormal vital sign value, the 
investigator will determine whether or not to report an AE (see definition in Section 12.1
and record the medical diagnosis [preferably], symptom, or sign on the AE CRF). 
Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal value, or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator.
12.9 Electrocardiograms
A 12-lead ECG will be performed at study visits according to the schedule described in 
Section 10.3 (see Table 3, Table 4, and Table 5).
Corrected QT (QTc) is to be calculated using Fridericia’s formula (where RR = 60/heart 
rate):
QTc = QT/(3√RR)
Electrocardiograms performed at regular study visits will be interpreted locally.


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13. STATISTICS
13.1 Sample Size and Power Calculations
The final sample size of the Safety Run-in (Part 1) is dependent on the pre-stated rules for
dose escalation (see Section 8.2.1). In Part 1, the sample size for each dosing regimen (ie, 
imalumab + 5-FU/LV and imalumab + panitumumab) is expected to be between 6 and 
12 subjects (ie, 3 to 6 subjects at each imalumab dose level). Non-evaluable subjects will 
be replaced to meet study objectives.
The sample size of the exploratory Phase 2a (Part 2) is estimated to be a total of 
66 subjects. Assuming that the median PFS is 2.4 months in the control arm and 
4.25 months in the experimental arm (hazard ratio 0.565), and using a one-sided α of 0.15 
and β of 0.20 with a drop-out rate of 20% at 6 months, 48 PFS events are needed. With 
an enrollment ratio of 2:1, and taking into account the time for accrual of 1 year and an 
additional follow-up period of 6 months after the last subject is enrolled, the sample size 
needed is a total of 44 subjects in the imalumab-containing treatment arms and 
22 subjects in the control arm (SoC), for a total of 66 subjects.
13.2 Datasets and Analysis Cohorts
The Safety Population is defined as all subjects who receive at least 1 administration of
IP. The Safety Population will be used for all safety analyses in the trial.
The Full Analysis Set (FAS) will serve as the population for the analyses of efficacy data 
in the trial. The FAS will include all subjects who 1) received at least 1 administration of 
IP, and 2) have 1 post-baseline tumor response assessment based on RECIST v1.1 or died 
within 18 weeks of the start of treatment.
13.3 Handling of Missing, Unused, and Spurious Data
For time-to-event type of endpoint, subjects will be censored if lost to follow-up. For all 
other analysis, only subjects for whom data are available will be included in the statistical 
analysis. No imputations will be carried out on missing values.
13.4 Methods of Analysis
13.4.1 General Considerations
In general, descriptive summaries will be presented for the safety and immunogenicity 
variables collected. Continuous variables will be summarized using mean, standard 
deviation, minimum, median, and maximum. Categorical variables will be summarized 
using frequency counts and percentages. For time-to-event variables, Kaplan-Meier (KM)
plots, median time-to-event, and other percentiles will be presented. For the purposes of 


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the data analysis, data cut-off for Part 2 will occur when 48 PFS events (progressions or 
deaths) have been observed.
Adverse events will be coded using the MedDRA and will be summarized by system 
organ class and preferred term. In addition, summaries of AEs by severity and 
relationship to study drug will be presented.
Further details are specified in the Statistical Analysis Plan.
13.4.2 Demographics and Other Subject Characteristics
The number of subjects enrolled in Part 1 and Part 2 will be summarized separately.
The number and percentage of subjects screened, randomly assigned to treatment, failed 
screening by the primary reasons for screening failure, treated, completed the trial, and 
discontinued by the primary reason for discontinuation will be displayed by treatment and 
overall. 
Subjects who were randomly assigned to trial medication but who discontinued prior to 
treatment with trial medication will be presented. Subjects who are treated but who were 
not randomly assigned to trial medication will be presented. All treated subjects who 
discontinue prematurely from the study will be presented. Randomized subjects for 
whom the blind was broken will also be presented.
All baseline and demographic variables will be summarized descriptively, using mean, 
standard deviation, median, minimum, median, and maximum for continuous measures, 
and frequency count and percentage for categorical and binary measures. The results will 
be presented in summary tables and by-subject listings.
The comparability of the treatment groups for baseline and demographic characteristics 
will be assessed by the use of tables and/or graphs. No statistical hypothesis tests will be 
performed. Demographic variables will be summarized by treatment and overall by either 
descriptive statistics or categorical tables:

Continuous demographic baseline variables: age (years), body weight, height

Categorical demographic baseline variables: age, gender, race
Medical history will also be summarized.


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13.4.3 Primary Outcome Measure
13.4.3.1 Primary Safety Outcome Measure
The primary safety outcome measure is the occurrence of DLTs (Part 1) (see
Section 8.4.1).
Where appropriate, point estimates and 95% two-sided confidence intervals (CIs) will be 
calculated for all safety outcome measures by treatment group.
For the determination of the RP2D, the analysis of the occurrence of DLTs will be 
performed on a subset of the safety analysis set, including all evaluable subjects. Subjects 
will be considered evaluable once they either complete their first treatment cycle or 
withdraw from study during the first treatment cycle due to DLT. The percentage of 
subjects experiencing DLT during their first treatment cycle will be displayed along with 
corresponding 95% CIs, where appropriate. The RP2D will be defined as the highest dose 
level examined at which < 33% of evaluable subjects experience a DLT during the first 
treatment cycle.
13.4.3.2 Primary Efficacy Outcome Measure
The primary efficacy outcome measure is PFS (Part 2), defined as time between 
treatment initiation and tumor progression (per RECIST v1.1) or death from any cause
(see Section 8.4.1).
Median PFS and corresponding 95% CI for each of the 2 treatment groups will be 
estimated based on the KM methodology for time-to-event data analysis. Other
percentiles of PFS may also be provided if estimable. Percentages and 95% CI of subjects
with PFS at Week 16 and other time points will also be based on the KM estimates. In 
addition, KM plots and a one-sided log-rank test will be presented.
In addition, median PFS of each stratum based on KRAS/NRAS status within will be 
reported and a KM curve will be displayed for each study arm.
13.4.4 Secondary Outcome Measures 
13.4.4.1 Immunogenicity Outcome Measures
The measure of immunogenicity is based on (see Section 8.4.2.1):

Occurrence of binding and/or neutralizing anti imalumab antibodies

Incidence and severity of infusion reactions after imalumab


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13.4.4.2 Safety Outcome Measures
The safety outcome measures are (see Section 8.4.2.2):

Occurrence of SAEs and/or TEAEs, regardless of causality or relationship to 
study drug using NCI CTCAE v4.03

Other safety measurements: physical or instrumental examinations, ECGs, vital 
signs, clinically relevant changes in instrumental examinations or laboratory 
values
Adverse events will be regarded as treatment emergent (ie, TEAEs) if they started on or 
after the date and time of administration of the first dose of study drug, or if they were 
present prior to the administration of the first dose of study drug and increased in severity 
during the study.
The number of subjects who experience SAEs and TEAEs will be tabulated and 
summarized by treatment group. The total number of subjects and events and the 
corresponding rates will be presented.
In addition, tables will be prepared to list each AE, the number of subjects in each 
treatment group who experienced an AE at least once, and the rate of subjects with 
AE(s). Adverse events will be grouped by system organ class. Each event will then be 
divided into defined severity grades (as described in Section 12.1.2.1). The tables will 
also divide the AEs into those considered related (a “possibly related” or a “probably 
related” AE will be considered as a “related AE”) to the treatment and those considered 
unrelated (an “unlikely related” or an “unrelated” AE will be considered as an 
“unrelated” AE).
All AEs for each subject, including the same event on several occasions, will be listed, 
detailing both the MedDRA preferred term and the original verbatim term used by the 
investigator, system organ class, severity grade, seriousness, relation to the treatment, 
onset date, and stop date.
Electrocardiograms and vital signs will be summarized using appropriate descriptive 
statistics. For each clinical laboratory value and change from baseline, summaries will be 
made via descriptive statistics (ie, mean, median, standard deviation, and range). A 
summary table showing incidence of clinically significant treatment-emergent laboratory 
values will be provided. Shift tables showing incidence of new or worsening clinically 
significant findings from baseline to endpoint will be provided.


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13.4.4.3 Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures are (see Section 8.4.2.3):

Response evaluation according to RECIST v1.1

OS time from randomization to death of any cause
The ORR and CBR and the exact 2-sided 95% CI will be reported for each treatment 
arm, and by KRAS status.
Overall survival will also be summarized similarly to PFS.
13.4.4.4 Secondary Pharmacokinetic Outcome Measure
The secondary PK outcome measure is the plasma concentrations of imalumab (see
Section 8.4.2.4):
Plasma concentrations of imalumab will be listed and summarized descriptively, as 
appropriate, for each treatment group. 
Imalumab plasma PK will be characterized using a population PK modeling approach, in 
combination with PK data from other studies. Results of population PK modeling and 
PK/PD correlations will be reported in a separate report.
13.4.4.5 Secondary Quality of Life Outcome Measures
The secondary QoL outcome measure is using a validated general questionnaire (see
Section 8.4.2.5):

The EORTC QLQ-C30 questionnaire
13.4.5 Exploratory Outcome Measures
The exploratory outcome measures are:

Levels of oxMIF and total MIF in plasma
The levels of oxMIF and total MIF in plasma will be presented in summary tables. 
Changes in the levels following imalumab treatment from baseline will be computed, as 
applicable and appropriate.

Tumor-associated genetic alterations in blood/urine (for subjects treated with 
imalumab in combination with 5-FU/LV or panitumumab who provide consent 
for exploratory biomarker analyses)


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The sponsor will obtain available historical tumor mutational testing results for subjects.
Other exploratory measures are assessed using validated general questionnaires (see 
Section 8.4.3:

EORTC QLQ-CR29

EQ-5D
13.5 Planned Interim Analysis of the Study
An interim analysis will be implemented for planning purposes when 33 PFS events have 
been observed. The interim analysis will primarily include a summary of safety (as 
measured by incidence of TEAEs) and PFS by treatment arm. The DSMB will be 
included in review of the interim analysis data (see Section 15.4.2).
For the purposes of the final analysis, data cut-off for Part 2 will occur when 48 PFS 
events (progressions or deaths) have been observed.
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements 
as described in the CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol, as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.


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15.1.1 Final Clinical Study Report
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start.
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand 
all requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to 
the study will be described in the clinical monitoring plan.
15.4 Safety Monitoring
15.4.1 Data Safety Monitoring (Part 1)
A Data Review Committee (DRC) will review accumulating unblinded safety data of the 
subjects enrolled in Part 1. 
The DRC members must include at least one participating investigator, the 
sponsor-designated Medical Monitor, and a sponsor representative (non-voting). 
The DRC will meet for safety reviews after 3 subjects in a dosing cohort have completed 
the first treatment cycle (ie, after 28 days) to decide if additional subjects must be 
enrolled or if the next dose level can be opened. All available safety data will also be 
provided for subjects who discontinue prior to this time. At the end of the escalation 
phase, the DRC will determine the RP2D for each imalumab combination, or decide if an 
intermediate dose level will be explored. 
Decisions will be made using the stopping rules and dose escalation procedures defined 
within the protocol (see Section 8.2.1.1) and shown in Figure 1.


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15.4.2 Data Safety Monitoring Board (Part 2)
This part of the study will be monitored by a DSMB. This DSMB will be composed of 
recognized experts in the field of oncology for clinical care and research, one of whom at 
least must be independent from the sponsor. 
The DSMB will evaluate the safety data during Part 2 of the trial on a quarterlybasis. The 
DSMB will also review data from the interim analysis (see Section 13.5). The DSMB can 
stop the trial for safety reasons at any time. Ad hoc reviews may be scheduled by the 
sponsor, as warranted, based on the number/severity of AEs/DLTs experienced by 
subjects in the ongoing trial. The composition, activities, and responsibilities of the 
DSMB are described in further detail in the DSMB Charter. 
15.5 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
15.6 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The sponsor (Baxalta) will also ensure the responsible EC and relevant 
competent authority is notified of the urgent measures taken in such cases according to 
local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.7 Laboratory and Reader Standardization
During both phases of the study (Part 1 and Part 2), local laboratories will be used for 
hematology and clinical chemistry assessments. Inter-laboratory standardization methods 
for hematology and clinical chemistry assessments will be described in the data 
management plan.


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16. ETHICS
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of subjects into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose subjects for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All subjects and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. An assent form may be provided and should be signed by 
subjects less than 18 years of age. Before use, the informed consent form will be 
reviewed by the sponsor and approved by the EC and regulatory authority(ies), where 
applicable, (see Section 16.2). The informed consent form will include a comprehensive 
explanation of the proposed treatment without any exculpatory statements, in accordance 
with the elements required by ICH GCP and applicable national and local regulatory 
requirements. Subjects or their legally authorized representative(s) will be allowed 
sufficient time to consider participation in the study. By signing the informed consent 
form, subjects or their legally authorized representative(s) agree that they will complete 
all evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.


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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which has been approved by the applicable EC and regulatory authorities, 
where applicable, will be provided by the investigator to the subjects who consented to 
participate in the study.
The sponsor will obtain available historical tumor mutational testing results for subjects. 
In subjects who provide consent, blood and urine samples will be collected for an 
optional exploratory analysis, to assess the effect of imalumab in combination with 
5-FU/LV or panitumumab on tumor-associated genetic biomarkers.
17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA.
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.8), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAER Forms, laboratory reports (if 
applicable), and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
Only authorized study site personnel will record or change data on the CRFs. If data is 
not entered on the CRFs during the study visit, the data will be recorded on paper, and
this documentation will be considered source documentation. Changes to a CRF will 
require documentation of the reason for each change. An identical (electronic/paper) 
version of the complete set of CRFs for each subject will remain in the investigator file at 
the study site in accordance with the data retention policy (see Section 17.3).


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The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (eg, ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan.
17.3 Document and Data Retention
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the CTA.
18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA.


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20. SUPPLEMENTS
20.1 Study 391401 Schematic
Figure 2
Study 391401 Schematic
Abbreviations: 5-FU=5-fluorouracil; BAX69=imalumab; LV=leucovorin; mut=mutated; RP2D=recommended Phase 2 dose; SoC=standard of care;
wt=wild type.
a
5-FU/LV regimen: Leucovorin 400 mg/m2 IV infusion over 2 hours followed by 5-FU 2400 mg/m² IV infusion over 46 hours Q2W.
b
Panitumumab dose = 6 mg/kg IV Q2W over 60 min.
c
Stratification is by KRAS/ NRAS status (mut or wt).
d
Imalumab dose for Part 2 will be the RP2D for QW dosing determined in Part 1 for each combination.
e
Dose according to drug label; choice includes panitumumab in KRAS and NRAS wt group only.


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20.2 Schedule of Study Procedures and Assessments
Table 3
Schedule of Study Procedures and Assessments: Parts 1 and 2
Trial Periods
Screening 
Visit
Baseline 
Visit
Study Visits Per Treatment Cyclea
End of 
Study/ Early 
Termination
Visit
Safety 
Follow-Up 
Visitb
Study Days
Procedures/Assessments
Days -28
to -1
Day 1 
Predose
Days 
1 to 7
Days 
8 to 14
Days 
15 to 21
Days 
22 to 28
Treatment Schedule
Imalumab administration (QW) 
(Part 1; Part 2, Arm A)
Day 1
Day 8
Day 15
Day 22
5-FU/LV or panitumumab
administration (Q2W) (Part 1; Part 2, 
Arm A) 
Day 1
Day 15
Visit window (days)
± 2
± 2
± 2
± 2
± 2
± 2
± 7
Informed consentc
X
Eligibility criteria
X
X
Demographics
X
Relevant medical and surgical history
X
Entry into IRT System
X
Xd
Day 1d
Day 8d
Day 15d
Day 22d
X
Vital signse
X
X
Day 1
Day 8
Day 15
Day 22
X
X
Physical examination
X
X
Day 1
Day 15
X
X
ECOG PS
X
X
Day 1
X
X


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Table 3
Schedule of Study Procedures and Assessments: Parts 1 and 2
Trial Periods
Screening 
Visit
Baseline 
Visit
Study Visits Per Treatment Cyclea
End of 
Study/ Early 
Termination
Visit
Safety 
Follow-Up 
Visitb
Study Days
Procedures/Assessments
Days -28
to -1
Day 1 
Predose
Days 
1 to 7
Days 
8 to 14
Days 
15 to 21
Days 
22 to 28
Treatment Schedule
EORTC QLQ-C30
X
X
X
EORTC QLQ-CR29
X
X
X
EQ-5D
X
X
X
12-lead ECGf
X
X
Day 1
X
X
ECHO/MUGA
X
Hematologyg
X
X
Day 1
Day 8
Day 15
Day 22
X
X
Chemistry/coagulationg
X
X
Day 1
Day 8 
(Cycle 1 
only)
Day 15
X
X
Pregnancy testh (if applicable)
X
X
Day 1
X
X
Urinalysis
X
X
Day 1
X
X
Genetic testingi (KRAS/NRAS)
X
Tumor measurement (RECIST v1.1)j
X
Day 28 of 
Cycle 2
and then 
every other 
cycle
Xk
Xk


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Table 3
Schedule of Study Procedures and Assessments: Parts 1 and 2
Trial Periods
Screening 
Visit
Baseline 
Visit
Study Visits Per Treatment Cyclea
End of 
Study/ Early 
Termination
Visit
Safety 
Follow-Up 
Visitb
Study Days
Procedures/Assessments
Days -28
to -1
Day 1 
Predose
Days 
1 to 7
Days 
8 to 14
Days 
15 to 21
Days 
22 to 28
Treatment Schedule
Blood sampling for immunogenicity 
(ADA and NADA)
X
X
X
PK blood samples (imalumab plasma 
levels)
X
X
Day 1 and 
Day 2 OR 
Day 4l
Day 8l
Day 15l
Day 22l
Blood samples for PD biomarkers 
(oxMIF and total MIF)
X
X
Day 1 and 
Day 2 OR 
Day 4l
Day 8l
Day 15l
Day 22l
Blood sample for genetic biomarkers 
(cfDNA)m
X
Day 28 of 
Cycle 1
and then 
every other 
cycle
X
Urine sample for genetic biomarkers 
(cfDNA)m
X
Day 28 of 
Cycle 1
and then 
every other 
cycle
X


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Table 3
Schedule of Study Procedures and Assessments: Parts 1 and 2
Trial Periods
Screening 
Visit
Baseline 
Visit
Study Visits Per Treatment Cyclea
End of 
Study/ Early 
Termination
Visit
Safety 
Follow-Up 
Visitb
Study Days
Procedures/Assessments
Days -28
to -1
Day 1 
Predose
Days 
1 to 7
Days 
8 to 14
Days 
15 to 21
Days 
22 to 28
Treatment Schedule
Adverse eventsn
X
X
X
X
X
X
X
X
Concomitant medications/non-drug 
therapies
X
X
X
X
X
X
X
X
Abbreviations: 5-FU=5-fluorouracil; ADA=anti-drug antibody; AE=adverse event; C1D1=Cycle 1 Day 1; cfDNA=cell-free DNA; CT=computerized 
tomography; ECG=electrocardiogram; ECHO=echocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-
C30=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-CR29=European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire for colorectal cancer 29; EQ-5D=European Quality of Life – 5 
Dimensions; IRT=Interactive Response Technology; KRAS=Kirsten rat sarcoma viral oncogene homolog; LV=leucovorin; MIF=macrophage 
migration inhibitory factor; MRI=magnetic resonance imaging; MUGA=multigated acquisition scan; NADA=neutralizing anti-drug antibody; 
NRAS=neuroblastoma RAS viral (v-ras) oncogene homolog; oxMIF=oxidated macrophage migration inhibitory factor; PD=pharmacodynamic; 
PK=pharmacokinetic; Q2W=every 2 weeks; QW=every week; RECIST=Response Evaluation Criteria in Solid Tumors; SoC=standard of care.
a
Treatment cycles are defined in this study as 4-week cycles. In each treatment cycle, imalumab is administered QW, and 5-FU/LV and panitumumab 
are administered Q2W in 4-week cycles. Treatment cycles will continue until progression, unacceptable toxicities, or withdrawal of consent.
b
The Safety Follow-up Visit should occur 30 (±7) days after the last dose of study treatment. For subjects who have stopped study drug or have 
documented disease progression, post-study telephone calls to assess overall survival will be made by site staff every 3 months.
c
Subject informed consent occurs at screening, prior to any study-specific procedure.
d
IRT will be utilized at screening and baseline visits for all subjects (Part 1 and Part 2), at all subsequent study visits in Part 1, and all subsequent study 
visits in Part 2 for subjects in Arm A only.
e
Vital signs, including body temperature, heart rate, blood pressure, and respiratory rate, are to be measured after a 5-minute rest. Sitting position is 
recommended for blood pressure measurement. Height and body weight will also be recorded. On the day of imalumab administration, vital signs will 
be taken within 30 minutes prior to dosing and within 30 minutes after completion of imalumab infusion. Weekly monitoring to be done in Cycle 1 
only, then Q2W.
Continued on next page


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Continued
f
The 12-lead ECG assessment at Screening should be performed no earlier than 1 week before C1D1. The 12-lead ECG assessment should be 
performed predose and 2 (± 1) hours postdose on Day 1 (Baseline, C1D1).
g
Laboratory assessments should be evaluated before drug administration. Immediately prior to Cycle 1, laboratory assessments can be performed either 
on Day -1 or on Day 1 predose. Hematology tests will be done weekly during each treatment cycle. Chemistry/coagulation tests will be done on Day 1 
and Day 15 of each treatment cycle, and Day 8 of Cycle 1 only. Laboratory tests include hematology (complete blood count with differential and 
platelet counts) and biochemistry (creatinine, creatinine clearance according to Cockcroft-Gault, sodium, potassium, calcium, magnesium, glucose, 
albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, C-reactive protein, and blood urea nitrogen). 
Coagulation panel includes International Normalized Ratio and activated partial thromboplastin time.
h
Serum human chorionic gonadotropin to be tested at screening; urine dipstick test to be performed on Day 1 of each cycle (prior to dosing), End of 
Study/Early Termination Visit, and at Safety Follow-up. A serum pregnancy test will be performed to confirm if a positive result is obtained in a 
dipstick test.
i
If not readily available, genetic testing for KRAS/NRAS mutation status needs to be done early enough to allow randomization within 4 weeks. If 
KRAS mutation status is known, the subject can start treatment while NRAS testing is pending.
j
Baseline CT or MRI scans can be accepted within 28 days prior to first imalumab administration (C1D1); assessments are to be repeated every 2 cycles 
using the same method at each measurement and tumor response evaluated before starting the next cycle. A 7-day window is permitted for all imaging 
studies for tumor measurement purposes.
k
A tumor measurement should be obtained at the End of Study/Early Termination visit, if no disease progression was confirmed previously and this visit 
occurs > 4 weeks after the last scan; no additional scans will be required if disease progression is confirmed at this visit. A tumor measurement should 
be obtained at the Safety Follow-up visit, if no disease progression was confirmed previously and this visit occurs > 4 weeks after the last scan.
l
For subjects receiving imalumab treatment, blood samples for PK (imalumab plasma levels) and PD biomarkers (oxMIF and total MIF) will be 
collected at the times indicated in Table 6. Cycle 1 only: Blood samples will be collected predose and postdose on Day 1, on either Day 2 (24 ± 4 h 
post first dose) OR Day 4 (72 ± 8 h post first dose), and then predose and postdose on Day 8, Day 15, and Day 22.
Subsequent treatment cycles: Blood samples will be collected predose and postdose only on Day 1.
m
Optional exploratory analysis for subjects treated with imalumab in combination with 5-FU/LV or panitumumab.
n
AEs to be collected on a continuous basis until the Safety Follow-up Visit.


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In subjects randomized to SoC (Part 2, Arm B), all Screening assessments and procedures should be performed according to 
Table 4 and Section 10.3.1. All Baseline assessments and procedures should be performed at C1D1 predose according to Table 4
and Section 10.3.2. These assessments should be completed prior to drug administration. If the study subject is receiving SoC on a 
4-week treatment cycle, the schedule of assessments should be as follows:
Table 4
Schedule of Study Procedures and Assessments: SoC Following Randomization (4-Week Cycles or if Subject is on Best Supportive Care)
Trial Periods
Screening 
Visit
Baseline 
Visit
Study Visits Per Treatment Cyclea
End of 
Study/ Early 
Termination 
Visit
Safety 
Follow-Up 
Visitb
Study Days
Procedures/Assessments
Days -28 
to -1
Day 1 
Predose
Days 
1 to 7
Days 
8 to 14
Days 
15 to 21
Days 
22 to 28
Treatment Schedule
SoC (Part 2, Arm B)
Dose according to Product Label
Visit window (days)
±2
±2
±2
±2
±2
±2
±7
Informed consentc
X
Eligibility criteria
X
X
Demographics
X
Relevant medical and surgical 
history
X
Entry into IRT System
X
Xd
X
Vital signse
X
X
Day 1
Day 8
Day 15
Day 22
X
X
Physical examination
X
X
Day 1
Day 15
X
X
ECOG PS
X
X
Day 1
X
X


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Table 4
Schedule of Study Procedures and Assessments: SoC Following Randomization (4-Week Cycles or if Subject is on Best Supportive Care)
Trial Periods
Screening 
Visit
Baseline 
Visit
Study Visits Per Treatment Cyclea
End of 
Study/ Early 
Termination 
Visit
Safety 
Follow-Up 
Visitb
Study Days
Procedures/Assessments
Days -28 
to -1
Day 1 
Predose
Days 
1 to 7
Days 
8 to 14
Days 
15 to 21
Days 
22 to 28
Treatment Schedule
EORTC QLQ-C30
X
X
X
EORTC QLQ-CR29
X
X
X
EQ-5D
X
X
X
12-lead ECGf
X
X
Day 1
X
X
ECHO/MUGA
X
Hematologyg
X
X
Day 1
Day 8
Day 15
Day 22
X
X
Chemistry/coagulationg
X
X
Day 1
Day 8 
(Cycle 1 
only)
Day 15
X
X
Pregnancy testh (if applicable)
X
X
Day 1
X
X
Urinalysis
X
X
Day 1
X
X
Genetic testingi (KRAS/NRAS)
X
Tumor measurement (RECIST v1.1)j
X
Day 28 of 
Cycle 2
and then 
every other 
cycle
Xk
Xk
Adverse Eventl
X
X
X
X
X
X
X
X


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Table 4
Schedule of Study Procedures and Assessments: SoC Following Randomization (4-Week Cycles or if Subject is on Best Supportive Care)
Trial Periods
Screening 
Visit
Baseline 
Visit
Study Visits Per Treatment Cyclea
End of 
Study/ Early 
Termination 
Visit
Safety 
Follow-Up 
Visitb
Study Days
Procedures/Assessments
Days -28 
to -1
Day 1 
Predose
Days 
1 to 7
Days 
8 to 14
Days 
15 to 21
Days 
22 to 28
Treatment Schedule
Concomitant medications/non-drug 
therapies
X
X
X
X
X
X
X
X
Abbreviations:  AE=adverse events; C1D1=Cycle 1 Day 1; cfDNA=cell-free DNA; CT=computerized tomography; ECG=electrocardiogram; 
ECHO=echocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30=European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-CR29=European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire for colorectal cancer 29; EQ-5D=European Quality of Life – 5 Dimensions; IRT=Interactive Response 
Technology; MRI=magnetic resonance imaging; MUGA=multigated acquisition scan; Q2W=every 2 weeks; RECIST=Response Evaluation Criteria in 
Solid Tumors; SoC=standard of care.
a
Treatment cycles for SoC are defined in this study as 3-week or 4-week cycles. Treatment cycles will continue until progression, unacceptable 
toxicities, or withdrawal of consent.
b
The Safety Follow-up Visit should occur 30 (±7) days after the last dose of study treatment. For subjects who have stopped study drug or have 
documented disease progression, post-study telephone calls to assess overall survival will be made by site staff every 3 months.
c
Subject informed consent occurs at screening, prior to any study-specific procedure.
d
IRT will be utilized at screening and baseline visits only for all subjects randomized to Arm B (Part 2) to receive SoC/best supportive care.
e
Vital signs, including body temperature, heart rate, blood pressure, and respiratory rate, are to be measured after a 5-minute rest. Sitting position is 
recommended for blood pressure measurement. Height and body weight will also be recorded. Weekly monitoring to be done in Cycle 1 only, then 
Q2W. Vital signs should be evaluated both predose and postdose during treatment with SoC.
f
The 12-lead ECG assessment should be performed predose and 2 (± 1) hours postdose on Day 1 (Baseline, C1D1).
Continued on Next Page


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Continued
g
Laboratory assessments should be evaluated before drug administration. Immediately prior to Cycle 1, laboratory assessments can be performed either 
on Day -1 or on Day 1 predose. Hematology tests will be done weekly during each treatment cycle. Chemistry/coagulation tests will be done on Day 1 
and Day 15 of each treatment cycle, and Day 8 of Cycle 1 only. Laboratory tests include hematology (complete blood count with differential and 
platelet counts) and biochemistry (creatinine, creatinine clearance according to Cockcroft-Gault, sodium, potassium, calcium, magnesium, glucose, 
albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, C-reactive protein, and blood urea nitrogen). 
Coagulation panel includes International Normalized Ratio and activated partial thromboplastin time.
h
Urine dipstick test to be performed on Day 1 of each cycle (prior to dosing), End of Study/Early Termination Visit, and at Safety Follow-up. A serum 
pregnancy test will be performed to confirm if a positive result is obtained in a dipstick test.
i
If not readily available, genetic testing for KRAS/NRAS mutation status needs to be done early enough to allow randomization within 4 weeks. If 
KRAS mutation status is known, the subject can start treatment while NRAS testing is pending.
j
Baseline CT or MRI scans can be accepted within 28 days prior to first imalumab administration (C1D1); assessments are to be repeated every 2 cycles 
using the same method at each measurement and tumor response evaluated before starting the next cycle. A 7-day window is permitted for all imaging 
studies for tumor measurement purposes.
k
A tumor measurement should be obtained at the End of Study/Early Termination visit, if no disease progression was confirmed previously and this visit 
occurs > 4 weeks after the last scan; no additional scans will be required if disease progression is confirmed at this visit. A tumor measurement should 
be obtained at the Safety Follow-up visit, if no disease progression was confirmed previously and this visit occurs > 4 weeks after the last scan.
l
AEs to be collected on a continuous basis until the Safety Follow-up Visit.


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In subjects randomized to SoC (Part 2, Arm B), all Screening assessments and procedures should be performed according to 
Table 5 and Section 10.3.1. All Baseline assessments and procedures should be performed at C1D1 predose according to Table 5
and Section 10.3.2. These assessments should be completed prior to drug administration. If the study subject is receiving SoC on a 
3-week treatment cycle, the schedule of assessments should be as follows:
Table 5
Schedule of Study Procedures and Assessments: SoC Following Randomization (3-Week Cycles)
Trial Periods
Screening 
Visit
Baseline 
Visit
Study Visits Per Treatment Cyclea
End of 
Study/ Early 
Termination 
Visit
Safety 
Follow-Up 
Visitb
Study Days
Procedures/Assessments
Days -28 to -1
Day 1 
Predose
Days 
1 to 7
Days 
8 to 14
Days 
15 to 21
Treatment Schedule
SoC (Part 2, Arm B)
Dose According to Product Label
Visit window (days)
±2
±2
±2
±2
±2
±7
Informed consentc
X
Eligibility criteria
X
X
Demographics
X
Relevant medical and surgical 
history
X
Entry into IRT System
X
Xd
X
Vital signse
X
X
Day 1
Day 8
Day 15
X
X
Physical examination
X
X
Day 1
Day 15
X
X
ECOG PS
X
X
Day 1
X
X


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Table 5
Schedule of Study Procedures and Assessments: SoC Following Randomization (3-Week Cycles)
Trial Periods
Screening 
Visit
Baseline 
Visit
Study Visits Per Treatment Cyclea
End of 
Study/ Early 
Termination 
Visit
Safety 
Follow-Up 
Visitb
Study Days
Procedures/Assessments
Days -28 to -1
Day 1 
Predose
Days 
1 to 7
Days 
8 to 14
Days 
15 to 21
Treatment Schedule
EORTC QLQ-C30
X
X
X
EORTC QLQ-CR29
X
X
X
EQ-5D
X
X
X
12-lead ECGf
X
X
Day 1
X
X
ECHO/MUGA
X
Hematologyg
X
X
Day 1
Day 8
Day 15
X
X
Chemistry/coagulationg
X
X
Day 1
Day 8 
(Cycle 1 only)
Day 15
X
X
Pregnancy testh (if applicable)
X
X
Day 1
X
X
Urinalysis
X
X
Day 1
X
X
Genetic testingi (KRAS/NRAS)
X
Tumor measurement (RECIST v1.1)j
X
Every 8 weeks
Xk
Xk


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Table 5
Schedule of Study Procedures and Assessments: SoC Following Randomization (3-Week Cycles)
Trial Periods
Screening 
Visit
Baseline 
Visit
Study Visits Per Treatment Cyclea
End of 
Study/ Early 
Termination 
Visit
Safety 
Follow-Up 
Visitb
Study Days
Procedures/Assessments
Days -28 to -1
Day 1 
Predose
Days 
1 to 7
Days 
8 to 14
Days 
15 to 21
Treatment Schedule
Adverse Eventl
X
X
X
X
X
X
X
Concomitant medications/non-drug 
therapies
X
X
X
X
X
X
X
Abbreviations:  AE=adverse events; C1D1=Cycle 1 Day 1; cfDNA=cell-free DNA; CT=computerized tomography; ECG=electrocardiogram; 
ECHO=echocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30=European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-CR29=European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire for colorectal cancer 29; EQ-5D=European Quality of Life – 5 Dimensions; IRT=Interactive Response 
Technology; MRI=magnetic resonance imaging; MUGA=multigated acquisition scan; Q2W=every 2 weeks; RECIST=Response Evaluation Criteria in 
Solid Tumors; SoC=standard of care.
a
Treatment cycles for SoC are defined in this study as 3-week or 4-week cycles. Treatment cycles will continue until progression, unacceptable 
toxicities, or withdrawal of consent.
b
The Safety Follow-up Visit should occur 30 (±7) days after the last dose of study treatment. For subjects who have stopped study drug or have 
documented disease progression, post-study telephone calls to assess overall survival will be made by site staff every 3 months.
c
Subject informed consent occurs at screening, prior to any study-specific procedure.
d
IRT will be utilized at screening and baseline visits only for all subjects randomized to Arm B (Part 2) to receive SoC/best supportive care.
e
Vital signs, including body temperature, heart rate, blood pressure, and respiratory rate, are to be measured after a 5-minute rest. Sitting position is 
recommended for blood pressure measurement. Height and body weight will also be recorded. Weekly monitoring to be done in Cycle 1 only, then 
Q2W. Vital signs should be evaluated both predose and postdose during treatment with SoC.
f
The 12-lead ECG assessment should be performed predose and 2 (± 1) hours postdose on Day 1 (Baseline, C1D1).
Continued on next Page


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Continued
g
Laboratory assessments should be evaluated before drug administration. Immediately prior to Cycle 1, laboratory assessments can be performed either 
on Day -1 or on Day 1 predose. Hematology tests will be done weekly during each treatment cycle. Chemistry/coagulation tests will be done on Day 1 
and Day 15 of each treatment cycle, and Day 8 of Cycle 1 only. Laboratory tests include hematology (complete blood count with differential and 
platelet counts) and biochemistry (creatinine, creatinine clearance according to Cockcroft-Gault, sodium, potassium, calcium, magnesium, glucose, 
albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, C-reactive protein, and blood urea nitrogen). 
Coagulation panel includes International Normalized Ratio and activated partial thromboplastin time.
h
Urine dipstick test to be performed on Day 1 of each cycle (prior to dosing), End of Study/Early Termination Visit, and at Safety Follow-up. A serum 
pregnancy test will be performed to confirm if a positive result is obtained in a dipstick test.
i
If not readily available, genetic testing for KRAS/NRAS mutation status needs to be done early enough to allow randomization within 4 weeks. If 
KRAS mutation status is known, the subject can start treatment while NRAS testing is pending.
j
Baseline CT or MRI scans can be accepted within 28 days prior to first imalumab administration (C1D1); assessments are to be repeated every 
8 weeks using the same method at each measurement and tumor response evaluated before starting the next cycle. A 7-day window is permitted for all 
imaging studies for tumor measurement purposes.
k
A tumor measurement should be obtained at the End of Study/Early Termination visit, if no disease progression was confirmed previously and this visit 
occurs > 4 weeks after the last scan; no additional scans will be required if disease progression is confirmed at this visit. A tumor measurement should 
be obtained at the Safety Follow-up visit, if no disease progression was confirmed previously and this visit occurs > 4 weeks after the last scan.
l
AEs to be collected on a continuous basis until the Safety Follow-up Visit.


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Table 6
Schedule of Pharmacokinetic and Pharmacodynamic Sample Collections (Parts 1 and 2) for Subjects Receiving Imalumab Treatment
Measurement of Imalumab, oxMIF, 
and Total MIF
Screening
Visit
Cycle 1
Subsequent 
Cycles
Time Intervala
for Collection of Blood Sample
Days 
-28 to -1
Dose 1
(Day 1)
Dose 2
(Day 8)
Dose 3
(Day 15)
Dose 4
(Day 22)
Dose 1
(Day 1)
No infusion (Screening)
1 sample
-2 to 0 hours before infusion start
1 sampleb
1 sample
1 sample
1 sample
1 sample
0 to 2 hours after infusion
1 sample
1 sample
1 sample
1 sample
1 sample
6 to 8 hours after infusion
1 sample
24 ± 4 hours OR 72 ±8 hours after infusion
1 sample
Abbreviations: MIF=macrophage migration inhibitory factor; oxMIF=oxidated macrophage migration inhibitory factor.
a
The scheduled samples may be collected at any time within the time interval specified.
b
This sample may be collected at any time on Day 1 before infusion start.


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Table 7
Blood Volumes (Parts 1 and 2) for Lab Tests and PK/PD for Subjects Receiving Imalumab Treatment
Assessments
Screening 
Visit
Cycle 1
Safety and 
PK/PD Cycle 1
Each Subsequent 
Cycle
Days 
-28 to -1
Dose 1
(Day 1)
Dose 2
(Day 8)
Dose 3
(Day 15)
Dose 4
(Day 22)
Total
Total
Hematology/blood 
chemistry/coagulationa
3 mL
10 mL
3mL
3 mL
3 mL
19 mL
Day 1, Day 8, 
Day 15 and Day 22
12 mL
Imalumab
concentrations, oxMIF, 
and total MIF
8 mL
32 mLb
16 mL
16 mL
16 mL
80 mL
Day 1 (predose and 
postdose)
16 mL
Total
11 mL
42 mL
19 mL
19 mL
19 mL
99 mL
28 mL
Abbreviations: MIF=macrophage migration inhibitory factor; oxMIF=oxidated macrophage migration inhibitory factor; PD=pharmacodynamic; 
PK=pharmacokinetic; RBC=red blood cells; WBC=white blood cells.
a
Laboratory tests include hematology (red blood cells, white blood cells, neutrophils, platelets, hematocrit, and hemoglobin) and biochemistry 
(creatinine, creatinine clearance according to Cockcroft-Gault, sodium, potassium, calcium, magnesium, glucose, albumin, alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, total bilirubin, C-reactive protein, blood urea, International Normalized Ratio, and activated partial 
thromboplastin time).


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Table 8
Blood and Urine Volumes (Parts 1 and 2) for Optional Genetic Biomarkers cfDNA Analysis for Subjects Receiving Imalumab Treatment
Assessments
Screening
Days -28 to -1
Cycle 1
Day 28
Every Other Cycle
Day 28a
End of Study/
Early Termination Visit
Blood sample for genetic 
biomarkers (cfDNA)
10 mL
10 mL
10 mL
10 mL
Urine sample for genetic 
biomarkers (cfDNA)
30 mL
30 mL
30 mL
30 mL
Total
40 mL
40 mL
40 mL
40 mL
Abbreviations:  5-FU=5-fluorouracil; cfDNA=cell-free DNA; LV=leucovorin.
a
For example, Cycle 3 Day 28, Cycle 5 Day 28, Cycle 7 Day 28, etc., in subjects receiving imalumab + 5-FU/LV or imalumab + panitumumab 
(Arm A).


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12. Hagemann T, Robinson SC, Thompson RG et al. Ovarian cancer cell-derived 
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18. Verjans E, Noetzel E, Bektas N et al. Dual role of macrophage migration inhibitory 
factor (MIF) in human breast cancer. BMC Cancer. 2009;9: 230.
19. He XX, Chen K, Yang J et al. Macrophage migration inhibitory factor promotes 
colorectal cancer. Mol.Med. 2009;15: 1-10.
20. Choi S, Kim HR, Leng L et al. Role of macrophage migration inhibitory factor in the 
regulatory T cell response of tumor-bearing mice. J.Immunol. 2012;189: 3905-3913.
21. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur.J.Cancer 2009;45:228-247.
22. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired 
resistance to anti-EGFR therapy in colorectal cancer. Nature 2012;486:532-536.
23. Thierry AR, Mouliere F, El Messaoudi S, et al. Clinical validation of the detection of 
KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014;20:430-5.


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24. Haber DA, Velculescu VE. Blood-based analyses of cancer: circulating tumor cells 
and circulating tumor DNA. Cancer Discov. 2014;4:650-661.
25. Tóth K, Barták BK, Tulassay Z, et al. Circulating cell-free nucleic acids as 
biomarkers in colorectal cancer screening and diagnosis. Expert Rev Mol Diagn. 
2016;16:239-252.
26. Patel GS, Karapetis CS. Personalized treatment for advanced colorectal cancer: 
KRAS and beyond. Cancer Manag Res. 2013;5:387-400.
27. Spindler KL, Pallisgaard N, Vogelius I, et al. Quantitative cell-free DNA, KRAS, and 
BRAF mutations in plasma from patients with metastatic colorectal cancer during 
treatment with cetuximab and irinotecan. Clin Cancer Res. 2012;18:1177-1185.
28. Kapur P. Predictive biomarkers for response to therapy in advanced colorectal/rectal 
adenocarcinoma. Critical Rev Oncog. 2012;17:361-372.
29. Ashraf N, Kothari N, Kim R. Predictive biomarkers for anti-epidermal growth factor 
receptor therapy: beyond KRAS testing. J Natl Compr Canc Netw 2014; 12: 1433-42.
30. Peeters M, Olinas KM, Parker A et al. Massively parallel tumor multigene 
sequencing to evaluate response to panitumumab in a randomized phase III study of 
metastatic colorectal cancer. Clin Cancer Res 2013;19:1902–1912.
31. Patterson SD, Peeters M, Siena S et al. Comprehensive analysis of KRAS and NRAS 
mutations as predictive biomarkers for single agent panitumumab (pmab) response in 
a randomized, phase III metastatic colorectal cancer (mCRC) study (20020408) 
[abstract]. J Clin Oncol 2013; 31(Suppl 1):Abstract 3617.
32. Sastre J, Massuti B, Pulido G et al. First-line single-agent panitumumab in frail 
elderly patients with wild-type KRAS metastatic colorectal cancer and poor 
prognostic factors: A phase II study of the Spanish Cooperative Group for the 
Treatment of Digestive Tumours. Eur J Cancer. 2015;51:1371-80.
33. Price TJ, Peeters M, Kim TW et al. Panitumumab versus cetuximab in patients with 
chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer 
(ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. 
Lancet Oncol. 2014;15:569-79.


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34. Amgen, Inc. Vectibix® (Panitumumab). Highlights of Prescribing Information. 
Revised: 2015 MAR. Accessed 2015 OCT 01. Link to publisher’s site: 
http://pi.amgen.com/united_states/vectibix/vectibix_pi.pdf.


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22. SUMMARY OF CHANGES
Protocol 391401: Amendment 5 (Global): 2016 MAY 09
Replaces: Amendment 2: 2015 JUL 13
In this section, changes described in the country-specific versions of the protocol, (dated 
2015 DEC 16 [Germany version] and 2015 OCT 02 [UK version]) as well as further 
minor updates, are described and their rationale is given.
1. Throughout the document
Description of Change: “BAX69” was changed to “imalumab”, where appropriate. 
“Patients” was changed to “subjects” where appropriate, per the Baxalta style guide, 
except where patients not enrolled in a clinical study are described. Minor 
grammatical and/or administrative changes have been made, including ensuring 
abbreviations are defined on first use and used thereafter (where appropriate).
Purpose of Change: Administrative, and to improve the readability and/or clarity of 
the protocol.
2. Throughout the document
Description of Change: Changes made according to the updated Baxalta protocol 
template dated 2016 MAR 16.
Purpose of Change: To maintain consistency with current Baxalta protocol template.
3. Synopsis, Exploratory Objectives; Synopsis, Exploratory Outcome Measures 
(Genetic biomarkers); Synopsis, Study Design (Assessments); Section 7.4, 
Exploratory Objectives; Section 8.2.2 Part 2: Exploratory Phase 2a; Section 8.4.3 
Exploratory Outcomes Measure; Section 10.3.1, Screening Assessments; 
Section 10.3.3.6 Day 28 (Cycle 1 and Every Other Cycle); Section 10.3.3.8 End of 
Study/Early Termination Visit; Section 13.4.5 Exploratory Outcome Measures; 
Section 16.3 Informed Consent
Description of Change: Exploratory objectives were added to this clinical study 
protocol, to be consistent with the exploratory outcome measures that will be made 
during the course of the study. A new exploratory outcome measure was added to this 
clinical study protocol (genetic biomarker analyses). These analyses will allow the 
characterization of tumor-associated genetic alterations in cfDNA samples from 
blood/urine that will be collected from subjects treated with imalumab in combination 
with 5-FU/LV or panitumumab who provide the additional consent for these 
biomarker analyses. The sponsor will also obtain available historical tumor 
mutational testing results for subjects.
Purpose of Change: Administrative (consistency of presenting exploratory objectives 
associated with all relevant exploratory outcome measures). The new genetic 
biomarker analyses were added to increase the knowledge of the effect of imalumab 
on well-known biomarkers of mCRC, as these biomarkers may correlate with clinical 
outcome (safety and efficacy).


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4. Synopsis, Planned Duration of Subject Participation; Section 8.3, Duration of Study 
Period(s) and Subject Participation; Section 20.2, Schedule of Study Procedures and 
Assessments: Parts 1 and 2 (Table 3)
Description of Change: The duration of Screening was extended from 3 weeks 
(21 days) to 4 weeks (28 days).
Purpose of Change: The Screening period was extended in response to feedback from 
investigators.
5. Synopsis, Inclusion Criteria; Synopsis, Exclusion Criteria; Section 9.1, Inclusion 
Criteria; Section 9.2, Exclusion Criteria
Description of Change: Minor updates to inclusion criteria #8, #11, #13, and #15, as 
well as to exclusion criteria #3, #9, and #15, to match exactly the equivalent 
eligibility criteria presented in Sections 9.1 and 9.2. Inclusion criterion #12 was 
updated due to change in abbreviation use. Changed as follows:

Inclusion criterion #8: “Known KRAS, NRAS mutation status (if unknown 
status for either of these genes, and no archival tissue is available, a fresh 
tumor biopsy will be obtainedmade)”

In inclusion criteria #11 and #13, the sub-bullets were changed from lower 
case roman numerals to lower case letters

Inclusion criterion #11c: “Absolute neutrophil count (ANC) ≥1,000/µL”

Inclusion criterion #12: “Adequate renal function, defined as serum creatinine 
≤2.0 times ULN and creatinine clearance > 50 mL/min or eGFR estimated 
glomerular filtration rate > 50 ml/min/1.73 m2”

Inclusion criterion #15: “Secondary contraception method contraceptive 
measures could be either birth control pills, or patches, or intrauterine 
devices”

Exclusion criterion #3: “Prior treatment with panitumumab for subjects with 
KRAS wt and /NRAS wt tumors”

Exclusion criterion #9: “Left ventricular ejection fraction (LVEF) < 40% as 
determined by echocardiogram (ECHO)/multigated acquisition scan 
(MUGA) performed at screening or within 90 days prior to C1D1”

Exclusion criterion #15: “Known history of, or active hepatitis B virus (HBV) 
and/or, hepatitis C virus (HCV), or active tuberculosis”
Purpose of Change: Administrative, correction for protocol inconsistencies.
6. Synopsis, Inclusion Criteria; Section 9.1, Inclusion Criteria
Description of Change: Inclusion criterion #3 was updated to clarify the definition of 
prior SoC treatment lines as “prior cancer drug therapy treatment lines including 
SoC in the metastatic setting.”
Purpose of Change: Administrative, to improve the clarity of the protocol.


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7. Synopsis, Inclusion Criteria; Section 9.1, Inclusion Criteria
Description of Change: Updated inclusion criteria #15 and #16 to harmonize the 
contraceptive advice given in this clinical trial protocol with the SmPC for 5-FU.
Added the following text:

“In addition, these birth control methods must be continued for at least 
180 days after last administration of 5-FU in subjects who receive this 
treatment.”
Purpose of Change: Safety, in response to feedback from the Medicines & Healthcare 
products Regulatory Agency (MHRA) (UK).
8. Synopsis, Exclusion Criteria; Section 9.2, Exclusion Criteria
Description of Change: Addition of a new exclusion criterion (#4) to exclude patients 
with KRAS wt and NRAS wt tumors who have a known history of keratitis, 
ulcerative keratitis, or severe dry eye, consistent with the SmPC for panitumumab. 
The subsequent exclusion criteria were renumbered. Added the following text:

“Known history of keratitis, ulcerative keratitis or severe dry eye in subjects 
with KRAS wt and NRAS wt tumors.”
Purpose of Change: Safety, in response to feedback from the MHRA (UK).
9. Synopsis, Exclusion Criteria; Section 9.2, Exclusion Criteria
Description of Change: Updated exclusion criterion #5 to clarify that residual AEs 
from previous treatment > Grade 1 in severity of neuropathy and alopecia are not 
exclusionary for participation in this study.
Purpose of Change: Administrative, to improve the clarity of the protocol.
10. Synopsis, Exclusion Criteria; Section 9.2, Exclusion Criteria
Description of Change: Updated the wording of exclusion criterion #20 to replace 
“nursing” with “breastfeeding”.
Purpose of Change: Administrative, to improve the clarity of the protocol.
11. Synopsis, Sample Size Calculations; Section 13.1, Sample Size and Power 
Calculations; Section 20.1, Study 391401 Schematic (Figure 2)
Description of Change: Updated the wording to clarify the number of subjects in the 
Phase 2a (Part 2) of the study, while also harmonizing the wording in the Synopsis 
and Section 13.1: “With an enrollment ratio of 2:1, and taking into account the time 
for accrual of 1 year and an additional follow-up period of 6 months after the last 
subject is enrolled, the sample size needed is a total of 44 approximately 22 subjects 
in each of the imalumab-containing treatment arms (imalumab + panitumumab and 
imalumab + 5 FU/LV) and 22 subjects in the control arm (SoC), for a total of 
66 subjects. The number of subjects allocated to each treatment in Part 2 of the study 
was removed from Figure 2 (Section 20.1).
Purpose of Change: Administrative correction.


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12. Synopsis, Planned Statistical Analysis; Section 13.5, Planned Interim Analysis of the 
Study
Description of Change: The timing of the interim analysis was updated as follows: 
“An interim analysis will be implemented for planning purposes when 33 PFS events 
have been observed in Part 2.”
Purpose of Change: Administrative, for clarification purposes.
13. Section 5, List of Abbreviations
Description of Change: Added new abbreviations (AUC0-tau, C2D15, cfDNA, CTA, 
EGFR, MHRA, NGS, PEI, qPCR, RSI, SmPC, SUSAR and UK). Deleted 
abbreviations no longer used (HLT, MSI and SMQ). Ensured that the list of 
abbreviations is in alphabetical order. Added “Continued” at the top of each page of 
the List of Abbreviations per Baxalta style guide.
Purpose of Change: Administrative.
14. Section 6.1.4, Genetic Biomarkers Analysis; Section 21, References
Description of Change: A new section was added to provide background information 
describing findings from previous studies of mCRC and the effect of changes in 
KRAS/NRAS mutation status during treatment (acquired treatment resistance). This 
new section provides the rationale for the addition of the genetic biomarkers analysis 
to this clinical study. Relevant publications were added to the References section to 
support the additional information summarized in this section.
Purpose of Change: Administrative, to provide context for the new genetic 
biomarkers analysis that was added to this clinical study protocol.
15. Section 6.1.5.1, Dose Rationale
Description of Change: Updated the data cut-off date for the safety data that 
contributed to the dose rationale for this study.

“30 Sep 2014” changed to “2015 JUL 01”.
Purpose of Change: Administrative, in response to feedback from the MHRA (UK)
and Paul-Ehrlich-Institute (PEI, Germany).


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16. Section 6.1.5.4, Rationale for Selection of Combination Therapies, Panitumumab
Description of Change: Included rationale for the inclusion of subjects in this study 
with ECOG PS 0-2 and potential treatment with panitumumab. Added the following 
text:

“Panitumumab has been approved in several countries including the United 
States (US) and Germany as standard therapy. The sponsor feels it is justified 
to administer panitumumab to subjects in this study with Eastern Cooperative 
Oncology Group (ECOG) Performance Status (PS) of 0-2. Panitumumab has 
been shown to be well tolerated in frail elderly patients (ECOG ≤3) with 
KRAS wt mCRC and poor prognostic factors in a Phase 2 study of the 
Spanish Cooperative Group for the Treatment of Digestive Tumours.32 In 
addition, panitumumab and cetuximab were compared in a randomized
Phase 3 study in patients with chemotherapy-refractory KRAS wt mCRC 
(ECOG ≤2).33 The incidence of adverse events (AEs) of any grade and 
grade 3-4 AEs was similar across treatment groups.”

As this is now the first use of the terms “United States”, “Eastern Cooperative 
Oncology Group”, “Performance Status” and “adverse events” within the 
body of the protocol, subsequent use of these terms has been changed to “US” 
(Section 8.1), “ECOG” and “PS” (Section 6.3), “AEs” (applied as necessary 
throughout).
Purpose of Change: Safety, in response to feedback from the MHRA (UK); 
Administrative (first use of terms and abbreviations).
17. Section 6.3, Population to be Studied; Section 8.1 Study Design
Description of Change: The definition of a prior line of treatment for this clinical 
study was clarified as follows: “Adjuvant therapy in the metastatic setting
(administered following a surgical procedure) and investigational products are 
included in the definition of a prior line of treatment for the purposes of this 
study.”
Purpose of Change: Administrative, to improve the clarity of the protocol.
18. Section 6.4.2.1, Clinical Protocol 391101; Section 6.5, Evaluation of Anticipated 
Risks and Benefits of the Investigational Product(s) to Human Subjects
Description of Change: Updated the total number of human subjects treated with 
imalumab up to the most recent data cut-off date (2015 JUL 01):

“28 subjects” was updated to “48 subjects”.

“30 Sep 2014” was updated to “2015 JUL 01”.
Purpose of Change: Administrative, in response to feedback from the MHRA (UK) 
and PEI (Germany).


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19. Section 6.4.2.1.1, Safety Summary
Description of Change: Summarized the safety data for imalumab reported up to the 
most recent data cut-off date (2015 JUL 01). The following changes were made:

Presented further details of the one SUSAR reported as of 2015 JUL 01 
(MedDRA preferred term: alveolitis allergic).

Presented more details of the cancer types treated in Cohorts 5, 7, 8 and 10 of 
Study 391101.

Presented details of an additional SUSAR reported after the data cut-off date 
(2015 JUL 01) on 2015 SEP 16 (nausea, vomiting, and constipation).

Presented summary of SAEs and related AEs that have occurred as of the 
2015 JUL 01 cut-off date and added a cross-reference to the IB.
Purpose of Change: Safety, in response to feedback from the MHRA (UK) and PEI
(Germany).
20. Section 8.2.1.1, Protocol 391401 Dose Escalation Scheme, Figure 1
Description of Change: Figure 1 was duplicated in error and a superfluous copy was 
included in the clinical trial protocol; the extra copy was deleted in this amendment.
Purpose of Change: Administrative, correction for clarity.
21. Section 8.2.3, Definition of Dose-Limiting Toxicity; Section 10.3.3.1, Study Drug 
Administration
Description of Change: Updated the protocol to provide reference for dose
modifications that will be implemented in response to a dermatologic reaction (NCI 
CTCAE Grade 3 or higher, or considered intolerable) in subjects treated with 
panitumumab (Amgen Inc., 2015).
Purpose of Change: Safety, in response to feedback from the MHRA (UK).
22. Sections 8.7.1.2, Leucovorin; 8.7.1.3, 5-Fluorouracil; 8.7.1.4, Panitumumab; 
9.1, Inclusion Criteria; 10.3.2.3, Day 8 of Each Cycle
Description of Change: Labeling details updated to include “if applicable”.
Purpose of Change: Administrative.


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23. Section 8.7.2.1 Imalumab; Section 8.7.3.1 Imalumab
Description of Change: Detailed information describing routine clinical practice for 
preparing products for injection was removed from the protocol and a reference to the 
Pharmacy Manual was added. The permissible time for vials of imalumab to be 
removed from storage prior to infusion was clarified as “7 hours (4 hours prior to 
aspiration and 3 hours after aspiration)”. Storage of product prior to administration 
was clarified that “Vials removed from storage to equilibrate to room temperature 
must not be removed from secondary packaging (original outer box), in order to 
protect product from light until administration.” The instructions for IV 
administration of imalumab were updated as follows: “The syringe may be
hand-pushed for IV administration; alternatively, a syringe-driver pump may be used 
to actuate the syringe depending on the user/administrator’s comfort and/or 
preference. Considerations include: the amount of product to be infused, the size of 
the syringe used, the length of time to administer the product, and the user’s ability to 
deliver the product as indicated.”
Purpose of Change: Administrative, to update and clarify procedures for imalumab 
administration.
24. Section 8.7.2.3, Standard of Care Drugs; Section 8.7.3.3, Standard of Care Drugs
Description of Change: Added a recommendation that investigators should respect the 
contraindications in the SmPCs of the comparators and give consideration to the 
special warnings and precautions in the SmPCs of comparators.
Purpose of Change: Safety, in response to feedback from the MHRA (UK).
25. Section 8.7.3.3, Standard of Care Drugs; Section 8.7.4.2.2, Arm B (Investigator 
Choice); Section 10.3.3.1.2, 5-Fluorouracil, Leucovorin, Panitumumab, and Standard 
of Care Administration
Description of Change: Reiterated that if subjects are to be treated with panitumumab 
as SoC they should not have a known history of keratitis, ulcerative keratitis or severe 
dry eye. Added a recommendation that investigators should advise subjects to 
minimize exposure to ultraviolet light (sunlight) following treatment with 5-FU or 
panitumumab, to be consistent with the advice given in the SmPCs for these products 
(Section 10.3.3.1.2 only).
Purpose of Change: Safety, in response to feedback from the MHRA (UK).
26. Section 9.1, Inclusion Criteria
Description of Change: Minor update to inclusion criterion #8 to match exactly the 
equivalent inclusion criterion presented in the Synopsis (Section 3). Changed as 
follows:

“Known KRAS, and NRAS mutation status (if unknown status for either of 
these genes and no archival tissue is available, a fresh tumor biopsy will be 
obtained)”.
Purpose of Change: Administrative, correction for protocol inconsistency.


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27. Section 9.3, Withdrawal and Discontinuation
Description of Change: Added use of prohibited therapies as an additional withdrawal 
criterion.
Purpose of Change: Safety, in response to feedback from the MHRA (UK).
28. Section 10.3, Screening and Study Visits
Description of Change: It was clarified that, at re-screening, results from assessments 
that were conducted within the previous 21 days can be reused, to avoid repetition of 
numerous Screening assessments.
Purpose of Change: Administrative, to improve the clarity of the protocol.
29. Section 10.3.1, Screening Assessments; Section 10.3.2, Baseline Assessments
(Cycle 1 Day 1, predose); Section 10.3.3.2, Day 1 of Each Cycle; Section 10.3.3.3, 
Day 8 of Each Cycle; Section 10.3.3.4 Day 15 of Each Cycle; Section 10.3.3.5, 
Day 22 of Each Cycle; Section 10.3.3.9 End of Study/Early Termination Visit;
Section 20.2, Schedule of Study Procedures and Assessments: Parts 1 and 2 
(Table 3); Section 20.2, Schedule of Study Procedures and Assessments: SoC 
Following Randomization (4-week Cycles or if Subject is on Best Supportive Care)
(Table 4); Section 20.2, Schedule of Study Procedures and Assessments: SoC 
Following Randomization (3-week Cycles) (Table 5)
Description of Change: The protocol was updated to replace “IRT System telephone 
call” with “Entry into IRT System”, as this is a computer-based system and does not 
operate via the telephone. This assessment was also added to the End of Study/Early 
Termination study visit (Section 10.3.3.9).
Purpose of Change: Administrative, to improve the clarity of the protocol.


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30. Section 10.3.1, Screening Assessments; Section 10.3.2 Baseline Assessments 
(Cycle 1 Day 1 predose); Section 20.2 Schedule of Study Procedures and 
Assessments: Parts 1 and 2 (Table 3)
Description of Change: Section 10.3.1 was split out into two distinct sections to 
describe separately the assessments and procedures to be conducted at Screening and 
Baseline. It was clarified that all Screening procedures should be performed within 
28 days of first imalumab administration (C1D1). Use of the micro satellite instability
technique for genetic testing was removed from the protocol. The timing of the 
Baseline Visit (Day -1) was changed; the Baseline Visit will now take place at C1D1. 
It was clarified that all questionnaires (EORTC QLQ-C30, EORTC QLQ-CR29, and 
EQ-5D) should be administered and completed prior to the start of any assessments at 
Baseline (C1D1). The timing of the laboratory assessments immediately prior to 
Cycle 1 was clarified (either on Day -1 or on Day 1 predose).
Purpose of Change: Administrative, to improve the clarity of the protocol.
31. Section 10.3.3.1 Study Drug Administration
Description of Change: It was clarified that if treatment with 5-FU/LV or 
panitumumab is interrupted due to an AE, and there are no concurrent safety concerns 
regarding imalumab, treatment with imalumab may be continued while treatment 
with 5-FU/LV or panitumumab is interrupted.
Purpose of Change: Administrative, to improve the clarity of the protocol.
32. Section 10.3.3.2 Day 1 of Each Cycle 
Description of Change: Updated to clarify that the assessments and procedures to be 
conducted at Baseline (C1D1) predose are described in Section 10.3.2.
Purpose of Change: Administrative, to improve the clarity of the protocol.
33. Section 10.3.2 Baseline Assessments (Cycle 1 Day 1, predose); Section 10.3.3.2 
Day 1 of Each Cycle; Section 10.3.3.3 Day 8 of Each Cycle; Section 10.3.3.4 Day 15 
of Each Cycle; Section 10.3.3.5 Day 28 of Each Cycle 
Description of Change: The timing of the collection of blood samples for PK 
(imalumab plasma level) and PD biomarkers (oxMIF and total MIF) analyses was 
clarified.
Purpose of Change: Administrative, to improve the clarity of the protocol and for 
consistency with Table 6.
34. Section 10.3.3.3, Day 8 of Each Cycle
Description of Change: Corrected minor typographical error.

“2” was removed from “Vital signs measurement should be recorded within 
30 minutes of completion of the imalumab injection2”.
Purpose of Change: Administrative, correction for clarity.


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35. Section 10.3.3.7 Day 28 (Cycle 2 and Every Other Cycle); Section 11.2, Antitumor 
Effect – Solid Tumors
Description of Change: The timing of tumor measurements by CT or MRI scans was 
clarified (every 8 weeks) for subjects receiving SoC in 3-weekly treatment cycles. As 
these subjects will not have a Day 28 in their treatment cycles, the study day of these 
assessments will vary from cycle to cycle. Day 22 will be the first day of the next 
treatment cycle in subjects receiving SoC in 3-weekly treatment cycles. The timing of 
the Baseline tumor measurements was clarified as being within 28 days prior to first 
imalumab administration (C1D1) rather than 28 days prior to screening 
(Section 11.2).
Purpose of Change: Administrative, to improve the clarity of the protocol.
36. Section 10.3.3.8 Day 29 = Day 1 of the Next Cycle
Description of Change: Section 10.3.3.8 (original numbering) was deleted from the 
protocol: “Section 10.3.3.8 Day 29 = Day 1 of the Next Cycle
Refer to procedures as outlined in Section 10.3.3.2.” 
Purpose of Change: Administrative, to improve the clarity of the protocol.
37. Section 10.3.3.8 End of Study/Early Termination Visit, Section 10.3.3.9 Safety 
Follow-up Visit
Description of Change: Section 10.3.2.8 (original numbering) was split out into two 
distinct sections to describe separately the assessments and procedures to be 
conducted at the End of Study/Early Termination Visit and Safety Follow-up Visit. 
It was clarified that at both of these visits all questionnaires (EORTC QLQ-C30, 
EORTC QLQ-CR29, and EQ-5D) should be administered and completed prior to the 
start of any assessments. 
Purpose of Change: Administrative, to improve the clarity of the protocol.
38. Section 10.3.3.8, End of Study/Early Termination Visit; Section 10.3.3.9, Safety 
Follow-up Visit; Section 11.2, Antitumor Effect - Solid Tumors; Section 20.2, 
Schedule of Study Procedures and Assessments: Parts 1 and 2 (Table 3); 
Section 20.2, Schedule of Study Procedures and Assessments: SoC Following 
Randomization (4-week Cycles or if Subject is on Best Supportive Care) (Table 4); 
Section 20.2 Schedule of Study Procedures and Assessments: SoC Following 
Randomization (3-week Cycles) (Table 5)
Description of Change: The tumor measurements to be conducted at the End of 
Study/Early Termination Visit and Safety Follow-up Visit were clarified as follows: 
“A tumor measurement should be obtained at the End of Study/Early Termination 
visit, if no disease progression was confirmed previously and this visit occurs 
> 4 weeks after the last scan; no additional scans will be required if disease 
progression is confirmed at this visit. A tumor measurement should be obtained at the 
Safety Follow-up visit, if no disease progression was confirmed previously and this 
visit occurs > 4 weeks after the last scan.
Purpose of Change: Administrative, to improve the clarity of the protocol.


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39. Section 10.4, Medications and Non-Drug Therapies
Description of Change: Updated list of prohibited medications and changed language 
around discontinuation of subjects who receive prohibited medications or non-drug 
therapies. In addition, corrected minor typographical error.

“Brivudin, sorivudine and other nucleoside analogues must be avoided in 
subjects who receive treatment with 5-FU” was added

“Live vaccines must be avoided for 6 weeks following last dose of imalumab” 
was added

“A subject who has taken any of these medications or received any of these 
non-drug therapies may be discontinued” was changed to “A subject who has 
taken any of these medications or received any of these non-drug therapies 
must be discontinued”

Changed “CID1” to “C1D1”
Purpose of Change: Safety, in response to feedback from the MHRA (UK); 
Administrative, correction of typographical error for clarity.
40. Section 11, ASSESSMENT OF EFFICACY, PHARMACOKINETICS, 
PHARMACODYNAMICS, AND GENETIC TESTING
Description of Change: The wording of the section heading was updated to take into 
consideration the additional genetic testing added to the protocol.
Purpose of Change: Administrative, for consistency with other updated sections of the 
protocol.
41. Section 11.3, Genetic Testing
Description of Change: Genetic testing for the MSI phenotype was removed from the 
protocol. It was specified that genetic testing for KRAS/NRAS mutation needs to be 
performed early enough to allow randomization within 4 weeks; however, if KRAS 
mutation status is known, it is permissible for the subject to start treatment while 
NRAS testing is pending.
Purpose of Change: Administrative, for consistency with other updated sections of the 
protocol.
42. Section 11.4, Tumor-associated Biomarkers
Description of Change: Details of the timing and procedures for assessing 
tumor-associated genetic biomarkers were added to the protocol. 
Purpose of Change: Administrative, for consistency with other updated sections of the 
protocol.
43. Section 12.1.1, Definitions
Description of Change: To ensure complete clarity of the instructions for assessing 
events relating to disease progression, updated this section as follows: “Events 
relating to clinical deterioration due to disease progression as a result of the 
underlying malignancy are not to be considered or analyzed as AEs (or SAEs), but 
will be recorded on the CRF.”
Purpose of Change: Administrative.


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44. Section 12.1.1.4, Unexpected Adverse Events
Description of Change: The statement “Unexpected” also refers to the AEs that are 
mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation” was changed to “The 
expectedness of AEs will be determined by the sponsor using the IB as the RSI. 
This determination will include considerations such as the number of AEs 
previously observed, but not on the basis of what might be anticipated from the 
pharmacological properties of a medicinal product.”
Purpose of Change: Safety, in response to feedback from the MHRA (UK) and PEI
(Germany).
45. Section 12.1.2, Assessment of Adverse Events
Description of Change: The permitted window for the follow-up of each TEAE was 
amended to ±7 days, instead of ±2 days. 
Purpose of Change: Administrative correction.
46. Section 12.1.2.3, Safety Reporting
Description of Change: As an eCRF will be used for this study, this section was 
included in the protocol per the instructions in the Baxalta clinical study protocol 
template. Section 12.11, Safety Reporting, was deleted to avoid redundancy with 
Section 12.1.2.3.
Purpose of Change: To maintain consistency with current Baxalta protocol template.
47. Section 12.2, Urgent Safety Measures
Description of Change: Revised this section of the protocol to indicate that, in 
addition to the responsible EC, Regulatory Authorities must be informed of any 
urgent safety measures. Text in bold was added:

“The sponsor will also ensure the responsible ethics committee (EC) and the 
relevant competent authorities are is notified (in writing, if applicable) of 
the urgent safety measures taken in such cases according to local regulations.”
Purpose of Change: Safety, in response to feedback from the MHRA (UK).
48. Section 13.2 Datasets and Analysis Cohorts
Description of Change: The “FAS Population” was changed, and is now referred to 
consistently as the “FAS”. The definition of the FAS was changed as follows: “The 
FAS will include all subjects who 1) received at least 1 administration of IP, and 
2) have 1 post-baseline tumor response assessment based on RECIST v1.1 or died 
within 18 weeks of the start of treatment.”
Purpose of Change: Administrative.
49. Section 13.4.4.2, Safety Outcome Measures
Description of Change: The analysis that will be conducted for AEs was updated as 
follows: “Adverse events will be grouped by system organ class, high level term 
(HLT), and .standardized MedDRA query (SMQ).”
Purpose of Change: Administrative.


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50. Section 15.4, Safety Monitoring
Description of Change: Section 12.10 (previous numbering), Safety Monitoring, and 
Section 16.4, Data Safety Monitoring, were merged in a new section (Section 15.4) to 
minimize repetition and as per the instructions in the Baxalta clinical study protocol.
Purpose of Change: To maintain consistency with current Baxalta protocol template.
51. Section 20.1, Study 391401 Schematic, Figure 2
Description of Change: Figure 2 was duplicated in error and a superfluous copy was 
included in the clinical trial protocol; the extra copy was deleted in this amendment.
Purpose of Change: Administrative, correction for clarity.
52. Section 20.2, Schedule of Study Procedures and Assessments: Parts 1 and 2 (Table 3)
Description of Change: Table 3 was updated to reflect all of the changes made 
elsewhere in the protocol, namely:

Screening was extended from 21 days (3 weeks) to 28 days (4 weeks)

The Baseline Visit was moved from Day -1 to coincide with Day 1

The End of Study/Early Termination Visit procedures were separated from the 
Safety Follow-up Visit procedures

The duration of the visit windows was extended from ±1 days to ±2 days 
(with the exception of the ±7-day window for Safety Follow-up Visit)

The footnotes for the vital signs, ECG and laboratory assessments were 
updated for consistency with other sections of the protocol. The timing of the 
laboratory assessments immediately prior to Cycle 1 was clarified (either on 
Day -1 or on Day 1 predose). The timing of the 12-lead ECG assessments at 
Screening and on Day 1 (Baseline, C1D1) was clarified.

BRAF/MIS components of the genetic testing were removed from the 
protocol

Blood/urine sample collection for assessment of genetic biomarkers from 
cfDNA was added to the schedule of assessments and a footnote added

Abbreviations were redefined according to updated Table 3 and footnotes

The timing of the Safety Follow-up Visit was specified (30 ±7 days after last 
dose of study treatment)

It was specified that genetic testing for KRAS/NRAS mutation needs to be 
performed early enough to allow randomization within 4 weeks; however, if 
KRAS mutation status is known, it is permissible for the subject to start 
treatment while NRAS testing is pending.

It was specified that baseline CT or MRI scans can be accepted within 28 days 
prior to first imalumab administration (C1D1), repeated every 2 cycles 
(8 weeks) with a 7-day window is permitted for all imaging studies for tumor 
measurement purposes

The timing of the collection of blood samples for PK (imalumab plasma level) 
and PD biomarkers (oxMIF and total MIF) analyses was clarified and 
harmonized with Table 6
Purpose of Change: Administrative, for consistency with the updates made 
throughout this clinical study protocol.


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53. Section 20.2, Schedule of Study Procedures and Assessments: SoC Following 
Randomization (4-week Cycles or if Subject is on Best Supportive Care) (Table 4); 
Schedule of Study Procedures and Assessments: SoC Following Randomization 
(3-week Cycles) (Table 5)
Description of Change: Two new schedules of assessments were added to the clinical 
study protocol: Table 4 and Table 5 describe the assessments and procedures for 
subjects receiving SoC on 4-week and 3-week treatment cycles, respectively.
Purpose of Change: Administrative, to provide greater clarity to investigators.
54. Section 20.2, Schedule of Pharmacokinetic and Pharmacodynamic Sample 
Collections (Parts 1 and 2) for Subjects Receiving Imalumab Treatment (Table 6)
Description of Change: Table 6 was updated to include the blood sample taken at 
Screening (Days -28 to -1) for PK and PD assessments. The acceptable time windows 
for the collection of blood samples at 24 hours (± 4 hours after infusion) and at 
72 hours (±8 hours after infusion) were also included.
Purpose of Change: Administrative, for consistency with other sections of the updated 
protocol.
55. Section 20.2, Blood Volumes (Parts 1 and 2) for Lab Tests and PK/PD for Subjects 
Receiving Imalumab Treatment (Table 7)
Description of Change: Table 7 was updated to include the blood samples taken at 
Screening (Days -28 to -1) for hematology/blood chemistry/coagulation and PK/PD 
assessments. The timing of taking these blood samples at each subsequent treatment 
cycle was corrected. Footnote b was deleted (not relevant to the contents of this 
table).
Purpose of Change: Administrative, for consistency with other sections of the updated 
protocol.
56. Section 20.2, Blood and Urine Volumes (Parts 1 and 2) for Optional Genetic 
Biomarkers cfDNA Analysis for Subjects Receiving Imalumab Treatment (Table 8)
Description of Change: Table 8 was included in the updated protocol to describe the 
volumes of blood and urine samples that will be taken for the genetic biomarker 
analyses at Screening (Days -28 to -1), Cycle 1 Day 28, every other cycle and at the 
End of Study/Early Termination Visit.
Purpose of Change: Administrative, for consistency with other sections of the updated 
protocol.


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57. Section 21, References
Description of Change: Addition of new references per new information included in 
the following sections:

Section 6.1.4: Misale et al 2012 (Ref #22); Thierry et al 2014 (Ref #23); 
Haber and Velculescu 2014 (Ref #24); Tóth et al 2016 (Ref #25); Patel and 
Karapetis 2013 (Ref #26); Spindler et al 2012 (Ref #27); Kapur 2012 
(Ref #28)

Section 6.1.5.4: Sastre et al, 2015 (Ref #32); Price et al, 2014 (Ref #33)

Section 8.2.3: Amgen Inc., 2015 (Ref #34).
Purpose of Change: Administrative, a consequence of feedback from the MHRA 
(UK), as well as to provide more background information on the genetic biomarkers 
analyses.


B A X 6 9 (i mal u ma b )
Pa ge 1 2 5 of 1 2 5
Cli nical St u d y Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 M A Y 0 9
B A X A L T A C O N FI D E N TI A L – R E S T RI C T E D: D O N O T D I S T RI B U T E WI T H O U T P RI O R A P P R O V A L
I N V E S TI G A T O R A C K N O W LE D G E M E N T
P R O D U C T: B A X 6 9 (I m al u m a b)
S T U D Y TI T L E: A P h ase 2 a R a n d o mize d, O pe n - La bel St u d y t o Assess t he S afet y, 
T ole r a bilit y, a n d Effic ac y of B A X 6 9 i n C o m bi n ati o n wit h 5 -F U/ Le uc o v ori n or 
P a nit u m u m a b vers us St a n d ar d of C are i n S u bjects wit h Met ast atic C ol orect al C a ncer
P R O T O C O L I D E N TI FI E R: 3 9 1 4 0 1
C LI NI C A L T RI A L P H A S E 2 a
A M E N D M E N T 5 ( G L O B A L): 2 0 1 6 M A Y 0 9
Re pl aces A me n d me n t 2 ( G L O B A L): 2 0 1 5 J U L 1 3
A L L V E R SI O N S:
A m e n d me nt 4 ( Ger m a n y Versi o n): 2 0 1 5 D E C 1 6
A m e n d me nt 3 ( U K Versi o n): 2 0 1 5 O C T 0 2
A m e n d me nt 2 ( G L O B A L): 2 0 1 5 J U L 1 3
A m e n d me nt 1 ( G L O B A L): 2 0 1 5 M A R 06
Ori gi n al ( G L O B A L): 2 0 1 4 D E C 1 0
O T H E R I D(s)
E u dr a C T N u m ber: 2 0 1 5 - 0 0 0 8 9 6- 2 8
I N D N U M B E R: 1 1 2 8 5 0
B y  si g ni n g bel o w, t he i n vesti gat or ac k n o wle d ges t hat he/s he has rea d a n d u n dersta n ds 
t his pr ot oc ol, a n d pr o vi des ass ura nce t hat t his st u d y will be c o n d ucte d acc or di n g t o all 
re q uire me nts as defi ne d i n t his pr ot oc ol, C T A , IC H G C P g ui deli nes, a n d all a p plica ble 
nati o nal a n d l ocal re g ulat or y re q uire me nts.
Si g nat ure of C o or di nati n g I n vesti gat or
Date
Pri nt Na me a n d Title of C o or di nati n g I n vesti gat or
Si g nat ure of S p o ns or Re prese ntati ve
Date
P P D
, M D, 
, Cli nical De vel o p me nt
P P D

SAP_001.pdf: 
S T A TI S TI C A L A N A L Y SI S P L A N
I m al u m a b ( B A X 6 9)
P H A S E 2 a
A P h a s e 2 a R a n d o mi z e d, O p e n - La b el St u d y t o A s s e s s t h e S af et y, T ol er a bilit y, 
a n d Effi c a c y of B A X 6 9 i n C o m bi n ati o n wit h 5 -F U/ L e u c o v ori n or P a nit u m u m a b 
v er s u s St a n d ar d of C ar e i n S u bj e ct s wit h M et a st ati c C ol or e ct al C a n c er
A P h a s e 2 a R a n d o mi z e d, O p e n - La b el St u d y t o A s s e s s t h e S af et y, T ol er a bilit y, 
a n d Effi c a c y of B A X 6 9 i n C o m bi n ati o n wit h 5 -F U/ L e u c o v ori n or P a nit u m u m a b 
v er s u s St a n d ar d of C ar e i n S u bj e ct s wit h M et a st ati c C ol or e ct al C a n c er
P R O T O C O L I D E N TI FI E R: 3 9 1 4 0 1
St u d y S p o ns or(s)
P P D
:
Ba x alta U S I nc.
O ne Ba xter Wa y
Westla ke Villa ge, C A  9 1 3 6 2
Ba xter I n n o vati o ns G m b H
I n d ustriestrasse 6 7
A- 1 2 2 1 Vie n na, A U S T RI A 
A ut h or:
, 
, Q ui ntiles
Pr ot oc ol:
A M E N D M E N T 5 : 2 0 1 6 M A Y 0 9
S A P Versi o n #:
1. 0
S A P Date:
2 0 1 6 O C T 1 0
Stat us:
A p pr o ve d
P P D


I mal u ma b ( B A X 6 9)
Pa ge 2 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
T A B L E O F C O N T E N T S
1.
I N T R O D U C TI O N A N D O B JE C TI V E S ............................................................. 5
1. 1
St u d y  O bjecti ves ................................................................................................. 5
1. 1. 1
Pri mar y  O bjecti ves.......................................................................................5
1. 1. 2
Sec o n dar y  O bjecti ve(s)................................................................................5
1. 1. 2. 1 Efficac y .............................................................................................. 5
1. 1. 2. 2 Safet y .................................................................................................. 6
1. 1. 2. 3 P har ma c o ki netics ............................................................................... 6
1. 1. 2. 4 Healt h -relate d Q ualit y of Life............................................................6
1. 1. 3
E x pl orat or y  O bjecti ves ................................................................................6
1. 1. 3. 1 P har mac o d y na mics ............................................................................. 6
1. 1. 3. 2 Ge netic Bi o mar kers ............................................................................6
1. 1. 3. 3 Q ualit y  of Life.................................................................................... 6
2.
S T U D Y D E SI G N .................................................................................................... 7
2. 1
St u d y  P o p ulati o n .................................................................................................9
2. 2
I ncl usi o n a n d E xcl usi o n Criteria ....................................................................... 1 0
2. 2. 1
I ncl usi o n Criteria .......................................................................................1 0
2. 2. 2
E xcl usi o n Criteria ......................................................................................1 1
2. 3 
Sa m ple Size a n d P o wer Calc ulati o ns................................................................ 1 2
2. 4
Ra n d o mizati o n .................................................................................................. 1 3
2. 5
Bli n di n g/ U n bli n di n g ......................................................................................... 1 3
2. 6
St u d y  St o p pi n g R ules........................................................................................1 3
2. 7
St u d y  Assess me nts............................................................................................1 4
2. 8
Data M o nit ori n g C o m mittee .............................................................................1 4
3. 
S T U D Y O U T C O M E M E A S U R E S .....................................................................1 4
3. 1
Efficac y  O utc o me Meas ures............................................................................. 1 4
3. 1. 1
Pri mar y  Efficac y O utc o me Meas ure.......................................................... 1 4
3. 1. 2
Sec o n dar y  Efficac y O utc o me Meas ures....................................................1 4
3. 2
Safet y  O utc o me Meas ures.................................................................................1 4
3. 2. 1
Pri mar y  Safety O utc o me Meas ures ...........................................................1 4
3. 2. 2
Sec o n dar y  Safety O utc o me Meas ures ....................................................... 1 4
3. 3
I m m u n o ge nicity O utc o me Meas ures ................................................................1 4
3. 4
P har mac o ki netic O utc o me Meas ures ................................................................1 5
3. 5
Q ualit y  of Life O utc o me Meas ures...................................................................1 5


I mal u ma b ( B A X 6 9)
Pa ge 3 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
3. 6
E x pl orat or y  O utc o me Meas ures........................................................................ 1 5
4.
A N A L Y SI S S E T S ................................................................................................. 1 5
4. 1
F ull A nal ys is Set...............................................................................................1 5
4. 2
Safet y  A nalys is Set ........................................................................................... 1 6
5.
S T A TI S TI C A L C O N SI D E R A TI O N S ...............................................................1 6
5. 1
I nteri m A nalys es ...............................................................................................1 6
5. 2
Ha n dli n g of Missi n g, U n use d, a n d S p uri o us Data ............................................1 6
5. 3
Defi niti o n of Baseli ne ....................................................................................... 1 7
5. 4
Defi niti o n of Treat me nt Gr o u ps ........................................................................1 7
5. 5
C ha n ges fr o m t he Pla n ne d Statistical A nal y sis i n Pr ot oc ol .............................. 1 8
6.
S T U D Y S U B J E C T S ............................................................................................. 1 9
6. 1
Dis p os iti o n of S u bjects ..................................................................................... 1 9
6. 2
De m o gra p hic a n d Baseli ne C haracteristics....................................................... 1 9
6. 3
Me dical Hist or y ................................................................................................. 1 9
6. 4
Pri or T hera pies a n d Me dicati o ns ...................................................................... 1 9
6. 5
C o nc o mita nt Me dicati o ns................................................................................. 2 0
6. 6
Pr ot oc ol De viati o ns ........................................................................................... 2 0
7.
E F FI C A C Y E V A L U A TI O N ............................................................................... 2 1
7. 1
A nal y sis of Pri mar y Efficac y O utc o me Meas ure.............................................. 2 1
7. 1. 1
Deri vati o n of Pri mar y  Efficac y O utc o me Meas ure...................................2 1
7. 1. 2
A nal y sis Met h o ds f or t he Pri mar y Efficac y O utc o me Meas ure................2 3
7. 2
A nal y sis of Sec o n dar y Efficac y O utc o me Meas ure .......................................... 2 3
7. 2. 1
Deri vati o n of Sec o n dar y  O utc o me Meas ures............................................2 3
7. 2. 1. 1 O verall S ur vi val ............................................................................... 2 3
7. 2. 1. 2 O verall Res p o nse Rate ..................................................................... 2 4
7. 3
Se nsiti vit y  A nalys es ..........................................................................................2 4
8.
S A F E T Y E V A L U A TI O N ....................................................................................2 5
8. 1
A nal y sis of Pri mar y Safet y O utc o me Meas ure................................................. 2 5
8. 2
E xte nt of E x p os ure ............................................................................................ 2 5
8. 3
A d verse E ve nts .................................................................................................. 2 6
8. 4
Cli nical L a b orat or y E val uati o ns .......................................................................2 7
8. 4. 1
He mat ol o g y ................................................................................................ 2 8


I mal u ma b ( B A X 6 9)
Pa ge 4 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
8. 4. 2
Ser u m C he mistr y ....................................................................................... 2 8
8. 4. 3
C oa g ulati o n ................................................................................................2 9
8. 4. 4
Uri nal y sis ...................................................................................................2 9
8. 5
E C G ................................................................................................................... 2 9
8. 6
Vital Si g ns ......................................................................................................... 3 0
8. 7
I m m u n o genicit y ................................................................................................ 3 1
9.
E V A L U A TI O N O F P H A R M A C O KI N E TI C S ................................................. 3 1
1 0.
E V A L U A TI O N O F Q U A LI T Y O F LI F E ......................................................... 3 2
1 0. 1
Q ualit y  of Life Sc ori n g..................................................................................... 3 2
1 0. 1. 1 E O R T C Q L Q -C 3 0 a n d Q L Q -C R 2 9 ...........................................................3 2
1 0. 1. 2 E Q - 5 D-5 L .................................................................................................. 3 5
1 0. 2
A nal y sis of Q o L Data........................................................................................ 3 6
1 1.
E V A L U A TI O N O F E X P L O R A T O R Y O U T C O M E M E A S U R E S ................ 3 6
1 1. 1
E val uati o n of P har mac o d y na mics ..................................................................... 3 6
1 1. 2
E x pl orat or y  Q uality of Life O utc o me Meas ures ............................................... 3 7
1 1. 3
Ge netic Bi o mar kers ........................................................................................... 3 7
1 2.
A N A L Y SI S S O F T W A R E ................................................................................... 3 7
1 3.
G U I D A N C E D O C U M E N T S ...............................................................................3 7
1 4.
R E F E R E N C E S .....................................................................................................3 8
1 5.
R E VI SI O N HI S T O R Y ........................................................................................3 9
1 6.
A P P E N DI C E S ...................................................................................................... 4 0
1 6. 1
Sc he d ule of St u d y  Pr oce d ures a n d Assess me nts .............................................. 4 1
1 6. 2
C T C gra des f or la b orat or y val ues .....................................................................4 6


I mal u ma b ( B A X 6 9)
Pa ge 5 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
1.
I N T R O D U C TI O N A N D O B JE C TI V E S
T he p ur p ose of t his st u d y, i n s u bjects wit h pr o gressi ve meas ura ble metastatic c ol orectal 
ca ncer ( m C R C), is as f oll o ws:

T o e val uate t he safet y a n d t olera bilit y of i mal u ma b i n c o m bi nati o n wit h 5-
fl u or o uracil ( 5-F U)/le uc o v ori n ( L V) or pa nit u m u ma b t o deter mi ne t he 
rec o m me n de d p hase 2 d ose ( R P 2 D) of eac h c o m bi nati o n

T o c o m pare t he efficac y  of i mal u ma b i n c o m bi nati o n wit h 5-F U/ L V vers us 
sta n dar d of care ( S o C) (i n vesti gat or c h oice) as t hir d or f o urt h treat me nt li ne i n 
s u bjects wit h K R A S m utate d ( m ut) a n d/ or N R A S m ut t u m ors

T o c o m pare t he efficac y  of i mal u ma b i n c o m bi nati o n wit h pa nit u m u ma b vers us 
S o C (i n vesti gat or c h oice) as t hir d or f o urt h treat me nt li ne i n s u bjects wit h K R A S 
wil d t y pe ( wt) a n d N R A S wt t u m ors
F urt her m ore, t he p har mac o ki netic ( P K) pr ofile of i mal u ma b i n c o m bi nati o n wit h 5-
F U/ L V or pa nit u m u ma b will be c haracterize d, a n d li mite d p har mac o d y na mic ( P D) ser u m 
mar kers will be e x pl ore d.
T he statistical a nal ys is pla n o utli nes t he met h o ds f or t he pla n ne d fi nal a nalysis i n t he 
pr ot oc ol.  As t he st u d y  will c o nti n ue t o be o n-g oi n g, a n a d diti o nal a nal ys is a d de n d u m t o 
t he st u d y re p ort will be perf or me d at t he c o m pleti o n of t he st u d y.
1. 1 
St u d y O bjecti ves
1. 1. 1
Pri m ar y O bjecti ve s
1.
T o deter mi ne t he R P 2 D of i mal u ma b i n c o m bi nati o n wit h 5-F U/ L V or 
pa nit u m u ma b ( Part 1)
2.
T o c o m pare pr o gressi o n -free s ur vi val ( P F S) bet wee n i mal u ma b i n c o m bi nati o n 
wit h 5 - F U/ L V f or s u bjects wit h K R A S m ut a n d/ or N R A S m ut t u m ors or i n 
c o m bi nati o n wit h pa nit u m u ma b f or s u bjects wit h K R A S wt a n d N R A S wt t u m ors, 
vers us S o C (i n vesti gat or c h oice) as t hir d or f o urt h treat me nt li ne ( Part 2)
1. 1. 2
Sec o n d ar y O bjecti ve( s)
1. 1. 2. 1
Effic ac y
1.
T o c o m pare o verall res p o nse rate ( O R R) a n d cli nical be nefit rate ( C B R) i n 
s u bjects treate d at R P 2 D wit h i mal u ma b i n c o m bi nati o n wit h 5-F U/ L V or 
pa nit u m u ma b vers us S o C (i n vesti gat or c h oice) as t hir d or f o urt h treat me nt li ne


I mal u ma b ( B A X 6 9)
Pa ge 6 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
2.
T o c o m pare o verall s ur vi val ( O S) of s u bjects w h o recei ve d i mal u ma b i n 
c o m bi nati o n wit h 5 -F U/ L V or pa nit u m u ma b vers us S o C (i n vesti gat or c h oice) as 
t hir d or f o urt h treat me nt li ne
1. 1. 2. 2
S afet y

T o assess t he safet y a n d t olera bilit y of i mal u ma b i n c o m bi nati o n wit h 5-F U/ L V or 
pa nit u m u ma b .
1. 1. 2. 3
P h ar m ac o ki netics

T o c haracterize t he P K of i mal u ma b i n c o m bi nati o n wit h 5-F U/ L V or 
pa nit u m u ma b .
1. 1. 2. 4
He alt h -rel ate d Q u alit y of Life

T o c o m pare healt h relate d q ualit y  of life ( Q o L) of s u bjects w h o recei ve d 
i mal u ma b i n c o m bi nati o n wit h 5-F U/ L V or pa nit u m u ma b vers us S o C 
(i n vesti gat or c h oice) as t hir d or f o urt h treat me nt li ne.
1. 1. 3
E x pl or at or y O bjecti ves
1. 1. 3. 1
P h ar m ac o d y n a mics
T he e x pl orat or y  P D o bjecti ve of t he st u d y is to c haracterize o xi date d macr o p ha ge 
mi grati o n i n hi bit or y  fact or ( o x MIF) a n d t otal MI F i n plas ma pri or t o a n d d uri n g 
treat me nt wit h i mal u ma b i n c o m bi nati o n wit h 5 -F U/ L V or pa nit u m u ma b .
1. 1. 3. 2
Ge netic Bi o m ar kers
T he e x pl orat or y  ge netic bi o mar ker o bjecti ve of t he st u d y is to c haracterize t u m or -
ass ociate d ge netic alterati o ns i n bl o o d/ uri ne (f or all su bjects treate d wit h i mal u ma b i n 
c o m bi nati o n wit h 5 - F U/ L V or pa nit u m u ma b w h o pr o vi de c o nse nt f or e x pl orat or y  
bi o mar ker a nal ys es).  
T he s p o ns or will o btai n a vaila ble hist orical t u m or m utati o nal testi n g res ults f or s u bjects.
1. 1. 3. 3
Q u alit y of Life
T he e x pl orat or y  Q o L o bjecti ve of t he st u d y  is to c o m pare disease -s pecific Q o L a n d 
healt h utilit y  i n s u bjects treate d wit h i mal u ma b i n c o m bi nati o n wit h 5-F U/ L V or 
pa nit u m u ma b vers us S o C (i n vesti gat or c h oice) as t hir d or f o urt h treat me nt li ne


I mal u ma b ( B A X 6 9)
Pa ge 7 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
2.
S T U D Y D E SI G N
T his st u d y  is P hase 2a, ra n d o mize d, o pe n -la bel st u d y t o assess t he safety, t olera bilit y , a n d 
efficac y of i mal u ma b i n c o m bi nati o n wit h 5-F U/ L V or pa nit u m u ma b vers us Sta n dar d of 
Care ( S O C) i n s u bjects wit h metastatic c ol orectal ca ncer.
T his st u d y  will be c o n d ucte d i n a p pr o xi matel y 4 0 st u d y sites i n t he U nite d States ( U S) 
a n d t he E ur o pea n U ni o n ( E U). T he st u d y will c o m prise 2 se q ue ntial parts (s u bjects ca n 
o nl y  partici pate i n eit her Part 1 or Part 2 of t he st u d y):

Part 1: A Safet y R u n -i n peri o d t o e val uate 2 pre defi ne d d oses ( 7. 5 m g/ k g a n d 1 0 
m g/ k g) of i mal u ma b gi ve n e ver y  wee k ( Q W) i n c o m bi nati o n wit h i nf usi o nal 5-
F U/ L V gi ve n e ver y  2 wee ks ( Q 2 W) i n s u bjects wit h m utate d t u m ors ( K R A S m ut, 
, N R A S m ut), or i mal u ma b i n c o m bi nati o n wit h pa nit u m u ma b gi ve n Q 2 W i n 
s u bjects wit h wil d t y pe t u m ors ( K R A S wt a n d N R A S wt). Pri or t o e ntr y  i nt o t he 
st u d y, s u bjects will be stratifie d acc or di n g t o t heir K R A S/ N R A S m utati o n stat us. 
Treat me nts will be a d mi nistere d i n 4- wee k ( 2 8 -d a y ) c ycles.

Part 2: A 2 -treat me nt-ar m desi g n usi n g a 2: 1 rati o f or s u bjects t o recei ve 
i mal u ma b + 5 -F U/ L V or i mal u ma b + pa nit u m u ma b ( Ar m A) or S o C per 
i n vesti gat or c h oice ( Ar m B). Pri or t o ra n d o mizati o n, s u bjects will be stratifie d 
acc or di n g t o t heir m utati o n stat us. Wit hi n eac h strat u m, s u bjects will be 
ra n d o mize d in a 2: 1 rati o t o recei ve i mal u ma b + 5 -F U/ L V ( K R A S m ut , N R A S 
m ut t u m ors) or i mal u ma b + pa nit u m u ma b ( K R A S wt a n d N R A S wt t u m ors) ( Ar m 
A) or S o C per i n vesti gat or c h oice ( Ar m B).
F or all s u bjects i n Parts 1 a n d 2, treat me nt will c o nti n ue u ntil disease pr o gressi o n, 
u nacce pta ble t o xicit y , or wit h dra wal of c o nse nt.
P art 1: S af et y R u n -i n
P art 1: S af et y R u n -i n
F or eac h c o m bi nati o n, s u bjects will be e nr olle d i nt o 2 se q ue ntial c o h orts, wit h a 
mi ni m u m of 3 a n d a ma xi m u m of 6 s u bjects per c o h ort.
F or eac h c o m bi nati o n, e nr oll me nt will pr ocee d acc or di n g t o t he f oll o wi n g r ules base d o n 
t he occ urre nce of d ose-li miti n g t o xicities ( D LTs):

If zer o o ut of 3 e val ua ble s u bjects e x perie nce a D L T d uri n g t he first 2 8 da ys after 
t he first a d mi nistrati o n of st u d y dr u g at t he first d ose le vel, t he sec o n d d ose le vel 


I mal u ma b ( B A X 6 9)
Pa ge 8 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
will be o pe ne d f or e nr oll me nt after re vie w of t he safet y data b y t he Data Re vie w 
C o m mittee ( D R C).

If 1 o ut of 3 e val ua ble s u bjects e x perie nces a D L T d uri n g t he first 2 8 da ys after 
a d mi nistrati o n of st u d y dr u g at t he first d ose le vel, 3 a d diti o nal s u bjects will be 
e nr olle d at t he first d ose le vel, f or a t otal of 6 e val ua ble s u bjects. After re vie w of 
t he safety data of all 6 e val ua ble s u bjects, t he D R C will deci de if t he sec o n d d ose 
le vel or a l o wer d ose le vel will be e x pl ore d.

If 2 or m ore e val ua ble s u bjects e x perie nce a D L T d uri n g t he first 2 8 da y s after t he 
first a d mi nistrati o n of st u d y dr u g at t he first d ose le vel, t he sec o n d d ose le vel will 
n ot be o pe n t o e nr oll me nt a n d t he D R C will deci de if a l o wer d ose le vel will be 
e x pl ore d.
T he D R C will meet f or safet y re vie ws after 3 s u bjects i n a d osi n g c o h ort ha ve c o m plete d 
t he first treat me nt c ycle. T he D R C will deci de eit her t o e nr oll a d diti o nal s u bjects or o pe n 
t he ne xt d ose le vel. F or eac h c o m bi nati o n, base d o n all data of all e val ua ble s u bjects, t he 
D R C will eit her deter mi ne t he R P 2 D, or will deci de t o e x pl ore a n i nter me diate d ose 
le vel.
D L T Defi niti o n
A D L T is defi ne d as a n y dr u g -relate d treat me nt-e mer ge nt a d verse e ve nt ( T E A E) ( gra de d 
acc or di n g t o t he Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y  Criteria f or A d verse 
E ve nts [ N CI  C T C A E] v 4. 0 3) t hat occ urs d uri n g t he first 2 8 da ys after treat me nt start a n d 
t hat meets a ny of t he f oll o wi n g criteria:

A n y  ≥ Gra de 3 n o n -he mat ol o gic t o xicit y  e xcl u di n g:
o
M uc ositis/st o matitis of Gra de 3 t hat res ol ves t o G ra de 1 or less wit h 
s u p p orti ve meas ures wit hi n 7 da ys
o
Diarr hea of < 3 da y s d urati o n f oll o wi n g a de q uate a n d o pti mal t hera p y
o
Na usea a n d v o miti n g of < 3 da y s d urati o n wit h a de q uate a n d o pti mal 
t hera py
o
Fati g ue of < 7 da y s d urati o n f oll o wi n g i nitiati o n of a de q uate s u p p orti ve 
care
o
Al o pecia
o
A n y  si n gle la b orat or y val ue o ut of t he n or mal ra n ge t hat has n o cli nical 
si g nifica nce a n d t hat res ol ves t o ≤ Gra de 2 wit h a de q uate meas ures wit hi n 


I mal u ma b ( B A X 6 9)
Pa ge 9 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
7 da y s; tra nsie nt Gra de 3 ele vati o ns (lasti n g < 5 da ys) of he patic 
tra nsa mi nases i n t he a bse nce of si m ulta ne o us i ncrease i n ser u m bilir u bi n

A n y  Gra de 4 he mat ol o gic t o xicit y e xcl u di n g:
o
Gra de 4 ne utr o pe nia lasti n g f or ≤ 5 da y s a n d n ot acc o m pa nie d by fe ver
o
Is olate d Gra de 4 ly m p h oc y t o pe nia wit h o ut cli nical c orrelate

Gra de 3 fe brile ne utr o pe nia

Gra de 3 t hr o m b oc y t o pe nia ass ociate d wit h blee di n g

A n y  life-t hreate ni n g c o m plicati o n or a b n or malit y n ot c o vere d i n t he N CI C T C A E 
v 4. 0 3
Deter mi n ati o n of R P 2 D
F or eac h c o m bi nati o n, base d o n all data of all e val ua ble s u bjects, t he D R C will deter mi ne 
t he R P 2 D, or deci de if a n i nter me diate d ose le vel m ust be e x pl ore d.
P art 2: E x pl or at or y P h ase 2 a
T his is a 2 -treat me nt-ar m st u d y i n w hic h s u bjects will recei ve i mal u ma b + 5 -F U/ L V or 
i mal u ma b + pa nit u m u ma b ( Ar m A) or S o C per i n vesti gat or c h oice ( Ar m B). Pri or t o 
ra n d o mizati o n, s u bjects will be stratifie d acc or di n g t o t heir K R A S/ N R A S stat us. Wit hi n 
eac h strat u m, s u bjects will be ra n d o mize d i n a 2: 1 rati o t o recei ve i mal u ma b + 5 -F U/ L V 
( K R A S m ut a n d/ or N R A S m ut t u m ors) or i mal u ma b + pa nit u m u ma b ( K R A S wt a n d 
N R A S wt t u m ors) ( Ar m A) or S o C per i n vesti gat or c h oice ( Ar m B). Ra n d o mizati o n will 
occ ur via a n I nteracti ve Res p o nse Tec h n ol o g y  (I R T) S yste m. F or eac h c o m bi nati o n i n 
Ar m A, s u bjects will recei ve i mal u ma b at t he R P 2 D deter mi ne d i n Part 1 f or t he 
c orres p o n di n g c o m b i nati o n. All s u bjects will be treate d u ntil disease pr o gressi o n, 
u nacce pta ble t o xicit y , or wit h dra wal of c o nse nt. 
A n i n de pe n de nt Data Safet y M o nit ori n g B oar d ( D S M B), c o m prise d of rec o g nize d 
e x perts i n t he fiel d of o nc ol o g y, bi ostatistics , cli nical care a n d researc h will re vie w 
acc u m ulati n g safet y data. T he c o m p ositi o n, acti vities, a n d res p o nsi bilities of t he D S M B 
are descri be d i n f urt her detail i n t he D S M B C harter.
2. 1
St u d y P o p ul ati o n 
Male a n d fe male s u bjects a ge d 1 8 ye ars or ol der wit h a c o nfir me d dia g n osis of m C R C 
are eli gi ble if t he y ha ve pr o gresse d after recei vi n g at least 2, b ut n o m ore t ha n 3, pri or 
treat me nt li nes i ncl u di n g S o C, a n d ha ve a n Easter n C o o perati ve O nc ol o g y Gr o u p 
( E C O G) Perf or ma nce Stat us ( P S) of 0- 2. 


I mal u ma b ( B A X 6 9)
Pa ge 1 0 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
2. 2
I ncl usi o n a n d E xcl usi o n Criteri a
2. 2. 1
I ncl usi o n Criteri a
S u bjects w h o meet A L L of t he f oll o wi n g criteria are eli gi ble f or t his st u d y :
1.
Pr o visi o n of a si g ne d i nf or me d c o nse nt
2.
Male a n d fe male s u bjects 1 8 y ears of a ge a n d ol der at t he ti me of scree ni n g
3.
S u bjects w h o pr o gresse d after recei vi n g at least 2 , b ut n o m ore t ha n 3, pri or 
ca ncer dr u g t hera p y treat me nt li nes i ncl u di n g S o C i n t he metastatic setti n g
4.
A ntici pate d life e x pecta nc y  > 3 m o nt hs at t he ti me of scree ni n g
5.
Wei g ht bet wee n 4 0 k g a n d 1 8 0 k g
6.
Hist ol o gicall y or c yt ol o gicall y  c o nfir me d dia g n osis of C RC
7.
Metastatic C R C n ot a me na ble t o s ur gical resecti o n
8.
K n o w n K R A S , N R A S m utati o n stat us (if u n k n o w n stat us f or eit her of t hese ge nes 
a n d n o arc hi val tiss ue is a vaila ble, a fres h t u m or bi o ps y  will be o btai ne d)
9.
At least 1 meas ura ble lesi o n as defi ne d b y R E CI S T v 1. 1
1 0. Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Stat us ( P S) of 0 -2
1 1. A de q uate he mat ol o gical f u ncti o n, defi ne d as:
a.
Platelet c o u nt ≥ 1 0 0, 0 0 0/ μ L
b.
Pr ot hr o m bi n ti me a n d acti vate d partial t hr o m b o plasti n ti me (a P T T) < 1. 5 
ti mes t he u p per li mit of n or mal (U L N)
c.
A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1 ,0 0 0/ μ L
d.
He m o gl o bi n ≥ 9 g/ d L, wit h o ut t he nee d f or tra nsf usi o n i n t he 2 wee ks 
pri or t o scree ni n g
1 2. A de q uate re nal f u ncti o n, defi ne d as ser u m creati ni ne ≤ 2. 0 ti mes U L N a n d 
creati ni ne cleara nce > 5 0 m L/ mi n or esti mate d gl o mer ular filtrati o n 
rate> 5 0 m L / mi n/ 1. 7 3 m2
1 3. A de q uate li ver f u ncti o n, defi ne d as:
a.
As partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T) 
≤2. 5 ti mes U L N f or s u bjects wit h o ut li ver metastases, or ≤ 5 ti mes U L N 
i n t he prese nce of li ver metastases
b.
Bilir u bi n ≤ 2. 0 ti mes U L N, u nless s u bject has k n o w n Gil bert’s s y n dr o me
1 4. A de q uate ve n o us access
1 5. F or fe male s u bjects of c hil d beari n g p ote ntial, t he s u bject prese nts wit h a ne gati ve 
ser u m pre g na nc y test at scree ni n g a n d a grees t o e m pl o y 2 f or ms of a de q uate birt h 
c o ntr ol met h o ds , i ncl u di n g at least 1 barrier met h o d (e g, dia p hra g m wit h 
s per mici dal jell y or f oa m, or [f or male part ner] c o n d o m) t hr o u g h o ut t he c o urse of 
t he st u d y a n d f or at least 9 0 da ys after t he last a d mi nistrati o n of i mal u ma b. In 


I mal u ma b ( B A X 6 9)
Pa ge 1 1 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
a d diti o n, t hes e birt h c o ntr ol met h o ds m ust be c o nti n ue d f or at least 1 8 0 da ys after 
last a d mi nistrati o n of 5-F U i n s u bjects w h o recei ve t his treat me nt. Sec o n dar y  
c o ntrace pti ve meas ures c o ul d be eit her birt h c o ntr ol pills, patc hes, or i ntra uteri ne 
de vices . 
1 6. F or male s u bj ects, t he y m ust a gree t o use a de q uate c o ntrace pti ve meas ures 
i ncl u di n g at least 1 barrier met h o d (e g, c o n d o m wit h s per mici dal jell y or f oa m 
a n d [f or t he fe male part ner] dia p hra g m wit h s per mici dal jell y  or f oa m, birt h 
c o ntr ol pills/ patc hes, or i ntra uteri ne de vice) a n d a bstai n fr o m s per m d o nati o n 
t hr o u g h o ut t he c o urse of t he st u d y a n d f or at least 9 0 da ys after t he last 
a d mi nistrati o n of i mal u ma b. I n a d diti o n, t hese birt h c o ntr ol met h o ds m ust be 
c o nti n ue d f or at least 1 8 0 da ys after last a d mi nistrati o n of 5- FU i n s u bjects w h o 
recei ve t his treat me nt.
1 7. S u bject is willi n g a n d a ble t o c o m pl y  wit h t he re q uire me nts of t he pr ot oc ol
2. 2. 2 
E xcl usi o n Criteri a
S u bjects w h o meet A N Y of t he f oll o wi n g criteria are n ot eli gi ble f or t his st u d y :
1.
K n o w n ce ntral ner v o us s yste m metastas es
2.
Pri or mali g na nc y (s) wit hi n t he past 3 years, wit h t he e xce pti o n of c urati vel y  
treate d basal or s q ua m o us cell carci n o ma of t he s ki n, l ocall y a d va nce d pr ostate 
ca ncer, d uctal carci n o ma i n sit u of breast, i n sit u cer vical carci n o ma a n d 
s u perficial bla d der ca ncer
3.
Pri or treat me nt wit h pa nit u m u ma b f or s u bjects wit h K R A S wt a n d N R A S wt 
t u m ors
4.
K n o w n hist or y of keratitis, ulcerati ve keratitis, or se vere dr y  e ye i n s u bjects wit h 
K R A S wt a n d N R A S wt t u m ors
5.
Resi d ual a d verse e ve nt ( A E) fr o m pre vi o us treat me nt > Gra de 1, e xce pt 
ne ur o pat h y a n d al o pecia
6.
Pri or i nt olera nce t o fl u or o p y ri mi di ne f or s u bjects wit h K R A S m ut a n d/ or N R A S 
m ut t u m ors
7.
M y ocar dial i nfarcti o n wit hi n 6 m o nt hs pri or t o C y cle 1 Da y 1 (C 1 D 1 ), a n d/ or 
pri or dia g n oses of c o n gesti ve heart fail ure ( Ne w Y or k Hea rt Ass ociati o n Class III 
or I V), u nsta ble a n gi na, u nsta ble car diac arr h yt h mia re q uiri n g me dicati o n; a n d/ or 
t he s u bject is at ris k f or p ol ym or p hic ve ntric ular tac h y car dia (e g, h yp o kale mia, 
fa mil y hist or y, or l o n g Q T s yn dr o me)
8.
U nc o ntr olle d h y perte nsi o n, defi ne d as s ys t olic bl o o d press ure ≥ 1 6 0 m m H g 
a n d/ or diast olic bl o o d press ure ≥ 1 0 0 m m H g c o nfir me d u p o n re peate d meas ures


I mal u ma b ( B A X 6 9)
Pa ge 1 2 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
9.
Left ve ntric ular ejecti o n fracti o n (L V E F ) < 4 0 % as deter mi ne d b y  
ec h ocar di o gra m ( E C H O)/ m ulti gate d ac q uisiti o n sca n ( M U G A) perf or me d at 
scree ni n g or wit hi n 9 0 da ys pri or t o C 1 D 1
1 0. Q T/ Q Tc i nter val > 4 5 0 msec, as deter mi ne d b y s cree ni n g E C G perf or me d n o 
earlier t ha n 1 wee k bef ore C 1 D 1
1 1. Pri or a nti -t u m or t hera py (c he m ot hera py, ra di ot hera p y, a nti b o d y t hera p y, 
m olec ular tar gete d t hera p y , reti n oi d t herap y , or h or m o nal t hera p y) wit hi n 4 wee ks 
( < 2 8 da ys) pri or t o C 1 D 1
1 2. Maj or s ur ger y  wit hi n 4 wee ks ( < 2 8 da ys) pri or t o C 1 D 1
1 3. Acti ve j oi nt i nfla m mati o n or hist or y  of i nfla m mat or y art hritis or ot her i m m u ne 
dis or der i n v ol vi n g j oi nts ( oste oart hritis is n ot e xcl usi o nar y)
1 4. Acti ve i nfecti o n i n v ol vi n g I V a nti bi otics wit hi n 2 wee ks pri or t o C 1 D 1
1 5. K n o w n hist or y  of or acti ve he patitis B vir us ( H B V) a n d/ or he patitis C vir us 
( H C V), or acti ve t u berc ul osis
1 6. K n o w n hist or y  of h u ma n i m m u n o deficie nc y vir us ( HI V) ty p e 1/ 2 or o t her 
i m m u n o deficie nc y disease
1 7. S u bject has recei ve d a li ve vacci ne wit hi n 4 wee ks ( < 2 8 da y s) pri or t o C 1 D 1
1 8. K n o w n h y perse nsiti vit y  t o a n y c o m p o ne nt of rec o m bi na nt pr otei n pr o d ucti o n b y 
C H O cells
1 9. E x p os ure t o a n i n vesti gati o nal pr o d uct or i n vesti gati o nal de vi ce i n a n ot her cli nical 
st u d y wit hi n 4 wee ks ( < 2 8 da ys) pri or t o C 1 D 1, or is sc he d ule d t o partici pate i n 
a n ot her cli nical st u d y i n v ol vi n g a n i n vesti gati o nal pr o d uct or de vice d uri n g t he 
c o urse of t his st u d y
2 0. S u bject is breastfee di n g or i nte n ds t o be gi n brea stfee di n g d uri n g t he c o urse of t he 
st u d y
2 1. A n y  dis or der or disease, or cli nicall y si g nifica nt a b n or malit y o n la b orat or y or 
ot her cli nical test(s) ( e g, bl o o d tests, E C G), t hat i n me dical j u d g me nt of t he 
i n vesti gat or ma y i m pe de t he s u bject’s partici pati o n i n the st u d y , p ose i ncrease d 
ris k t o t he s u bject, a n d/ or c o nf o u n d t he res ults of t he st u d y
2 2. S u bject is a fa mil y  me m ber or e m pl o yee of t he i n vesti gat or
2. 3
S a m ple Size a n d P o wer C alc ul ati o ns
T he fi nal sa m ple size of Part 1 ( Safet y R u n -i n) is de pe n de nt o n t he pre-state d r ules f or 
d ose escalati o n. I n Part 1, t he sa m ple size f or eac h d osi n g re gi me n (ie, i mal u ma b + 5 -
F U/ L V a n d i mal u ma b + pa nit u m u ma b) is e x pecte d t o be bet wee n 6 a n d 1 2 s u bjects ( ie, 3 
t o 6 s u bjects at eac h 7. 5 m g/ k g a n d 1 0 m g/ k g i mal u ma b d ose le vel). N o n -e val ua ble 
s u bjects will be re place d t o meet st u d y o bjecti ves.


I mal u ma b ( B A X 6 9)
Pa ge 1 3 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
T he sa m ple size of Part 2 ( E x pl orat or y  P hase 2a) is esti mate d t o be a t otal of 6 6 s u bjects. 
Ass u mi n g t hat t he me dia n P F S is 2. 4 m o nt hs i n t he c o ntr ol ar m a n d 4. 2 5 m o nt hs i n t he 
e x peri me ntal ar m (a c o nsta nt hazar d rati o 0. 5 6 5), a n d usi n g a o ne -si de d l o g-ra n k test wit h 
α of 0. 1 5 a n d β of 0. 2 0 wit h a dr o p- o ut rate of 2 0 % at 6 m o nt hs, 4 8 P F S e ve nts are 
nee de d. Wit h a n e nr oll me nt rati o of 2: 1, a n d ta ki n g i nt o acc o u nt t he ti me f or accr ual of 1 
ye ar a nd a n a d diti o nal f oll o w - u p peri o d of 6 m o nt hs after t he last s u bject is e nr olle d, t he 
sa m ple size nee de d is a p pr o xi matel y 2 2 s u bjects i n eac h of t he 2 i mal u ma b-c o ntai ni n g 
treat me nt ar ms (i mal u ma b + pa nit u m u ma b a n d i mal u ma b + 5 - F U/ L V) a n d i n t he c o ntr ol 
ar m ( S o C).
2. 4
R a n d o miz ati o n
T here is n o ra n d o mizati o n i n Part 1. I n Part 2, ra n d o mizati o n i n per m utate d bl oc ks will 
occ ur t o mi ni mize bias a n d f ulfill a 2: 1 rati o bet wee n Ar m A a n d Ar m B. Pri or t o 
ra n d o mizati o n, s u bjects will be stratifie d acc or di n g t o t heir K R A S a n d N R A S m utati o n 
stat us. Ra n d o mizati o n will occ ur via a n I RT S ys te m u ntil t he tar gete d n u m ber of s u bjects 
i n eac h treat me nt-ar m is ac hie ve d.
2. 5
Bli n di n g/ U n bli n di n g 
T his is a n o pe n -la bel st u d y.
2. 6
St u d y St o p p i n g R ules 
T his st u d y  will be st o p pe d if 1 or m ore of t he f oll o wi n g criteria are met:

E xcessi ve t o xicit y  or cli nicall y mea ni n gf ul S A E t hat ma y p ose si g nifica nt healt h 
ris ks

Decisi o n b y t he s p o ns or t o i nterr u pt or ter mi nate t he st u d y at a n y ti me f or reas o ns
i ncl u di n g, b ut n ot li mite d t o, safety or et hical iss ues or i ns ufficie nt c o m plia nce 
W he n feasi ble, t he s p o ns or will pr o vi de a d va nce n otificati o n t o t he i n vesti gat or of t he 
i m pe n di n g acti o n pri or t o its ta ki n g effect. T he s p o ns or will pr o m ptl y i nf or m all ot her 
i n vesti gat ors a n d/ or i nstit uti o ns c o n d ucti n g t he st u d y if t he st u d y is i nterr u pte d or 
ter mi nate d f or safety reas o ns, a n d will als o i nf or m t he re g ulat or y a ut h orities of t he 
i nterr u pti o n or ter mi nati o n of t he st u d y a n d t he reas o n(s) f or t he acti o n. If re q uire d b y 
a p plica ble re g ulati o ns, t he i n vesti gat or m ust i nf or m t he i n de pe n de nt et hics 
c o m mittee/i nstit uti o nal re vie w b oar d (I E C/I R B) pr o m ptl y  a n d pr o vi de t he reas o n f or t he 
i nterr u pti o n or ter mi nati o n.
St u d y  c o m pleti o n is esti mate d t o occ ur w he n 7 5 % of O S e ve nts ha ve bee n re p orte d.


I mal u ma b ( B A X 6 9)
Pa ge 1 4 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
T here are n o s pecific statistical st o p pi n g r ules defi ne d f or t his st u d y .
2. 7
St u d y Assess me nts
A sc he d ule of assess me nts is pr o vi de d i n Secti o n  1 6. 1.
2. 8
D at a M o nit ori n g C o m mittee
T he c o m p ositi o n, acti vities, a n d res p o nsi bilities of t he D S M B are descri be d i n f urt her 
detail i n t he D S M B C harter.
3. 
S T U D Y O U T C O M E M E A S U R E S 
3. 1
Effic ac y O utc o me Me as ures
3. 1. 1
Pri m ar y Effic ac y O utc o me Me as ure
T he pri mar y  efficac y o utc o me meas ure is P F S defi ne d as ti me bet wee n treat me nt 
i nitiati o n a n d t u m or pr o gressi o n ( per R E CI S T v 1. 1 criteria) or deat h fr o m a n y ca use, wit h 
ce ns ori n g of s u bjects w h o are l ost t o f oll o w- u p or wit h dra w c o nse nt.
3. 1. 2
Sec o n d ar y Effic ac y O utc o me Me as ures
T he sec o n dar y  o utc o me meas ures are:

Res p o nse e val uati o n acc or di n g t o R E CI S T v 1. 1. 

O S, defi ne d as ti me fr o m ra n d o mizati o n t o deat h of a n y ca use.
3. 2
S afet y O utc o me Me as ures
3. 2. 1
Pri m ar y S afet y O utc o me Me as ures
T h e pri mar y safety o utc o me meas ure is t he occ urre nce of D L Ts ( Part 1).
3. 2. 2
Sec o n d ar y S afet y O utc o me Me as ures

Occ urre nce of seri o us a d verse e ve nts ( S A Es) a n d/ or T E A Es, re gar dless of 
ca usalit y or relati o ns hi p t o st u d y dr u g a n d c o de d acc or di n g t o N CI C T C A E v 4. 0 3

O t her safet y meas ure me nts: p h ysical or i nstr u me ntal e xa mi nati o ns, 
electr ocar di o gra ms ( E C Gs), vital si g ns, a n d cli nicall y  rele va nt c ha n ges i n 
i nstr u me ntal e xa mi nati o ns or la b orat or y val ues
3. 3
I m m u n o ge nicit y O utc o me Me as ures

Occ urre nce of bi n di n g a n d/ or ne utrali zi n g a nti-i mal u ma b a nti b o dies


I mal u ma b ( B A X 6 9)
Pa ge 1 5 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0

I nci de nce a n d se verit y of i nf usi o n reacti o ns after i mal u ma b
3. 4
P h ar m ac o ki netic O utc o me Me as ures
T he P K o utc o me meas ure is t he plas ma c o nce ntrati o ns of i mal u ma b.  Imal u ma b plas ma P K 
will be c haracterize d usi n g a p o p ulati o n P K m o d eli n g a p pr oac h, i n c o m bi nati o n wit h data 
fr o m ot her st u dies. T he p o p ulati o n P K m o deli n g a p pr oac h will be descri be d a n d re p orte d
i n se parate d oc u me nts.
3. 5
Q u alit y of Life O utc o me Me as ures
T he Q o L o utc o me meas ure s are deri ve d fr o m a ns wers t o t he E O R T C Q L Q -C 3 0
q uesti o n naire .
3. 6
E x pl or at or y O utc o me Me as ures
T he e x pl orat or y  P D o utc o me meas ures i ncl u de plas ma le vels of o xi date d macr o p ha ge 
mi grati o n i n hi bit or y  fact or ( o x MIF) a n d t otal MI F. 
Ge netic bi o mar kers will als o be i n vesti gate d as a n o pti o nal e x pl orat or y  o utc o me. 
E x pl orat or y  ge netic bi o mar ker o utc o me meas ures i ncl u de t u m or-ass ociate d ge netic 
alterati o ns of cf D N A i n bl o o d/ uri ne, f or s u bjects treate d wit h i mal u ma b i n c o m bi nati o n 
wit h 5 -F U/ L V or pa nit u m u ma b w h o pr o vi de c o nse nt f or t hese a nal ys es. T he s p o ns or will 
o btai n a vaila ble hist orical t u m or m utati o nal testi n g res ults f or s u bjects.
T he e x pl orat or y  Q o L o utc o me meas ures use t he E O R T C Q LQ f or c ol orectal ca ncer 2 9 
( E O R T C Q L Q-C R 2 9) a n d t he E ur o pea n Q ualit y  of Life – 5 Di me nsi o ns q uesti o n naire 
( E Q- 5 D). T he E O R T C Q L Q-C R 2 9 will be use d as a s u p ple me nt t o t he E O R T C Q L Q-
C 3 0 t o assess t he disease -s pecific as pects of c ol orectal ca ncer. T he E Q-5 D is a healt h 
utilit y  meas ure.
4.
A N A L Y SI S S E T S
4. 1
F ull A n al ysis Set 
T he F ull A nal ys is Set ( F A S) will ser ve as t he p o p ulati o n f or t he a nal ys es of efficac y data 
i n t he trial. T he F A S will i ncl u de all s u bjects w h o 1) recei ve d at least 1 a d mi nistrati o n of 
st u d y dr u g, a n d 2) ha ve 1 p ost -baseli ne t u m or res p o nse assess me nt base d o n R E CI S T 
v 1. 1, or die d wit hi n 1 8 wee ks of t he start of treat me nt .
T he pr o p ose d deri vati o n of P F S ( Secti o n  7. 1. 1) i n dicates t hat s u bjects w h o miss 2 
pla n ne d t u m or assess me nts will be ce ns ore d at t he last t u m or assess me nt bef ore t he 


I mal u ma b ( B A X 6 9)
Pa ge 1 6 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
misse d assess me nts.  F or t his st u d y , t he e xact ti me peri o d t hat i de ntifies t hat 2 t u m or 
assess me nts ha ve bee n misse d will be defi ne d as t wice t he pr ot oc ol -defi ne d ti me bet wee n 
sca ns ( 8 wee ks) + t he pr ot oc ol all o we d visit wi n d o w ( 1 wee k) (ie, 2 * 8 + 1 = 1 8 wee ks ).
4. 2
S afet y A n al ysis Set
T he Safet y A nal y sis S et is defi ne d as all s u bjects w h o recei ve at least 1 a d mi nistrati o n of 
st u d y dr u g. T he Safet y P o p ulati o n will be use d f or all safet y a nal ys es i n t he trial. 
5.
S T A TI S TI C A L C O N SI D E R A TI O N S 
T he n u merical data will be s u m marize d wit h n, mea n, S D, mi n, ma x, me dia n, Q 1, a n d 
Q 3 .  Cate g orical data will be s u m marize d wit h n a n d perce nta ges.  
T here are n o m ulti plicit y a dj ust me nts i n t his e x pl orat or y  P hase 2 A st u d y.  
All sec o n dar y  a n d e x pl orat or y en d p oi nts are c o nsi dere d s u p p orti ve a n d a n y statistical 
tests c o m pari n g treat me nts will be ma de wit h o ut a dj ust me nt f or m ulti plicit y. T he 
res ulti n g p-val ues fr o m t hese s u p p orti ve a nal y ses will be i nter prete d descri pti vel y as 
s u m marizi n g t he wei g ht of e vi de nce f or a treat me nt differe nce a n d ma y  s u g gest a ve n ues 
f or f urt her e x pl orat or y a nal yses or ge nerate f or mal h yp ot heses t o be teste d i n f ut ure trials.
5. 1
I nteri m A n al yses
A n i nteri m a nal ys is was t o be i m ple me nte d f or pla n ni n g p ur p oses b ut was re m o ve d fr o m 
t he pla n ( See Secti o n  5. 5 ).
5. 2
H a n dli n g of Missi n g, U n use d, a n d S p uri o us D at a
Re gar di n g missi n g data i n A E rec or ds :
o
Ha n dli n g of u n k n o w n ca usalit y  assess me nt:

If a s u bject e x perie nces a n A E wit h a missi n g ca usalit y  assess me nt, t he 
relati o ns hi p of t he A E will be c o u nte d as “relate d”.
o
Ha n dli n g of u n k n o w n t o xicit y gra des:

If a s u bject e x perie nces m ore t ha n o ne A E cate g orize d u n der t he sa me 
preferre d ter m, t he s u bject will be co u nte d u n der t he m ost se vere t o xicit y  
gra de re p orte d f or t hat A E. 

If a s u bject e x perie nces a n A E a nd t he t o xicit y  gra de was n ot pr o vi de d, t he 
t o xicit y gra de of t his A E s h o ul d be c o u nte d as “ u n k n o w n”.   A r o w or 
c ol u m n la belle d “U n k n o w n ” s h o ul d be i nserte d f or t h ose A Es i n ta bles 
w here A Es are s u m marize d b y  t o xicit y gra de.


I mal u ma b ( B A X 6 9)
Pa ge 1 7 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
F or la b val ues t hat are a b o ve or bel o w t he li mit of q ua ntitati o n a n d are re p orte d as “ <” or 
“ >” t he assa y li mit, t he assa y li mit will be use d f or calc ulati o n of s u m mary statistics , 
e xce pt f or P K para meters w hic h will be s pecifie d i n a se parate d oc u me nt.
5. 3
Defi niti o n of B aseli ne
Baseli ne will be defi ne d as t he last assess me nt bef ore t he date a n d ti me of first 
a d mi nistrati o n ( C 1 D 1) of i mal u ma b or S o C. F or s u bjects w h o ha ve n ot recei ve d a n y  
st u d y dr u g, t he baseli ne will be t he last assess me nt perf or me d at Scree ni n g, Baseli ne, or 
C 1 D 1.
If m ore t ha n o ne baseli ne sca n is rec or de d t he n meas ure me nts fr o m t he o ne t hat is cl osest 
a n d pri or t o t he date of ra n d o mizati o n will be use d t o defi ne t he baseli ne.
5. 4  
Defi niti o n of Tre at me nt Gr o u ps
Data will be prese nte d f or t he c o h orts i n Part 1 a n d Part 2 of t his st u d y  w hic h are liste d i n 
Ta ble 1.   
T he d ose of i mal u ma b selecte d f or Part 2 is 1 0 m g/ k g.  S u bjects fr o m Part 1 a n d Part 2 
w h o recei ve d t he 1 0 m g/ k g d ose will be c o m bi ne d f or s o me a nal yses of safet y a n d 
efficac y.  T he Part 1 a n d 2 a nal ys es will i n dicate t hat s u bjects i n 1 0 m g/ k g c o h orts i n Part 
1 will be c o m bi ne d wit h t he Part 2 c o h orts t hat recei ve d t he sa me treat me nt.  
Data fr o m t he c o h orts recei vi n g 7. 5 m g/ k g i mal u ma b i n Part 1 will n ot be i ncl u de d i n t he 
i nte grate d Part 1 a n d 2 a nal yses.  
T a ble 1:  
C o m bi n ati o n a n d P o ole d Tre at me nt Gr o u ps
St u d y P art
St u d y C o h ort
I nte gr ate d Tre at me nt 
Gr o u p
Part 1
I mal u ma b 7. 5 m g/ k g + 5-
F U/ L V 
Part 1
I mal u ma b 7. 5 m g/ k g + 
Pa nit u m u ma b 
Part 1
I mal u ma b 1 0. 0 m g / k g + 5-
I mal u ma b 1 0. 0 m g/ k g + 5-


I mal u ma b ( B A X 6 9)
Pa ge 1 8 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
F U/ L V 
F U/ L V 
Part 2
I mal u ma b 1 0. 0 m g/ k g + 5-
F U/ L V 
Part 1
I mal u ma b 1 0. 0 m g/ k g + 
Pa nit u m u ma b 
I mal u ma b 1 0. 0 m g/ k g + 
Pa nit u m u ma b 
Part 2
I mal u ma b 1 0. 0 m g/ k g + 
Pa nit u m u ma b 
Part 2
S o C M utate d 
S o C M utate d 
Part 2
S o C Wil dt y pe 
S o C Wil dt y pe
5. 5
C h a n ges fr o m t he Pl a n ne d St atistic al A n al ysis i n Pr ot oc ol 
I n t he pr ot oc ol 
I n t he S A P
J ustificati o n
A n i nteri m a nal ys is will 
be i m ple me nte d f or 
pla n ni n g p ur p oses w he n 
3 3 P F S e ve nts ha ve bee n 
o bser ve d.
A n i nteri m a nal ys is will 
n ot be pref or me d
T he i nter val bet wee n 
o bser vi n g 3 3 P F S e ve nts 
a n d o bser vi n g t he 4 8 
P F S e ve nts nee de d f or 
fi nal a nalys is was s h ort. 
T heref ore, i nteri m 
a nal ys is was n ot 
perf or me d.
T he pri mar y  efficac y 
o utc o me meas ure is P F S 
( Part 2), defi ne d as ti me 
bet wee n treat me nt 
i nitiati o n a n d t u m or 
pr o gressi o n ( per 
R E CI S T v 1. 1) or deat h 
fr o m a ny ca use
(see Secti o n 8. 4. 1).
T he P F S will be defi ne d 
as ti me bet wee n
ra n d o mizati o n a n d t u m or 
pr o gressi o n ( per 
R E CI S T v 1. 1) or deat h 
fr o m a ny ca use (see 
Secti o n 8. 4. 1).
T o ali g n t he starti n g 
p oi nt of P F S a n d O S.  


I mal u ma b ( B A X 6 9)
Pa ge 1 9 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
6.
S T U D Y S U B J E C T S
6. 1
Dis p ositi o n of S u bjects
A s u m mar y  of patie nt e nr oll me nt will dis pla y  t he n u m ber of patie nts w h o were scree ne d, 
scree n fail ures, ra n d o mize d a n d treate d.  S u bject dis p ositi o n will s u m marize t he n u m ber
( %) of s u bjects t hat c o m prise d eac h a nalys is p o p ulati o n.  A listi n g of s u bject d is p ositi o n, 
i ncl u di n g a nal ysis p o p ulati o ns, will be create d.
6. 2
De m o gr a p hic a n d B aseli ne C h ar acteristics
T he f oll o wi n g baseli ne data will be s u m marize d a n d l iste d f or t he F A S a n d Safet y 
A nal y sis Set: a ge ( years), se x, race, et h nicit y, c o u ntr y, Easter n C o o perati ve O nc ol o g y  
Gr o u p ( E C O G) perf or ma nce stat us,  left ve ntric ular i njecti o n fracti o n ( L V E F), hei g ht 
(c m), wei g ht ( k g), a n d B MI  ( k g/ m2).
De m o gra p hics a n d baseli ne c haracteristics will be 
s u m marize d f or st u d y c o h ort a n d i nte grate d treat me nt gr o u p.
6. 3
Me dic al Hist or y 
Disease hist or y  will be s u m marize d f or t he Safet y A nal ysis Set f or st u d y c o h ort a n d 
i nte grate d treat me nt gr o u ps.  Disease hist or y will i ncl u de t ype of c ol orectal ca ncer, sta ge 
at i nitial dia g n osis, hist ol o gical s u bt y pes , ti me si nce pri mar y dia g n osis ( y ears), dia g n osis 
c o nfir mati o n t yp e (hist ol o gicall y  or c yt ol o gically ), K R A S / NR A S stat us, T N M sta gi n g at 
i nf or me d c o nse nt, a n d sites of dista nt metastatic disease .
D urati o n fr o m i nitial dia g n osis ( y ears) dia g n osis will be calc ulate d at t he date of 
i nf or me d c o nse nt usi n g t he f oll o wi n g f or m ula:

D urati o n fr o m i nitial dia g n osis ( years):  ( Date i nf or me d c o nse nt si g ne d – Date of 
i nitial dia g n osis) / 3 6 5. 2 5.
Me dical hist or y  will be s u m marize d f or t he Safet y A nal ysis Set f or st u d y c o h ort.  
Me dical c o n diti o ns c ollecte d will be ma p pe d b y t he Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) a n d will be s u m marize d b y  sys te m or ga n class ( S O C) a n d preferred ter m.  
F or s u m mar y  ta bles, a s u bject will be c o u nte d o nl y  o nce per b o d y s yste m a n d preferre d 
ter m. Disease a n d me dical hist or y  will be i ncl u de d i n data listi n gs.
6. 4
Pri or T her a pies a n d Me dic ati o ns
Pri or t hera pies a n d me dicati o ns i ncl u de pri or ca ncer- relate d s ur geries, ra di ot hera pies, a n d 
me dicati o ns as well as ot her ge neral me dicati o ns ta ke n pri or t o t he first d ose i n C ycle 1.  
Pri or ca ncer -relate d s ur geries, ra di ot hera pies, a n d me dicati o ns are c ollecte d o n 


I mal u ma b ( B A X 6 9)
Pa ge 2 0 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
s pecifically- desi g ne d C R Fs.  O t her pri or me dicati o ns will be rec or de d o n t he c o nc o mita nt 
me dicati o ns e C R F a n d c o de d usi n g t he W H O Dr u g Dicti o nar y  versi o n Se pte m ber 2 0 1 5.  
Me dicati o n start dates will be use d t o i de ntif y w hic h me dicati o ns e ntere d o n t he 
c o nc o mita nt me dicati o ns e C R F c o ul d be c o nsi dere d as pri or me dicati o ns.  Pri or ca ncer -
relate d s ur geries, ra di ot hera pies, a n d me dicati o ns will be s u m marize d f or t he Safet y 
A nal y sis Set f or st u d y c o h ort a n d i nte grate d treat me nt gr o u p.
Pri or me dicati o ns will be ta b ulate d b y W H O Preferre d Na me f or t he F ull A nal y sis Set
a n d will be i ncl u de d i n a ge neral c o nc o mita nt me dicati o n listi n g t hat will i de ntif y  pri or 
me dicati o ns .  T he n u m ber a n d perce nt of s u bjects w h o e x perie nce d p ri or ca ncer-relate d 
s ur geries a n d ra di ot hera pies will be ta b ulate d al o n g wit h ot her ca ncer-relate d me dicati o ns 
ta b ulate d by W H O Preferre d Na me.  Pri or me dicati o ns will be s u m marize d f or t he Safet y 
A nal y sis Set f or st u d y c o h ort a n d i nte grate d treat me nt gr o u p.  Pri or ca ncer -relate d 
s ur geries, ra di ot hera pies, a n d me dicati o ns will als o be i ncl u de d i n data listi n gs.
6. 5
C o nc o mit a nt Me dic ati o ns 
C o nc o mita nt me dicati o ns are defi ne d as me dicati o ns ta ke n after t he start of st u d y  
treat me nts.  C o nc o mita nt me dicati o ns will be rec or de d o n t he e C R F a n d c o de d usi n g t he 
W H O Dr u g Dicti o nar y  versi o n Se pte m ber 2 0 1 5.  Me dicati o n start a n d e n d dates
will be 
use d t o i de ntif y  w hic h me dicati o ns e ntere d o n t he c o nc o mita nt me dicati o ns e C R F c o ul d 
be c o nsi dere d as c o nc o mit a nt me dicati o ns.  C o nc o mita nt me dicati o ns will be 
s u m marize d f or t he Safet y A nal ysis Set f or st u d y c o h orts a n d i nte grate d treat me nt 
gr o u ps .  All c o nc o mita nt me dicati o ns will be i ncl u de d i n b y -s u bject data listi n gs. 
6. 6
Pr ot oc ol De vi ati o ns
A pr ot oc ol de viati o n s u m mar y will be pr o vi de d.  T he n u m ber a n d perce nt of s u bjects 
wit h pr ot oc ol de viati o ns will be s u m marize d b y  se verit y a n d cate g or y f or t he Part 1 a n d 2
safety a nal ysis set b y st u d y c o h ort.  T he pr ot oc ol de viati o n cate g ories are:
1.
I nf or me d C o nse nt Criteria
2.
Eli gi bilit y  a n d E ntr y Criteria
3.
C o nc o mita nt Me dicati o n Criteria
4.
La b orat or y Assess me nt Criteria
5.
St u d y  Pr oce d ures Criteria
6.
Seri o us A d verse E ve nt Criteria
7.
Ra n d o mizati o n Criteria
8.
Visit Sc he d ule Criteria
9.
I P C o m plia nce
1 0. Efficac y  Criteria
1 1. A d mi nistrati ve Criteria


I mal u ma b ( B A X 6 9)
Pa ge 2 1 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
1 2. S o urce D oc u me nt Criteria
1 3. Re g ulat or y  or Et hics A p pr o vals Criteria
1 4. Ot her Criteria
All pr ot oc ol de viati o ns will be i ncl u de d i n b y -s u bject data listi n gs. 
7.
E F FI C A C Y E V A L U A TI O N
7. 1
A n al ysis of Pri m ar y Effic ac y O utc o me Me as ure
7. 1. 1
Deri v ati o n of Pri m ar y Effic ac y O utc o me Me as ure
T he re vise d R E CI S T g ui deli nes (Eise n ha uer et al., 2 0 0 9 ) will be use d t o deter mi ne 
disease pr o gressi o n.  Date of disease pr o gressi o n is t he earliest date of t he i ma gi n g 
met h o d t o deter mi ne disease pr o gressi o n.  
F or a n i n di vi d ual s u bject, t he i ma gi n g met h o d  use d t o meas ure t u m or b ur de n at baseli ne 
s h o ul d be use d f or eac h f ut ure t u m or assess me nt. Baseli ne t u m or meas ure me nts a n d 
i de ntificati o n of tar get lesi o ns ma y be base d o n i ma gi n g o btai ned wit hi n 2 8 da y s pri or t o 
scree ni n g. Sc he d ule d t u m or res p o nse assess me nts m ust be i nter prete d pri or t o t he start of 
t he ne xt treat me nt c ycle.  
D ate of Pr o gressi o n will be deri ve d as f oll o ws:
1.
F or pr o gressi o n base d o n ne w lesi o n(s), t he date of pr o gressi o n is t he first sca n 
date o n w hic h t he ne w lesi o n is detecte d.
2.
F or pr o gressi o n base d o n tar get lesi o ns, , t he date of pr o gressi o n is t he date of t he 
i nitial sca n of tar get lesi o ns s h o wi n g > 2 0 % i ncrease i n t he s u m of dia meters of 
tar get lesi o ns; 
3.
F or pr o gress i o n base d o n n o n-tar get lesi o ns, t he date of pr o gressi o n is t he date of 
t he first sca n t hat i n dicated u ne q ui v ocal pr o gressi ve disease of e xisti n g n o n -tar get 
lesi o ns.
T he date of pr o gressi o n will be t he earliest date a m o n g dates descri be d a b o ve. 
F or t u m or res p o nse e val uati o n fr o m assess me nts o n w hic h m ulti ple sca ns are d o ne o n 
differe nt dates a n d n o e vi de nce of pr o gressi o n is i n dicate d, t he latest date of all sca ns will 
be c o nsi dere d as t he e val uati o n date s h o wi n g n o e vi de nce of pr o gressi o n f or t hat 
assess m e nt. I n cases w here o ne or m ore lesi o ns (tar get or n o n-tar get lesi o ns i de ntifie d at 
baseli ne) d o n ot ha ve a n assess me nt at a gi ve n p ost- baseli ne e val uati o n, t he assess me nt 


I mal u ma b ( B A X 6 9)
Pa ge 2 2 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
f or t u m or res p o nse f or t hat visit will be c o nsi dere d “n ot e val ua ble ( N E) ” u nless disease 
pr o gressi o n is n ote d.  
P F S is defi ne d as t he ti me bet wee n ra n d o mizati o n a n d t u m or pr o gressi o n ( per R E CI S T 
v 1. 1 criteria) or deat h fr o m a n y  ca use, wit h ce ns ori n g of s u bjects w h o are l ost t o f oll o w-
u p or wit h dra w c o nse nt . 
T his will be re gar dless of w het her t he s u bject recei ves a n ot her a nti-ca ncer t hera p y pri or 
t o pr o gressi o n.  S u bjects w h o ha ve n ot pr o gresse d or die d at t he ti me of a nal ysis will be 
ce ns ore d at t he ti me of t he latest date of assess me nt fr o m t heir last e val ua ble R E CI S T 
assess me nt.  H o we ver, if t he s u bject pr o gresses or dies after t w o or m ore misse d t u m or 
assess me nts , t he s u bject will be ce ns ore d at t he ti me of t he latest e val ua ble R E CIS T 
assess me nt.  If t he s u bject has n o e val ua ble visits or d oes n ot ha ve baseli ne data t he y will 
be ce ns ore d at 1 da y  u nless t he y die wit hi n t w o visits of baseli ne.  F or t his st u d y, t he 
e xact ti me peri o d t hat i de ntifies t hat t w o t u m or assess me nts ha ve bee n misse d will be 
defi ne d as t wice t he pr ot oc ol -defi ne d ti me bet wee n sca ns + t he pr ot oc ol al l o we d visit 
wi n d o w.  R E CI S T assess me nts are sc he d ule d t o occ ur e ver y  ot her c ycle, ie, e ver y 8 
wee ks ± 1 wee k. If t u m or sca ns i n dicate pr o gressi o n or t he s u bject dies m ore t ha n 2 * 9 
wee ks = 1 8 wee ks ( 1 2 6 da y s) after t he pre vi o us t u m or assess me nt, t he s u bject will be 
ce ns ore d o n t he date of t he assess me nt pri or t o pr o gressi o n or deat h.
T a ble 2 bel o w s pecifies t he date of disease pr o gressi o n or ce ns ori n g r ule s t hat will be 
carrie d o ut f or t he P F S a nal ysis:
T a ble 2:
Date of Pr o gressi o n or Ce ns ori n g f or Pr o gressi o n -free S ur vi val
Sit u ati o n
D ate of Dise ase Pr o gressi o n or Ce ns ori n g
O utc o m e
Ali ve wit h n o p ost -baseli ne 
assess me nts f or t u m or res p o nse
Treat me nt start date
Ce ns ore d
Disease pr o gressi o n or deat h after t w o 
or m ore c o nsec uti ve misse d t u m or 
res p o nse assess me nts 
Date of last sca n f or t u m or assess me nt 
s h o wi n g n o e vi de nce of disease pr o gressi o n 
t hat is bef ore t he first misse d visit.  
Ce ns ore d
N ot k n o w n t o ha ve pr o gresse d or die d 
acc or di n g t o data i n t he data base as of 
data -c ut -of f 
Date of last sca n f or t u m or assess me nt 
s h o wi n g n o e vi de nce of disease pr o gressi o n 
Ce ns ore d
Wit h dra w al fr o m t he st u d y or l oss t o 
f oll o w-u p
Date of last sca n f or t u m or assess me nt pri or 
t o wit h dra wal or l oss t o f oll o w- u p 
Ce ns ore d
Disease pr o gressi o n re p orte d o n 
m ulti ple res p o nse assess me nts
Earliest Date of Pr o gressi o n as defi ne d i n t his 
Secti o n 
Pr o gresse d
Deat h wit h o ut Disease Pr o gressi o n
Date of deat h 
Pr o gresse d


I mal u ma b ( B A X 6 9)
Pa ge 2 3 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
7. 1. 2
A n al ysis Met h o ds f or t he Pri m ar y Effic ac y O utc o me Me as ure
Pr o gressi o n -free s ur vi val i n t he Part 2 treat me nt gr o u ps will be c o m pare d wit h a 1 -si de d 
l o g-ra n k test.  T he l o g -ra n k will be t he pri mar y assess me nt. Ka pla n -Meier ( K M) m e dia n 
P F S ti mes a n d t heir 9 5 % c o nfi de nce i nter vals, esti mates of first a n d t hir d q uartiles, as 
well as K M c ur ves will be s u m marize d b y  treat me nt gr o u p. A C o x re gressi o n m o del will 
be use d t o c o m pare t he hazar d rate bet wee n t he t w o treat me nt gr o u ps wit h o ut 
stratificati o n.  A si n gle hazar d rati o a n d its 9 5 % c o nfi de nce i nter val will be calc ulate d.   
Res ults of t u m or sca ns a n d relate d res p o nse assess me nts f or s u bjects e nr olle d i n t his 
st u d y will be i ncl u de d i n b y -s u bject data listi n gs.  
7. 2
A n al ysis of Sec o n d ar y Effic ac y O utc o me Me as ure
7. 2. 1
Deri v ati o n of Sec o n d ar y O utc o me Me as ures 
7. 2. 1. 1
O ver all S ur vi v al
O verall s ur vi val is defi ne d as t he ti me fr o m ra n d o mizati o n u ntil deat h d ue t o a n y ca use. 
A n y  s u bject n ot k n o w n t o ha ve die d at t he ti me of a nalys is will be ce ns ore d base d o n t he 
last rec or de d date o n w hic h t he s u bject was k n o w n t o be ali ve. 
Last date k n o w n t o be ali ve will be o btai ne d fr o m t he s ur vi val f oll o w - u p C R F.  If t hat 
C R F has n’t bee n c o m plete d t he f oll o wi n g C R F fiel ds will be use d t o deter mi ne t he las t 
date k n o w n t o be ali ve :

Dates of a d mi nistrati o n of c he m ot hera p y a n d st u d y dr u g

La b orat or y  s peci me n c ollecti o ns dates

P K /P D bl o o d sa m pli n g dates

C T a n d/ or M RI  sca n dates

Date of vital si g n assess me nts

Date of E C G assess me nts

Date of c o ntact o n t he s ur vi val f oll o w- u p C R F

Date of Q ualit y  of Life assess me nts

Start a n d st o p dates f or c o nc o mita nt treat me nts

Date of o nset a n d res ol uti o n of A Es

C o m pleti o n/ter mi nati o n date .
O verall s ur vi val will be a nal y ze d wit h t he met h o ds use d f or t he a nal ys is of P F S.


I mal u ma b ( B A X 6 9)
Pa ge 2 4 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
7. 2. 1. 2  
O ver all Res p o nse R ate
T u m or res p o nse will be assesse d b y t he i n vesti gat or base d o n t he re vise d R E CI S T 
g ui deli nes ( Versi o n 1. 1) at eac h ra di o gra p hic assess me nt.  Ra di o l o gical e xa ms are 
re q uire d e ver y 8 wee ks ( ± 7 da ys) starti n g fr o m date of ra n d o mizati o n wit h o ut dela ys f or 
t o xicit y u ntil pr ot oc ol-defi ne d disease pr o gressi o n is n ote d. Res ults base d u p o n sca ns 
perf or me d after start of ne w a nti -ca ncer t hera p y will be e xcl u de d w he n calc ulati n g t he 
best o verall res p o nse. O bjecti ve res p o nse rate will be defi ne d as t he pr o p orti o n of 
s u bjects wit h a c o m plete res p o nse ( C R) or a parti al res p o nse ( P R) per R E CI S T base d 
u p o n t he best res p o nse as assesse d b y t he i n vesti gat or; c o nfir mati o n of res p o nse is n ot 
re q uire d.  Cli nical be nefit rate ( C B R) will be defi ne d as t he pr o p orti o n of s u bjects wit h a 
c o m plete res p o nse ( C R), a partial res p o nse ( P R), or sta ble disease ( S D) per R E CI S T 
base d u p o n t he best res p o nse as assesse d b y t he i n vesti gat or. T he a nal y sis of O R R a n d 
C B R will be perf or me d usi n g Fis her’s e xact test t o c o m pare t he relati ve rate of s u bjects 
wit h a n o bjecti ve res p o nse i n t he treat me nt gr o u ps wit h o ut stratificati o n .  Cl o p per-
Pears o n e xact 2 -si de d 9 5 % c o nfi de nce li mits will be calc ulate d f or t he pr o p orti o n of 
s u bjects wit h O R R i n eac h ar m.  
Si nce t he prese nce of meas ura ble disease is a n i ncl usi o n criteri o n, t he de n o mi nat or f or 
t he rate will be t he n u m ber of s u bjects i n t he F A S.  In a d diti o n t o re prese nti n g O R R a n d 
C B R, t he best o verall res p o nse ( B O R) usi n g res p o nse cate g ories C R, P R, S D , pr o gressi ve 
disease ( P D), a n d n ot e val ua ble ( N E) will be ta b ulate d. T he pr o p orti o n of s u bjects i n eac h 
res p o nse cate g or y will be calc ulate d f or t he st u d y c o h orts a n d t he i nte grate d treat me nt 
gr o u ps.  
S u bjects w h o d o n ot ha ve a n y p ost - baseli ne t u m or assess me nt will be c o u nte d u n der t he 
cate g or y N ot E val ua ble ( N E).
7. 3
Se nsiti vit y A n al yses
A se nsiti vit y  a nalys is will be c o n d ucte d f or P F S.  T he calc ulati o n of P F S will be t he sa me 
as descri be d i n Secti o n  7. 1. 1 e xce pt t hat s u bjects will a ls o be ce ns ore d at t he latest t u m or 
assess me nt pri or t o t he start of a ne w a nti -ca ncer t hera p y.  
If a ny s u bjects are ce ns ore d beca use t he y misse d 2 t u m or assess me nts, a sec o n d 
se nsiti vit y a nalys is will be c o n d ucte d t o i ncl u de t hese s u bjects as e ve nts.  Ot her wise, t he 
calc ulati o n of P F S will be t he sa me as descri be d i n Secti o n  7. 1. 1.   
A t hir d se nsiti vit y  a nalys is will i ncl u de s u bjects i n Part 1 c o h orts a n d be s u m marize d b y 
i nte grate d treat me nt gr o u p.


I mal u ma b ( B A X 6 9)
Pa ge 2 5 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
T he sa me statistical a nal ysis met h o ds use d f or t he pri mar y  a nalys is of P F S, ie, l o g-ra n k 
test a n d C o x re gressi o n, will be use d f or all of t hese se nsiti vit y a nalys es.  
T he best % c ha n ge fr o m baseli ne i n tar get t u m or dia meters will be prese nte d f or eac h 
s u bject i n a waterfall pl ot b y  st u d y c o h ort.
8.
S A F E T Y E V A L U A TI O N 
8. 1
A n al ysis of Pri m ar y S afet y O utc o me Me as ure
F or t he deter mi nati o n of t he R P 2 D, t he a nal ysis of t he occ urre nce of D L Ts will be 
perf or me d o n a s u bset of t he safet y a nal ys is set, i ncl u di n g all e val ua ble s u bjects. S u bjects 
will be c o nsi dere d e val ua ble o nce t he y  eit her c o m plete t heir first treat me nt c ycle or 
wit h dra w fr o m st u d y d uri n g t he first treat me nt c ycle d ue t o D L T. T he R P 2 D will be 
defi ne d as t he hi g hest d ose le vel e xa mi ne d at w hic h < 3 3 % of e val ua ble s u bjects 
e x perie nce a D L T d uri n g t he first treat me nt c y cle.
8. 2
E xte nt of E x p os ure
T he f oll o wi n g varia bles will calc ulate d:

E x p os ure d urati o n ( da y s):  date of last d ose – date of first d ose ( C 1 D 1) + 7, 7 is 
a d de d t o e x p os ure d urati o n t o acc o u nt f or t he 7 -d a y  rest peri o d bet wee n i mal u ma b 
a d mi nistrati o ns .

N u m ber of c ycles: T otal n u m ber of c o m plete or partial treat me nt c y cles t he 
s u bject recei ve d. 

N u m ber of S u bjects wit h d ose i nterr u pte d/ d ose re d ucti o n
F or i mal u ma b, t he f oll o wi n g para meters will be calc ulate d:

C u m ulati ve d ose ( m g): T otal act ual d ose ( m g) t he s u bject recei ve d acr oss all 
c ycles, defi ne d as t he s u m of act ual d ose ( m g) recei ve d acr oss all c y cles.

Calc ulate d c u m ulati ve d ose le vel ( m g/ k g): C u m ulati ve d ose ( m g) di vi de d b y  t he 
a vera ge wei g ht ( k g) acr oss all c y cles.

D ose i nte nsit y  ( m g/ k g/ wee k): { Calc ulate d c u m ulati ve d ose le vel ( m g/ k g) / 
(e x p os ure d urati o n ( da ys) } x 7 

E x pecte d d ose i nte nsit y  ( m g/ k g/ wee k): 7. 5 or 1 0 m g/ k g/ wee k base d o n treat ment 
ar m

Relati ve d ose i nte nsit y  ( %): (( D ose i nte nsit y) / (e x pecte d d ose i nte nsit y)) × 1 0 0.  


I mal u ma b ( B A X 6 9)
Pa ge 2 6 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
8. 3
A d verse E ve nts
A d verse e ve nts ( A E) will be c o de d b y S ys te m Or ga n Class ( SO C ) a n d preferre d ter m 
usi n g Me dical Dicti o nar y f or Re g ulat or y  Acti vities (Me d D R A ), versi o n 1 8. 0.  A E
se verity will be base d o n Nati o nal Ca ncer I nstit ute ( N CI ) C o m m o n Ter mi n ol o g y  Criteria 
f or A d verse E ve nts ( C T C A E) Gra de ( versi o n 4. 0 3).
A treat me nt -e mer ge nt A E ( T E A E) is defi ne d as defi ne d as a n y  e ve nt n ot prese nt pri or t o 
t he i nitiati o n of t he treat me nts or a ny e ve nt alrea d y prese nt t hat w orse ns i n eit her 
i nte nsit y or fre q ue nc y f oll o wi n g e x p os ure t o t he treat me nts.  A n A E t hat was prese nt at 
treat me nt i nitiati o n, b ut res ol ve d a n d t he n rea p peare d w hile t he patie nt was o n treat me nt, 
is a T E A E (re gar dless of t he i nte nsit y of t he A E w he n t he treat me nt was i nitiate d).  If t he 
start date of a n A E is u na vaila ble or i nc o m plete, t he A E C R F as ks t he 
s u bject/i n vesti gat or t o i de ntif y w het her it occ urre d bef ore t he first treat me nt, d uri n g 
treat me nt, wit hi n 2 4 h o urs after t he last treat me nt, or m ore t ha n 2 4 h o urs after t he last 
treat me nt.  T his i nf or mati o n will use d to deter mi ne if t he A E will be c o nsi dere d as 
T E A E , w he n necessar y.  If t he start ti me of t he A E is pr o vi de d, t he n t he A E start date a n d 
ti me will be use d t o classif y t he A E as T E A E or n ot.  I f t he start ti me is n ot pr o vi de d a n d 
t he A E occ urs o n t he sa me da y of first st u dy dr u g a d mi nistrati o n ( C 1 D 1) t he n t he A E will 
be classifie d as T E A E.  
A d verse e ve nt data will be descri pti vel y e val uate d b y treat me nt ar m a n d f or o verall 
s u bjects. I nci de nce of T E A Es b y Me d D R A S O C, preferre d ter m, a n d relati o ns hi p 
( Relate d/ N ot Relate d) t o st u d y dr u g will be s u m marize d base d o n t he safet y p o p ulati o n. 
A d verse e ve nt i nci de nce rates will be s u m marize d wit h fre q ue nc y of e v e nts, fre q ue nc y of 
s u bjects affecte d a n d perce nta ge ( base d o n # s u bjects affecte d).  
F or s u bject le vel s u m maries, s u bjects wit h m ulti ple occ urre nces of e ve nts wit h t he sa me 
preferre d ter ms a n d S O C will be c o u nte d o nce at t he hi g hest Gra de a n d t he str o n gest 
relati o ns hi p t o st u d y dr u g f or eac h preferre d ter m, a n d s yste m or ga n class.  
A d verse e ve nts t hat are re p orte d as p ossi bl y or pr o ba bl y  relate d t o st u d y dr u g will be 
c o u nte d as relate d t o st u d y dr u g.  A d verse e ve nts t hat are re p orte d as u nli kel y  relate d a n d 
u nrelate d will be s u m marize d as n ot relate d.  A Es wit h a missi n g relati o ns hi p will be 
c o nsi dere d “ Relate d” f or t his s u m mar y .
T he a d verse e ve nts s u m maries liste d i n Ta ble 3 will be pr o vi de d f or st u d y c o h ort, 
i nte grate d treat me nt gr o u p, a n d t otals f or t he ta ble f or t he safety a nal ys is set: 
T a ble 3:
A E ta bles pr o d uce d f or treat me nt wit h a n d wit h o ut stratificati o n
A E S u m m ar y
St u d y C o h ort
I nte gr ate d 
Tre at m e nt 
Gr o u p


I mal u ma b ( B A X 6 9)
Pa ge 2 7 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
A E S u m m ar y
St u d y C o h ort 
I nte gr ate d 
Tre at m e nt 
Gr o u p
T E A Es s u m mar y 
Y
Y
T E A Es b y S yste m Or ga n Class a n d Preferre d Ter m
Y
Y
T E A Es b y Preferre d Ter m a n d b y Desce n di n g I nci de nce 
Y
N
T E A Es b y S yste m Or ga n Class a n d Preferre d Ter m  a n d 
C T C A E Gra de
Y
N
Gra de 3 or Hi g her T E A Es b y S y ste m Or ga n Class a n d 
Preferre d Ter m
Y
N
Seri o us T E A Es b y S yste m Or ga n Class a n d Preferre d 
T er m  
Y
Y
N o n -Seri o us T E A Es b y S yste m Or ga n Class a n d Preferre d 
T er m  a n d b y Desce n di n g I nci de nce 
Y
N
Seri o us T E A Es b y S yste m Or ga n Class a n d Preferre d 
T er m  a n d C T C A E Gra de
Y
N
Treat me nt- Relate d T E A Es b y  S yste m Or ga n Class a n d 
Preferre d Ter m 
Y
N
Treat me nt- Relate d T E A Es b y  Preferre d Ter m a n d b y 
Desce n di n g I nci de nce
Y
Y
Treat me nt- Relate d T E A Es b y  S yste m Or ga n Class a n d 
Preferre d Ter m a n d C T C A E Gra de
Y
N
T E A Es Lea di n g T o St u d y Dr u g Disc o nti n uati o n b y 
S y st e m Or ga n Class a n d Preferre d Ter m
Y
Y
T E A Es Lea di n g T o St u d y Dr u g Disc o nti n uati o n b y 
S y st e m Or ga n Class a n d Preferre d Ter m a n d C T C A E 
Gra de
Y
N
T E A Es Lea di n g t o Deat h b y S yste m Or ga n Class a n d 
Preferre d Ter m  
Y
Y
Listi n gs of all A Es a n d als o all seri o us A Es will be pr o d uce d.
A L isti n g will be pr o d uce d f or A Es wit h ge netic i nf or mati o n, act ual dr u g recei ve d, a n d 
c ycles o n treat me nt.
8. 4
Cli nic al L a b or at or y E v al u ati o ns 
F or he mat ol o g y , c he mistr y, a n d c oa g ulati o n, t he o bser ve d val ues a n d c ha n ges fr o m 
baseli ne will be s u m marize d.  C ha n ge fr o m baseli ne will be calc ulate d as ( val ue at a 
treat me nt c ycle – val ue at baseli ne).  La b orat or y  res ults will be classifie d acc or di n g t o t he 
N CI - C T C A E Versi o n 4. 0 3. Gra des are assi g ne d base d s olely o n la b val ues a n d C T C A E 
re q uire me nts re gar di n g relate d cli nical si g ns or sy m pt o ms are n ot re q uire d.  


I mal u ma b ( B A X 6 9)
Pa ge 2 8 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
T heref ore, cli nical assess me nt of t he s u bjects c o ul d res ult i n a differe nt gra de. 
La b orat or y res ults n ot c orres p o n di n g t o C T C A E ter ms will n ot be gra de d. T hres h ol ds are 
s pecifie d i n Secti o n  1 6. 2.  T he n u m ber ( %) of s u bjects wit h val ues t hat satisf y  C T C A E 
criteria at a n y ti me d uri n g treat me nt will be s u m marize d b y  test, gra de , a n d visit.  Eac h 
s u bject will be cate g orize d base d o n t heir p ost - baseli ne C T C A E gra de at eac h pla n ne d 
assess me nt ti me . S hift ta bles relati ve t o t he C T C A E Gra de will be use d t o s u m mariz e t he 
c ha n ge fr o m baseli ne t o t he ma xi m u m p ost -baseli ne C T C A E gra de .
A ta ble will s u m marize t he s hift i n t he a bse nce/ prese nce of pr otei n, gl uc ose, a n d bl o o d i n 
t he uri ne.
La b orat or y  res ults will be s u m marize d i n sta n dar d i nter nati o nal u nits.  
T a bles s u m marizi n g o bser ve d val ues a n d c ha n ges fr o m baseli ne a n d s hifts i n C T C A E 
gra de will be c o m plete d f or st u d y c o h ort.  T he n u m ber ( %) of s u bjects wit h val ues t hat 
satisf y C T C A E criteria at a n y ti me d uri n g treat me nt will be pr o vi de d f or t he treat me nt 
st u d y c oh ort a n d i nte grate d treat me nt gr o u p.
A ll la b orat or y test res ults (i ncl u di n g uri nal ysis) will be prese nte d i n b y -s u bject data 
listi n gs. A list of a b n or mal la b orat or y  val ues will als o be pr o d uce d w here a b n or mal is 
defi ne d as a val ue wit h C T C A E Gra de 1 or hi g her.  If a s u bject has at least o ne a b n or mal 
val ue f or a s pecific a nal yte, all n or mal a n d a b n or mal val ues f or t hat s u bject a n d a nal yt e 
will be i ncl u de d i n t he listi n g.   
P ost baseli ne a b n or mal he patic a n d re nal res ults will be s u m marize d b y  C T C A E T o xicit y
Gra de a m o n g s u bjects wit h n or mal res ults pri or t o first d ose, a n d a listi n g will be create d 
t o s u p p ort t his ta ble. 
8. 4. 1
He m at ol o g y 
Bl o o d sa m ples f or he mat ol o g y  will be a nal yze d f or t he c ollecte d ti me p oi nts .  
He mat ol o g y  testi n g will i ncl u de c o m plete bl o o d c o u nt ( C B C) wit h differe ntial a n d 
platelet c o u nts. 
8. 4. 2
Ser u m C he mistr y
Bl o o d sa m ples f or ser u m c he mistr y will be a nal yz e d f or t he c ollecte d ti me p oi nts.  
C he mistr y  tests will i ncl u de creati ni ne, creati ni ne cle ara nce, s o di u m, p otassi u m, calci u m, 
ma g nesi u m, gl uc ose, al b u mi n , ala ni ne a mi n otra nsferase ( A L T), as partate 
a mi n otra nsferase ( A S T), al kali ne p h os p hatase, t otal bilir u bi n ( T BI L), C- reacti ve pr otei n 
( C R P), a n d bl o o d urea .  C T C A E gra de f or calci u m will be base d o n c orrecte d ser u m 
calci u m, w hic h will be calc ulate d as f oll o ws:


I mal u ma b ( B A X 6 9)
Pa ge 2 9 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
C orrecte d ser u m calci u m = ser u m calci u m ( m g/ d L) + 0. 8 *[( 4 - ser u m al b u mi n ( g/ d L)].
8. 4. 3
C o a g ul ati o n
Bl o o d sa m ples f or c oa g ulati o n para meters will be c ollecte d will be a nal y ze d f or t he 
c ollecte d ti me p oi nts.  T he c oa g ulati o n para meters i ncl u de i nter nati o nal n or malize d rati o 
(I N R) a n d acti vate d partial t hr o m b o plasti n ti me (a P T T). 
8. 4. 4
Uri n al ysis
Uri ne sa m ples will be will be a nal yz e d f or t he c ollecte d ti me p oi nts.  A ta ble will 
s u m marize t he s hift i n t he a bse nce/ prese nce of pr otei n, gl uc ose, a n d bl o o d i n t he ur i ne
fr o m baseli ne t o da y 1 of eac h c ycle a n d t he e n d of st u d y visit.
8. 5
E C G
1 2- Lea d E C Gs will be a nal yze d f or t he c ollecte d ti me p oi nts.  E C G c o n d ucti o n ti mes will 
i ncl u de P R i nter val, Q R S d urati o n, Q T a n d Q Tc i nter val usi n g Fre dericia’s c orrecti o n, 
a n d t he heart rate. T he o bser ve d val ues a n d c ha n ges fr o m baseli ne will be s u m marize d 
ti me p oi nts c ollecte d.  C ha n ge fr o m baseli ne will be calc ulate d as ( val ue at a treat me nt 
c ycle – val ue at baseli ne).  Fre q ue ncies a n d perce nta ge of val ues meeti n g p ote ntiall y  
cli nicall y si g nifica nt ( P C S) criteria (Ta ble 4 ) at a n y ti me will be prese nte d. T he 
de n o mi nat or f or perce nta ges will be t he n u m ber of patie nts w h o ha ve a val ue at baseli ne 
a n d p ost -baseli ne.   
Ta bles s u m marizi n g o bser ve d val ues a n d c ha n ges fr o m baseli ne will be a nal yze d.  T he 
n u m ber ( %) of s u bjects wit h val ues t hat satisf y P C S criteria at a n y ti me d uri n g treat me nt 
will be pr o vi de d.
All s u m mar y  ta bles will be pr o vi de d f or t he Part 1 a n d 2 safety a nal ys is set.  All E C G 
data will be i ncl u de d i n a listi n g.
T a ble 4:
P ote nti all y Cli nic all y Si g nif ic a nt P ost-b aseli ne E C G C o n d ucti o n 
Ti mes
C o n d ucti o n 
Ti me
U nit
P C S Criteri a
P R I nter val
msec
A bs ol ute val ue ≥ 2 0 0
Q R S D urati o n
msec
A bs ol ute val ue ≥ 1 0 0
Q T I nter val
msec
A bs ol ute val ue ≥ 4 5 0
Q Tc F I nter val
msec
Males: A bs ol ute Val ue > = 4 5 0
Fe males: A bs ol ute Val ue > = 4 7 0


I mal u ma b ( B A X 6 9)
Pa ge 3 0 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
C o n d ucti o n 
Ti me
U nit
P C S Criteri a
msec
I ncrease fr o m baseli ne 3 0 – 6 0 
msec
I ncrease fr o m baseli ne > 6 0 
Heart Rate
beats per mi n ute
A bs ol ute val ue ≤ 4 0 
A bs ol ute val ue ≥ 1 2 0
8. 6
Vit al Si g ns 
F or vital si g ns, t he o bser ve d val ues a n d c ha n ges fr o m baseli ne will be s u m marize d b y  
c ollecte d ti me p oi nts.  C ha n ge fr o m baseli ne will be calc ulate d as ( val ue at a treat me nt 
c ycle – val ue at baseli ne).  Fre q ue ncies a n d perce nta ge of val ues meeti n g P C S criteria 
(Ta ble 5 ) at a n y ti me p ost -baseli ne will be prese nte d. T he de n o mi nat or f or perce nta ges 
will be t he n u m ber of s u bjects w h o ha ve a val ue at baseli ne a n d p ost -baseli ne.
Ta bles s u m marizi n g o bser ve d val ues a n d c ha n ges fr o m baseli ne will be c o m plete d f or t he 
st u d y c o h orts.  T he n u m ber ( %) of s u bjects wit h val ues t hat satisf y P C S criteria at a ny 
ti me d uri n g treat me nt will be pr o vi de d f or t he st u d y c o h ort a n d t he i nte grate d treat me nt 
gr o u p . P C S Hi g h criteria f or B P are c o nsiste nt wit h s pecific le vels i ncl u de d i n C T C A E 
criteria f or Gra de 1, 2, a n d 3 h yperte nsi o n. 
All vital si g n data will be i ncl u de d i n a b y- s u bject data listi n g.
T a ble 5:
P ote nti all y Cli nic all y Si g nific a nt P ost -B aseli ne Vit al Si g ns
Vit al Si g n 
U nit
P C S L o w 
P C S Hi g h 
S B P
m m H g
Decrease fr o m baseli ne ≥3 0   
I ncrease fr o m baseli ne ≥3 0 
A bs ol ute val ue < 8 0 m m H g
A bs ol ute val ue 1 2 1 – 1 3 9
A bs ol ute val ue 1 4 0 – 1 5 9
A bs ol ute val ue ≥ 1 6 0
D B P
m m H g
Decrease fr o m baseli ne ≥ 2 0 
m m H g  
I ncrease fr o m baseli ne ≥ 2 0
A bs ol ute val ue < 6 0 m m H g
A bs ol ute val ue 8 0 – 8 9


I mal u ma b ( B A X 6 9)
Pa ge 3 1 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
Vit al Si g n 
U nit
P C S L o w 
P C S Hi g h 
A bs ol ute val ue 9 0 – 9 9
A bs ol ute val ue ≥ 1 0 0
P ulse
b eats 
p er 
m i n ute
A bs ol ute val ue ≤ 4 0  
A bs ol ute val ue ≥ 1 2 0
Res pirat or y  
Rate
breat hs 
per 
mi n ute
A bs ol ute val ue < 1 2  
A bs ol ute val ue > 2 0
Wei g ht
k g 
≥ 7 % decrease fr o m Baseli ne  
≥ 7 % i ncrease fr o m Baseli ne 
8. 7
I m m u n o ge nicit y
Bl o o d sa m ples f or i m m u n o ge nicit y  testi n g will be a nal yz e d f or t he c ollecte d ti me p oi nts.  
I m m u n o ge nicity res ults will be a nal yz e d descri pti vel y b y s u m marizi n g t he n u m ber a n d 
perce nta ge of s u bjects w h o de vel o p detecta ble bi n di n g a n d/ or ne utralizi n g a nti -i mal u ma b
a nti b o dies.  
S u m maries will be base d u p o n all s u bjects fr o m t he safety p o p ulati o n. T he effect of 
i m m u n o ge nicity o n P K, P D, efficac y a n d safet y will be e val uate d, b ut s uc h a nal ys es, if 
a p plica ble, will be s u m marize d i n a se parate re p ort.
9.
E V A L U A TI O N O F P H A R M A C O KI N E TI C S 
A listi n g of P K bl o o d sa m ple c ollecti o n ti mes, deri ve d sa m pli n g ti mes, a n d i mal u ma b 
c o nce ntrati o ns will be pr o vi de d. 
Plas ma c o nce ntrati o ns of i mal u ma b d uri n g C ycle 1 will be s u m marize d b y d ose le vel, 
treat me nt gr o u p, a n d st u d y da y/ meas ure me nt ti me i nter val usi n g descri pti ve statistics 
( n u m ber of s u bjects [ N], n u m ber of o bser vati o ns [ n], mea n, S D, c oefficie nt of variati o n 
[ C V %], me dia n, mi ni m u m, a n d ma xi m u m). If n f or a s u m mar y le vel is ≥3, all descri pti ve 
statistics will be prese nte d; if n = 2, mea n, me dia n, mi ni m u m, a n d ma xi m u m will be 
prese nte d a n d all ot her descri pti ve st atistics will be re p orte d as n ot deter mi ne d ( N D); if 
n = 1, t he si n gle a vaila ble val ue will be prese nte d f or mea n, me dia n, mi ni m u m, a n d 
ma xi m u m, a n d all ot her descri pti ve statistics will be re p orte d as N D. F or t he 1 0 m g/ k g 
treat me nt gr o u ps, c o nce ntrati o ns will be s u m marize d se paratel y b y st u d y part a n d f or 


I mal u ma b ( B A X 6 9)
Pa ge 3 2 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
b ot h st u d y  parts c o m bi ne d. C o nce ntrati o ns t hat are bel o w t he li mit of q ua ntitati o n ( B L Q) 
will be treate d as zer o f or t he c o m p utati o n of descri pti ve statistics.
S u bjects a n d/ or data affecte d b y pr ot oc ol de viati o ns or e ve nts t hat i m pact P K (s uc h as 
i nc orrect d ose, etc. ) will be i ncl u de d i n listi n gs b ut e xcl u de d fr o m descri pti ve statistics. A
se parate p o p ulati o n P K a nal ysis pla n a n d c orres p o n di n g re p ort will be writ te n t o a d dress 
t he p o p ulati o n P K a nal ysis pla n ne d f or t his st u d y.
1 0.
E V A L U A TI O N O F Q U A LI T Y O F LI F E
1 0. 1
Q u alit y of Life Sc ori n g
1 0. 1. 1
E O R T C Q L Q - C 3 0 a n d Q L Q-C R 2 9
T he E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer ( E O R T C) Q L Q-C 3 0 
( versi o n 3. 0) ( Aar o ns o n et. al., 1 9 9 3) s u p ple me nte d b y t he c ol orectal ca ncer m o d ule 
( Q L Q-C R 2 9) (W hista nce et. al., 2 0 0 9 ) are vali date d i nstr u me nts a n d will be use d t o 
meas ure q ualit y of life a n d assess s y m pt o ms a n d si de effects of treat me nt a n d t heir 
i m pact o n e ver yd a y  life. 
T he Q L Q -C 3 0 is c o m p ose d of 5 m ulti-ite m f u ncti o nal scales ( p hys ical, r ole, s ocial, 
e m oti o nal a n d c o g niti ve f u ncti o ni n g), a gl o bal healt h stat us/ Q o L  scale, a n d 9 s ym pt o m 
scales (fati g ue, na usea/ v o miti n g, pai n , fi na ncial i m pact, a p petite l oss, diarr hea, 
c o nsti pati o n, slee p dist ur ba nce a n d d ys p nea).  
T he c ol orectal ca ncer m o d ule ( Q L Q- CR 2 9 ) i nc or p orates f u ncti o nal scales t o assess b o d y  
i ma ge, a n xiet y, wei g ht , a n d se x ual i nterest.  T he Q L Q- C R 2 9 als o i ncl u des s y m pt o m 
scales t o assess uri nar y fre q ue nc y, bl o o d a n d m uc us i n st o ol, st o ol fre q ue nc y, uri nar y 
i nc o nti ne nce, dys uria, a b d o mi nal pai n, b utt oc k pai n, bl oati n g, dr y m o ut h, hair l oss, taste, 
flat ule nce, fecal i nc o nti ne nce, s ore s ki n, e m barrass me nt, st o ma care pr o ble ms, 
i m p ote nce, a n d dys pare u nia .  
M ost ite ms are a ns were d o n a 4- p oi nt scale (i.e., 1 = N ot at all, 2 = A Little, 3 = Q uite a Bit, 
4 = Ver y M uc h) e xce pt t he ite ms c o ntri b uti n g t o t he gl o bal healt h stat us/ Q o L, w hic h ha ve 
a 7- p oi nt scale ( 1 = Ver y P o or t o 7 = E xcelle nt).  Ra w sc ores (re p orte d o n e C R Fs) will be 
tra nsf or me d usi n g a li near tra nsf or mati o n t o sta n dar dize t he res ults s o t hat sc ores f or eac h 
f u ncti o nal a n d sy m pt o m scale ra n ge fr o m 0 t o 1 0 0.  
T he calc ulati o n f or sc ori n g t hese scales is t he sa me i n all cases (Fa ye rs et. al., 2 0 0 1)
1.
Calc ulate t he a vera ge of t he ite ms t hat c o ntri b ute t o t he scale; t his is t he ra w 
sc ore.


I mal u ma b ( B A X 6 9)
Pa ge 3 3 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
2.
Use a li near tra nsf or mati o n t o sta n dar dize t he ra w sc ore, s o t hat sc ores ra n ge fr o m 
0 t o 1 0 0; a hi g her sc ore re prese nts a hi g her (" better") le vel of f u ncti o ni n g, or a 
hi g her (" w orse") le vel of s y m pt o ms.
Calc ulati o ns f or ra w sc ore a n d li near tra nsf or mati o n are as f oll o ws:
I n practical ter ms, if ite ms I1, I2, ... In are i ncl u de d i n a scale, w here n is n u m ber of ite ms 
i n t he scale, t he pr oce d ure is as f oll o ws:
R a w sc ore
R S ( R a w Sc ore) = ( I1 + I2 + I3+ … +I n )/ n
Li ne ar tr a nsf or m ati o n
A p pl y  t he li near tra nsf or mati o n t o 0-1 0 0 t o o btai n t he sc ore S,
F u ncti o nal scales:  S = { 1 – ( R S - 1)/ra n ge } x 1 0 0
S y m pt o m scales / ite ms:  S = {( R S - 1)/ra n ge } x 1 0 0
Gl o bal healt h stat us / Q o L: S = {( R S - 1)/ra n ge } x 1 0 0
R a n ge is t he differe nce bet wee n t he ma xi m u m p ossi ble val ue of R S a n d t he mi ni m u m 
p ossi ble val ue. 
T he r a w sc ore a n d li near tra nsf or me d sc ore will be calc ulate d w he n at least 5 0 % of t he 
ite ms fr o m t he scale ha ve bee n a ns were d. Ot her wise, t he sc ore will be missi n g.
T he str uct ure of t his q uesti o n naire a n d sc ori n g are prese nte d i n  T a ble 6 a n d T a ble 7 .
T a ble 6:
Sc ori n g f or Q L Q -C 3 0 versi o n 3. 0
Sc ale
Sc ale a b bre vi ati o n
N u m ber of 
ite ms
R a n ge
Ite m N u m ber
Gl o b al he alt h st at us / Q o L
Gl o bal healt h stat us/ Q o L
Q L
2
6
2 9, 3 0
F u ncti o n al sc ales
P h y sical f u ncti o ni n g
P F
5
3
1 t o 5
R ole f u ncti o ni n g
R F
2
3
6, 7
E m oti o nal f u ncti o ni n g
E F
4
3
2 1 t o 2 4
C o g niti ve f u ncti o ni n g
C F
2
3
2 0, 2 5
S ocial f u ncti o ni n g
S F
2
3
2 6, 2 7
S y m pt o m  sc ales / ite ms
Fati g ue
F A
3
3
1 0, 1 2, 1 8


I mal u ma b ( B A X 6 9)
Pa ge 3 4 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
Na usea a n d v o miti n g
N V
2
3
1 4, 1 5
Pai n
P A
2
3
9, 1 9
D y s p n oea
D Y
1
3
8
I ns o m nia
S L
1
3
1 1
A p petite l oss
A P
1
3
1 3
C o nsti pati o n
C O
1
3
1 6
Diarr hea
DI
1
3
1 7
Fi na ncial diffic ulties
FI
1
3
2 8


I mal u ma b ( B A X 6 9)
Pa ge 3 5 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
T a ble 7:
Sc ori n g f or Q L Q -C R 2 9
Sc ale
Sc ale a b bre vi ati o n
N u m ber of 
ite ms
R a n ge
Ite m N u m ber
F u ncti o n al sc ales
B o d y  I ma ge
BI
3
3
1 5 -1 7
A n xiet y
A N X
1
3
1 3
Wei g ht
W EI
1
3
1 4
Se x ual i nterest ( me n)
S E X M
1
3
2 6 a, c
Se x ual i nterest ( w o m e n)
S E X W
1
3
2 8 a, c
S y m pt o m  sc ales / ite ms
Uri nar y fre q ue nc y
U F
2
3
1, 2
Bl o o d a n d m uc us i n st o ol
B M S
2
3
8, 9
St o ol fre q ue nc y
S F
2
3
2 2, 2 3 b
Uri nar y i nc o nti ne nce
UI
1
3
3
D y s uria
D Y
1
3
4
A b d o mi nal pai n
A P
1
3
5
B utt oc k pai n
B P
1
3
6
Bl oati n g
B F
1
3
7
Dr y  mo ut h
D M
1
3
1 0
Hair l oss
H L
1
3
1 1
Taste
T A
1
3
1 2
Flat ule nce
F L
1
3
1 9 b
Fecal i nc o nti ne nce
FI
1
3
2 0 b
S ore s ki n
S S
1
3
2 1 b
E m barrass me nt
E M B
1
3
2 4 b
St o ma care pr o ble ms
S T O
1
3
2 5
I mp ote nce
I M P
1
3
2 7 a
D y s pare u nia
D S Y
1
3
2 9 a
a N ote t hat ite ms 2 6 a n d 2 7 are f or me n o nl y, a n d ite ms 2 8 a n d 2 9 are f or w o m e n o nl y. T h us, t hese 
q uesti o ns will be a ns were d o nl y b y a s u bset of patie nts.
b W he n sc ori n g scales or si n gle ite ms t hat i ncl u de q uesti o ns 1 9 t o 2 4, use t he a ns wer t o q uesti o n 1 8: ‘ D o 
y o u ha ve a s o ma ba g (c ol ost o m y/ile ost o m y)? Yes/ N o t o ens ure t hat a ns wers are ta ke n fr o m t he rele va nt 
b o x of q uesti o ns
c I n or der f or t he t wo se x ual i nt erest scales t o be i nter prete d as f u ncti o nal scales ( i.e. a hi g her sc ore is 
better), t he y s h o ul d be sc ore d acc or di n g t o t he s y m pt o m scale al g orit h m.
1 0. 1. 2
E Q - 5 D- 5 L
T he E Q -5 D descri pti ve s y ste m c o m prises t he f oll o wi n g 5 di me nsi o ns: m o bilit y, self-care, 
us ual act i vities, pai n/ disc o mf ort a n d a n xiet y/ de pressi o n.  Eac h di me nsi o n has 5 le vels: n o 


I mal u ma b ( B A X 6 9)
Pa ge 3 6 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
pr o ble ms, s li g ht pr o ble ms, m o derate pr o ble ms, se vere pr o ble ms, a n d u na ble t o perf or m 
t he acti vit y. T here will be n o i m p utati o n of missi n g data. I n a d diti o n, the E Q V A S 
rec or ds t he res p o n de nt’s self-rate d healt h o n a 2 0 c m vertical, vis ual a nal o g ue scale wit h 
e n d p oi nts la belle d 0 = ‘t he best healt h yo u ca n i ma gi ne’ a n d 1 0 0 = ‘t he w orst healt h yo u 
ca n i ma gi ne’.
1 0. 2
A n al ysis of Q o L D at a
F or eac h Q L Q -C 3 0 a n d Q L Q -C R 2 9 , t he s u m mar y statistics of a bs ol ute sc ores a n d 
c ha n ges fr o m baseli ne will be calc ulate d f or t he li near tra nsf or me d sc ore f or Gl o bal 
Healt h stat us, f u ncti o nal a n d s ym pt o m scale f or t he Safety A nal ys is Set.    
F or Part 2, t he st u d y dr u g a n d S o C is c o m pare d b y a 2- si de d Wilc o x o n ra n k s u m test wit h 
t he t-A p pr o xi mati o n at a n al p ha of 0. 0 5.  
F or eac h of t he 5 di me nsi o ns of t he E Q -5 D, ta bles will be pr o vi de d t o s u m marize t he 
fre q ue nc y a n d perce nta ge of s u bjects wit h n o, sli g ht, m o derate, a n d se vere pr o ble ms wit h 
or were u na ble t o perf or m eac h di me nsi o n at baseli ne a n d e n d of st u d y.  I n a d diti o n, t he 
s hift i n t he le vels of percei ve d pr o ble ms at baseli ne t o t he le vels of percei ve d res p o nse at 
e n d of st u d y will be s u m marize d. T he E Q V A S a n d c ha n ge fr o m baseli ne will be 
s u m marize d b y  st u d y c o h ort.
All s u m mar y  ta bles will be pr o vi de d f or t he st u d y c o h orts.  Data f or all s u bjects will be 
i ncl u de d i n listi n gs.
1 1. 
E V A L U A TI O N O F E X P L O R A T O R Y O U T C O M E M E A S U R E S
1 1. 1
E v al u ati o n of P h ar m ac o d y n a mics
A listi n g of bl o o d sa m ple c ollecti o n ti mes, deri ve d sa m pli n g ti mes, a n d o bser ve d, c ha n ge 
fr o m baseli ne a n d perce nt c ha n ge fr o m baseli ne val ues will be pr o vi de d f or t otal MI F a n d 
o x MI F data. Baseli ne f or t otal MI F a n d o x MI F will be t he Da y  1 meas ure me nt at -2 t o 
0 h o urs pri or t o start of i nf usi o n. 
T otal MI F a n d o x MI F data d uri n g C ycl e 1 will be s u m marize d b y d ose le vel a n d 
treat me nt gr o u p usi n g descri pti ve statistics ( n u m ber of patie nts [ N], n u m ber of 
o bser vati o ns [ n], mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m ). If n f or a s u m mar y le vel 
is ≥3, all descri pti ve statistics will be prese nte d; if n = 2, mea n, me dia n, mi ni m u m, a n d 
ma xi m u m will be prese nte d a n d all ot her descri pti ve statistics will be re p orte d as n ot 
deter mi ne d ( N D); if n = 1, t he si n gle a vaila ble val ue will be prese nte d f or mea n, me dia n, 
mi ni m u m, a n d ma xi m u m, a n d all ot her descri pti ve statistics will be re p orte d as N D. F or 


I mal u ma b ( B A X 6 9)
Pa ge 3 7 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
t he 1 0 m g/ k g treat me nt gr o u ps, data will be s u m marize d se parately b y st u d y part a n d f or 
b ot h st u d y  parts c o m bi ne d. T otal MI F a n d ox MI F t hat are bel o w t he li mit of q ua ntitati o n 
( B L Q) will be set t o 1/ 2 t he l o wer li mit of q ua ntitati o n ( L L O Q) f or t he calc ulati o n of 
c ha n ge fr o m baseli ne val ues, a n d f or t he c o m p utati o n of descri pti ve statistics f or 
o bser ve d val ues.
1 1. 2
E x pl or at or y Q u alit y of Life O utc o me Me as ures
A nal y ses of E O R T C Q L Q-C R 2 9 s y m pt o m a n d f u ncti o nal scales as well as t he E Q - 5 D-
5 L d i me nsi o ns are descri be d i n Secti o ns 1 0. 1 a n d 1 0. 2.
1 1. 3
Ge netic Bi o m ar kers
Ge netic bi o mar kers will als o be i n vesti gate d as a n o pti o nal e x pl orat or y  o utc o me. 
E x pl orat or y  ge netic bi o mar ker o utc o me meas ures i ncl u de t u m or-ass ociate d ge netic 
alterati o ns of cf D N A i n bl o o d/ uri ne, f or s u bjects treate d wit h i mal u ma b i n c o m bi nati o n 
wit h 5 -F U/ L V or pa nit u m u ma b w h o pr o vi de c o nse nt f or t hese a nal ys es. T he s p o ns or will 
o btai n a vaila ble hist orical t u m or m utati o nal testi n g res ults f or s u bjects.   T he o bjecti ves 
are e x pl orat or y a n d s u bject-a p pr o val f or bl o o d/ uri ne c ollecti o n is o pti o nal, a nal ys es will 
be data dri ve n.  Data s u m maries will be de vel o pe d a n d pre pare d base d o n a n assess me nt 
of t he a vaila ble data at t he ti me of t he pri mar y  a nal ysis.
1 2.
A N A L Y SI S S O F T W A R E
All data pr ocessi n g, s u m marizati o n a n d a nal ys es will utilize S A S ® s oft ware pac ka ge, 
Versi o n 9. 4.  If t he use of ot her s oft ware is warra nte d , t he fi nal cli nical st u d y re p ort will 
detail w hat s oft ware was use d.
1 3.
G UI D A N C E D O C U M E N T S
G ui da nce f or I n d ustr y Cli nical Trial E n d p oi nts f or t he A p pr o val of Ca ncer Dr u gs a n d 
Bi ol o gics
E 3 Str uct ure a n d C o nte nt of Cli nical St u d y  Re p orts
E 9 Statistical Pri nci ples f or Cli nical Trials


I mal u ma b ( B A X 6 9)
Pa ge 3 8 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
1 4.
R E F E R E N C E S
Aar o ns o n N K, A h me dzai S, Ber g ma n B, et al. T he E ur o pea n Or ga nizati o n f or Researc h 
a n d Treat me nt of Ca ncer Q L Q -C 3 0: A q ualit y - of-life i nstr u me nt f or use i n i nter nati o nal 
cli nical trials i n o nc ol o g y. J o ur n al of t he N ati o n al C a ncer I nstit ute . 8 5: 3 6 5- 7 6, 1 9 9 3.
Eise n ha uer E A, T herasse P, B o gaerts J, et al.  Ne w res p o nse e val uati o n criteria i n s oli d 
t u m ors: Re vise d R E CIS T g ui deli ne ( versi o n 1. 1). E ur J C a ncer . 2 0 0 9; 4 5: 2 2 8- 2 4 7.
Fa ye rs P M, Aar o ns o n N K, Bj or dal K, Gr oe n v ol d M, C urra n D, B ott o mle y A, o n be half 
of t he E O R T C Q ualit y  of Life Gr o u p. E O R T C Q L Q -C 3 0 Sc ori n g M a n u al ( 3 r d e diti o n). 
Br ussels: E O R T C, 2 0 0 1. I S B N: 2 - 9 3 0 0 6 4- 2 2- 6.
W hista nce R N, C o nr o y T, C hie W, et al. Cli nical a n d Ps yc h o metric Vali dati o n of t he
E O R T C Q L Q -C R 2 9 Q uesti o n naire M o d ule t o Assess Healt h -Relate d Q ualit y of Life
i n Patie nts wit h C ol orectal Ca ncer. E ur J C a ncer 4 5: 3 0 1 7 - 3 0 2 6, 2 0 0 9.


I mal u ma b ( B A X 6 9)
Pa ge 3 9 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
1 5.
R E VI SI O N HI S T O R Y
Versi o n 
Iss ue Date
S u m mar y  of C ha n ges
1. 0
2 0 1 6 O C T 0 6
Ne w D oc u me nt


I mal u ma b ( B A X 6 9)
Pa ge 4 0 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
1 6.
A P P E N DI C E S


I mal u ma b ( B A X 6 9)
Pa ge 4 1 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
1 6. 1 Sc he d ule of St u d y Pr oce d ures a n d Assess me nts
Sc he d ule of St u d y Pr oce d ures a n d Assess me nts: P arts 1 a n d 2
Tri al Peri o ds
Scree ni n g 
Visit
B aseli ne 
Visit
St u d y Visits Per Tre at m e nt C ycle a
E n d of 
St u d y/ E arl y 
Ter mi n ati o n 
Visit
S afet y 
F oll o w -U p 
Visit b
St u d y D a ys
Pr oce d ures/ Assess me nts
D a ys -2 8 
t o - 1
D a y 1 
Pre d ose
D a ys 
1 t o 7
D a ys 
8 t o 1 4
D a ys 
1 5 t o 2 1
D a ys 
2 2 t o 2 8
Tre at m e nt Sc he d ule
I mal u ma b a d mi nistrati o n ( Q W) 
( Part 1; Part 2, Ar m A)
Da y  1
Da y  8
Da y  1 5
D a y  2 2
5- F U/ L V or pa nit u m u ma b 
a d mi nistrati o n ( Q 2 W) ( Part 1; Part 2, 
Ar m A) 
Da y  1
Da y  1 5
Visit wi n d o w ( d a ys)
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 7
I nf or me d c o nse ntc
X
Eli gi bilit y criteria
X  
X
D e m o gra p hics
X
Rele va nt me dical a n d s ur gical hist or y
X
E ntr y i nt o I R T S yste m
X  
X d
Da y  1d
Da y  8d
Da y  1 5d
D a y  2 2d
X
Vital si g ns e
X  
X
Da y  1
Da y  8
Da y  1 5
Da y  2 2
X
X
P h y sical e xa mi nati o n
X  
X
Da y  1
Da y  1 5
X
X
E C O G P S
X  
X
Da y  1
X
X


I mal u ma b ( B A X 6 9)
Pa ge 4 2 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
Sc he d ule of St u d y Pr oce d ures a n d Assess me nts: P arts 1 a n d 2
Tri al Peri o ds
Scree ni n g 
Visit
B aseli ne 
Visit
St u d y Visits Per Tre at m e nt C ycle a
E n d of 
St u d y/ E arl y 
Ter mi n ati o n 
Visit
S afet y 
F oll o w -U p 
Visit b
St u d y D a ys
Pr oce d ures/ Assess me nts
D a ys -2 8 
t o - 1
D a y 1 
Pre d ose
D a ys 
1 t o 7
D a ys 
8 t o 1 4
D a ys 
1 5 t o 2 1
D a ys 
2 2 t o 2 8
Tre at m e nt Sc he d ule
E O R T C Q L Q -C 3 0
X
X
X
E O R T C Q L Q -C R 2 9
X
X
X
E Q -5 D
X
X
X
1 2 -lea d E C Gf
X  
X
Da y  1
X
X
E C H O/ M U G A
X
H e m at ol o g y g
X  
X
Da y  1
Da y  8
Da y  1 5
Da y  2 2
X
X
C he mistr y/c oa g ulati o n g
X  
X
Da y  1
Da y  8 
( C ycle 1 
o nl y)
Da y  1 5
X
X
Pre g na nc y test h (if a p plica ble)
X  
X
Da y  1
X
X
Uri nal ysis
X  
X
Da y  1
X
X
Ge netic testi n g i ( K R A S/ N R A S)
X
T u m or meas ure me nt ( R E CI S T v 1. 1) j
X
D a y  2 8 of 
C ycle 2
a n d t he n 
e ver y ot her 
c ycle
X k
X k


I mal u ma b ( B A X 6 9)
Pa ge 4 3 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
Sc he d ule of St u d y Pr oce d ures a n d Assess me nts: P arts 1 a n d 2
Tri al Peri o ds
Scree ni n g 
Visit
B aseli ne 
Visit
St u d y Visits Per Tre at m e nt C ycle a
E n d of 
St u d y/ E arl y 
Ter mi n ati o n 
Visit
S afet y 
F oll o w -U p 
Visit b
St u d y D a ys
Pr oce d ures/ Assess me nts
D a ys -2 8 
t o - 1
D a y 1 
Pre d ose
D a ys 
1 t o 7
D a ys 
8 t o 1 4
D a ys 
1 5 t o 2 1
D a ys 
2 2 t o 2 8
Tre at m e nt Sc he d ule
Bl o o d sa m pli n g f or i m m u n o ge nicit y 
( A D A a n d N A D A)
X
X
X
P K bl o o d sa m ples (i mal u ma b plas ma 
le vels)
X  
X
Da y  1 a n d 
Da y  2 O R 
Da y  4l
Da y  8l
Da y  1 5l
D a y  2 2l
Bl o o d sa m ples f or P D bi o mar kers 
( o x MI F a n d t otal MI F)
X  
X
Da y  1 a n d 
Da y  2 O R 
Da y  4l
Da y  8l
Da y  1 5l
D a y  2 2l
Bl o o d sa m ple f or ge netic bi o mar kers 
(cf D N A)m
X
D a y  2 8 of 
C ycle 1
a n d t he n 
e ver y ot her 
c ycle
X
Uri ne sa m ple f or ge netic bi o mar kers 
(cf D N A)m
X
D a y  2 8 of 
C ycle 1
a n d t he n 
e ver y ot her 
c ycle
X
A d verse e ve nts n
X  
X
X  
X
X
X
X
X
C o nc o mita nt me dicati o ns/ n o n -dr u g 
t hera pies
X  
X
X  
X
X
X
X
X


I mal u ma b ( B A X 6 9)
Pa ge 4 4 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
A b bre viati o ns:  5 -F U = 5 -fl u or o uracil; A D A =a nti-dr u g a nti b o d y; A E =a d verse e ve nt; C 1 D 1 = C ycle 1 Da y 1; cf D N A =cell -free D N A; C T =c o m p uterize d 
t o mo gra p h y; E C G =electr ocar di o gra m; E C H O =ec h ocar di o gra m; E C O G P S = Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma nce Stat us ; E O R T C Q L Q -
C 3 0 = E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life Q uesti o n naire C ore 3 0; E O R T C Q L Q -C R 2 9 = E ur o pea n 
Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life Q uesti o n naire f or c ol orectal ca ncer 2 9; E Q -5 D = E ur o pea n Q ualit y of Life – 5 
Di m e nsi o ns; I R T =I nteracti ve Res p o nse Tec h n ol o g y; K R A S = Kirste n rat sarc o ma viral o nc o ge ne h o m ol o g; L V = le uc o v ori n; MI F = macr o p ha ge 
mi grati o n i n hi bit or y fact or; M RI = ma g netic res o na nce i ma gi n g; M U G A = m ulti gate d ac q uisiti o n sca n; N A D A = ne utralizi n g a nti -dr u g a nti b o d y; 
N R A S = ne ur o blast o ma R A S viral ( v -ras) o nc o ge ne h o m ol o g; o x MI F = o xi date d macr o p ha ge mi grati o n i n hi bit or y fact or; P D = p har mac o d y na mic; 
P K = p har mac o ki netic; Q 2 W =e ver y 2 wee ks; Q W =e ver y wee k; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors ; S o C =sta n dar d of care.
a
Treat me nt c ycles are defi ne d i n t his st u d y as 4-wee k c ycles. I n eac h treat me nt c ycle, i mal u ma b is a d mi nistere d Q W, a n d 5 -F U/ L V a n d pa nit u m u ma b 
are a d mi nistere d Q 2 W i n 4 -wee k c ycles. Treat me nt c ycles will c o nti n ue u ntil pr o gressi o n, u nacce pta ble t o xicities, or w it h dra wal of c o nse nt.
b
T h e Safet y F oll o w-u p Visit s h o ul d occ ur 3 0 ( ± 7) da ys after t he last d ose of st u d y treat me nt. F or s u bjects w h o ha ve st o p pe d st u d y dr u g or ha ve 
d oc u me nte d disease pr o gressi o n, p ost -st u d y tele p h o ne calls t o assess o verall s ur vi val will be ma de b y site staff e ve r y 3 m o nt hs.
c
S u bject i nf or me d c o nse nt occ urs at scree ni n g, pri or t o a n y st u d y -s pecific pr oce d ure.
d
I R T will be utilize d at scree ni n g a n d baseli ne visits f or all s u bjects ( Part 1 a n d Part 2), at all s u bse q ue nt st u d y visits i n Part 1, a n d all s u bse q ue nt s t u d y 
visits i n Part 2 f or s u bjects i n Ar m A o nl y.
e
Vital si g ns, i ncl u di n g b o d y  te mperat ure, heart rate, bl o o d press ure, a n d res pirat or y rate, are t o be meas ure d after a 5 -mi n ute rest. Sitti n g p ositi o n is 
rec o m me n de d f or bl o o d press ure meas ure me nt. Hei g ht a n d b o d y wei g ht will als o be rec or de d. O n t he da y of i mal u ma b a d mi nistrati o n, vital si g ns will 
be ta ke n wit hi n 3 0 mi n utes pri or t o d osi n g a n d wit hi n 3 0 mi n utes after c o m pleti o n of i mal u ma b i nf usi o n. Wee kl y m o nit ori n g t o be d o ne i n C ycle 1 
o nl y, t he n Q 2 W.
f
T he 1 2 -lea d E C G assess me nt at Scree ni n g s h o ul d be perf or me d n o earlier t ha n 1 wee k bef ore C 1 D 1. T he 1 2 -lea d E C G assess me nt s h o ul d be 
perf or me d pre d ose a n d 2 ( ± 1) h o urs p ost d ose o n Da y 1 ( Baseli ne, C 1 D 1).
g
La b orat or y assess me nts s h o ul d be e val uate d bef or e dr u g a d mi nistrati o n. I m me diatel y pri or t o C y cle 1, la b orat or y assess me nts ca n be perf or me d eit her 
o n Da y - 1 or o n Da y 1 pre d ose. He mat ol o g y tests will be d o ne wee kl y d uri n g eac h treat me nt c ycle. C he mistr y/c oa g ulati o n tests will be d o ne o n Da y 1 
a n d Da y 1 5 of eac h treat me nt c ycle, a n d Da y 8 of C ycle 1 o nl y. La b orat or y tests i ncl u de he mat ol o g y (c o m plete bl o o d c o u nt wit h differe ntial a n d 
platelet c o u nts) a n d bi oc he mistr y (creati ni ne, creati ni ne cleara nce acc or di n g t o C oc kcr oft -Ga ult, s o di u m, p otassi u m, calci u m , ma g nesi u m, gl uc ose, 
al b u mi n, ala ni ne a mi n otra nsferase, as partate a mi n otra nsferase, al kali ne p h os p hatase, t otal bilir u bi n, C -reacti ve pr otei n, a n d bl o o d urea nitr o ge n). 
C oa g ulati o n pa nel i ncl u des I nter nati o nal N or malize d Rati o a n d acti vate d partial t hr o m b o plasti n ti me.
h
Ser u m h u ma n c h ori o nic g o na d otr o pi n t o be teste d at scree ni n g; uri ne di pstic k test t o be perf or me d o n Da y 1 of eac h c ycle ( pri or t o d osi n g), E n d of 
St u d y/ Earl y Ter mi nati o n Visit, a n d at Safet y F oll o w -u p. A ser u m pre g na nc y test will be per f or me d t o c o nfir m if a p ositi ve res ult is o btai ne d i n a 
di pstic k test.
i
If n ot rea dil y a vaila ble, ge netic testi n g f or K R A S/ N R A S m utati o n stat us nee ds t o be d o ne earl y e n o u g h t o all o w ra n d o mizati o n wit hi n 4 wee ks. If 
K R A S m utati o n stat us is k n o w n, t he s u bj ect ca n start treat me nt w hile N R A S testi n g is pe n di n g.
C o nti n ue d o n next p a ge


I mal u ma b ( B A X 6 9)
Pa ge 4 5 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
C o nti n ue d
j
Baseli ne C T or M RI sca ns ca n be acce pte d w it hi n 2 8 da ys pri or t o first i mal u ma b a d mi nistrati o n ( C 1 D 1); assess me nts are t o be re peate d e ver y 2 c ycles 
usi n g t he sa me met h o d at eac h meas ure me nt a n d t u m or res p o nse e val uate d bef ore starti n g t he ne xt c ycle. A 7 -d a y  wi n d o w is per mitte d f or all i ma gi n g 
st u dies f or t u m or meas ure me nt p ur p oses.
k
A t u m or meas ure me nt s h o ul d be o btai ne d at t he E n d of St u d y/ Earl y Ter mi nati o n visit , if n o disease pr o gressi o n was c o nfir me d pre vi o usl y a n d t his visit 
occ urs > 4 w ee ks after t he last sca n; n o a d diti o nal sca ns will be re q uire d if disease pr o gressi o n is c o nfir me d at t his visit. A t u m or meas ure me nt s h o ul d 
be o btai ne d at t he Safet y F oll o w -u p visit, if n o disease pr o gressi o n was c o nfir me d pre vi o usl y a n d t his visit occ urs > 4 wee ks after t he last sca n.
l
F or s u bjects recei vi n g i mal u ma b treat me nt, bl o o d sa m ples f or P K (i mal u ma b plas ma le vels) a n d P D bi o mar kers ( o x MI F a n d t otal M I F) will be 
c ollecte d at t he ti mes i n dicate d i n Ta ble 6 of t he pr ot oc ol . Cycle 1 o nly: Bl o o d sa m ples will be c ollecte d pre d ose a n d p ost d ose o n Da y 1, o n eit her 
D a y 2 ( 2 4 ± 4 h p ost first d ose) O R Da y 4 ( 7 2 ± 8 h p ost first d ose), a n d t he n pre d ose a n d p ost d ose o n Da y 8, Da y 1 5, a n d Da y 2 2. 
S u bse q ue nt tre at me nt cycles: Bl o o d sa m ples will be c ollecte d pre d ose a n d p ost d ose o nl y o n Da y 1.
m
O pti o nal e x pl orat or y a nal ysis f or s u bjects treate d w it h i mal u ma b i n c o mbi nati o n wit h 5 -F U/ L V or pa nit u m u ma b.
n
A E s t o be c ollecte d o n a c onti n u o us basis u ntil t he Safet y F oll o w -u p Visit.


I mal u ma b ( B A X 6 9)
Pa ge 4 6 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
1 6. 2
C T C gr a des f or l a b or at or y v al ues
L a b P ar a meter 
N CI  C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  ( C T C A E) v 4. 0 3
Gr a de 1
Gr a de 2
Gr a de 3
Gr a de 4
He m at ol o g y
A cti v at e d p arti al 
t hr o m b o pl a sti n ti m e pr ol o n g e d   
( a P T T)
> U L N - 1. 5 x U L N 
> 1. 5 x U L N - 2. 5 x U L N 
> 2. 5 x U L N
H e m o gl o bi n i n cr e a s e d
I n cr e a s e i n > 0 - 2 g/ d L a b o v e 
U L N or a b o v e b a s eli n e if 
b a s eli n e i s a b o v e U L N 
I n cr e a s e i n > 2 - 4 g/ d L a b o v e 
U L N or a b o v e b a s eli n e if 
b a s eli n e i s a b o v e U L N 
I n cr e a s e i n > 4 g/ d L a b o v e 
U L N or a b o v e b a s eli n e if 
b a s eli n e i s a b o v e U L N 
H e m o gl o bi n d e cr e a s e d 
(A n e mi a )
H e m o gl o bi n ( H g b) < L L N - 1 0. 0 
g/ d L; < L L N - 6. 2 m m ol/ L;
< L L N - 1 0 0 g/ L
H g b < 1 0. 0 - 8. 0 g/ d L;
< 6. 2 - 4. 9 m m ol/ L;  < 1 0 0 - 8 0 g/ L
H g b < 8. 0 g/ d L;
< 4. 9 m m ol/ L ;
< 8 0 g/ L;
I N R i n cr e a s e d*
> U L N - 1. 5 x U L N;
> 1. 5 x U L N - 2. 5 x U L N;
> 2. 5 x U L N;
L y m p h o c yt e c o u nt d e cr e a s e d
< L L N - 8 0 0/ m m 3;  < L L N - 0. 8 x 
1 0 e 9/ L
< 8 0 0 - 5 0 0/ m m 3; < 0. 8 - 0. 5 x 
1 0 e 9 / L
< 5 0 0 - 2 0 0/ m m 3; < 0. 5 - 0. 2 x 
1 0 e 9 / L
< 2 0 0/ m m 3; < 0. 2 x 
1 0 e 9 / L
L y m p h o c yt e c o u nt i n cr e a s e d
> 4 0 0 0/ m m 3 - 2 0, 0 0 0/ m m 3 
> 2 0, 0 0 0/ m m 3 
N e utr o p hil c o u nt d e cr e a s e d
< L L N - 1 5 0 0/ m m 3; < L L N - 1. 5 x 
1 0 e 9 / L
< 1 5 0 0 - 1 0 0 0/ m m 3; < 1. 5 - 1. 0 x 
1 0 e 9 / L
< 1 0 0 0 - 5 0 0/ m m 3; < 1. 0 - 0. 5 x 
1 0 e 9 / L
< 5 0 0/ m m 3; < 0. 5 x 
1 0 e 9 / L
Pl at el et c o u nt d e cr e a s e d
< L L N - 7 5, 0 0 0/ m m 3; 
< L L N - 7 5. 0 x 1 0 e 9 / L
< 7 5, 0 0 0 - 5 0, 0 0 0/ m m 3; 
< 7 5. 0 - 5 0. 0 x 1 0 e 9 / L
< 5 0, 0 0 0 - 2 5, 0 0 0/ m m 3; 
< 5 0. 0 - 2 5. 0 x 1 0 e 9/ L
< 2 5, 0 0 0/ m m 3; < 2 5. 0 x 
1 0 e 9 / L
W h it e bl o o d c ell d e cr e a s e d 
( WB C)
< L L N - 3 0 0 0/ m m 3; < L L N - 3. 0 x 
1 0 e 9 / L
< 3 0 0 0 - 2 0 0 0/ m m 3; 
< 3. 0 - 2. 0 x 1 0 e 9 / L
< 2 0 0 0 - 1 0 0 0/ m m 3; < 2. 0 - 1. 0 
x 1 0 e 9 / L
< 1 0 0 0/ m m 3; < 1. 0 x 
1 0 e 9 / L
Cli nic al C he mistr y
Al b u mi n d e cr e a s e d 
( H y p o al b u mi n e mi a)
< L L N - 3 g/ d L; < L L N - 3 0 g/ L
< 3 - 2 g/ d L; 
< 3 0 - 2 0 g/ L
< 2 g/ d L; 
< 2 0 g/ L


I mal u ma b ( B A X 6 9)
Pa ge 4 7 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
L a b P ar a meter 
N CI  C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  ( C T C A E) v 4. 0 3
Gr a de 1
Gr a de 2
Gr a de 3
Gr a de 4
Al a ni n e a mi n otr a n sf er a s e 
i n cr e a s e d
( A L T or S G P T)
> U L N - 3. 0 x U L N 
> 3. 0 x U L N - 5. 0 x U L N; 
> 5. 0 x U L N - 2 0. 0 x U L N; 
> 2 0. 0 x U L N 
Al k ali n e p h o s p h at a s e 
i n cr e a s e d
> U L N - 2. 5 x U L N 
> 2. 5 x U L N - 5. 0 x U L N 
> 5. 0 x U L N - 2 0. 0 x U L N 
> 2 0. 0 x U L N 
A m yl a s e i n cr e a s e d
> U L N - 1. 5 x U L N 
> 1. 5 x U L N - 2. 0 x U L N 
> 2. 0 x U L N - 5. 0 x U L N 
> 5. 0 x U L N 
A s p art at e a mi n otr a n sf er a s e 
i n cr e a s e d
( A S T or S G O T)
> U L N - 3. 0 x U L N 
> 3. 0 x U L N - 5. 0 x U L N; 
> 5. 0 x U L N - 2 0. 0 x U L N 
> 2 0. 0 x U L N 
Bl o o d bilir u bi n i n cr e a s e d
> U L N - 1. 5 x U L N 
> 1. 5 x U L N - 3. 0 x U L N 
> 3. 0 x U L N - 1 0. 0 x U L N 
> 1 0. 0 x U L N 
C al ci u m hi g h 2)
(H y p er c al c e mi a )
C orr e ct e d s er u m c al ci u m of 
> U L N - 1 1. 5 m g/ d L; 
> U L N - 2. 9 m m ol/ L;  
C orr e ct e d s er u m c al ci u m of 
> 1 1. 5 - 1 2. 5 m g/ d L; 
> 2. 9 - 3. 1 m m ol/ L;   
C orr e ct e d s er u m c al ci u m of 
> 1 2. 5 - 1 3. 5 m g/ d L;
> 3. 1 - 3. 4 m m ol/ L;   
C orr e ct e d s er u m 
c al ci u m of > 1 3. 5 
m g/ d L; > 3. 4 m m ol/ L;   
C al ci u m l o w2)
( H y p o c al c a e mi a)
C orr e ct e d s er u m c al ci u m of 
< L L N - 8. 0 m g/ d L; 
< L L N - 2. 0 m m ol/ L;
C orr e ct e d s er u m c al ci u m of < 8. 0 
- 7. 0 m g/ d L; 
< 2. 0 - 1. 7 5 m m ol/ L;  
C orr e ct e d s er u m c al ci u m of 
< 7. 0 - 6. 0 m g/ d L; 
< 1. 7 5 - 1. 5 m m ol/ L;   
C orr e ct e d s er u m 
c al ci u m of  < 6. 0 
m g/ d L; < 1. 5 m m ol/ L;   
Cr e ati ni n e i n cr e a s e d
> b a s eli n e - 1. 5 x b a s eli n e;
> U L N - 1. 5 x U L N 
> 1. 5 x b a s eli n e - 3. 0 x b a s eli n e;
> 1. 5 x U L N - 3. 0 x U L N 
> 3. 0 x b a s eli n e; 
> 3. 0 x U L N - 6. 0 x U L N 
> 6. 0 x U L N 
Gl u c o s e d e cr e a s e d 
(H y p o gl y c e mi a )
< L L N - 5 5 m g/ d L; < L L N - 3. 0 
m m ol/ L
< 5 5 - 4 0 m g/ d L; < 3. 0 - 2. 2 
m m ol/ L
< 4 0 - 3 0 m g/ d L; < 2. 2 - 1. 7 
m m ol/ L
< 3 0 m g/ d L; < 1. 7 
m m ol/ L; 
Gl u c o s e i n cr e a s e d
(H y p er gl y c e mi a ) 
F a sti n g gl u c o s e v al u e > U L N -
1 6 0 m g/ d L;
F a sti n g gl u c o s e v al u e > U L N -
8. 9 m m ol/ L
F a sti n g gl u c o s e v al u e > 1 6 0 - 2 5 0 
m g/ d L; 
F a sti n g gl u c o s e v al u e > 8. 9 - 1 3. 9 
m m ol/ L
F a sti n g gl u c o s e v al u e > 2 5 0 -
5 0 0 m g/ d L;
F a sti n g gl u c o s e v al u e > 1 3. 9 -
2 7. 8 m m ol/ L; 
F a sti n g gl u c o s e v al u e 
> 5 0 0 m g/ d L;
F a sti n g gl u c o s e v al u e 
> 2 7. 8 m m ol/ L; 
M a g n e si u m
hi g h
(H y p o m a g n e s a e mi a )
> U L N - 3. 0 m g/ d L; > U L N - 1. 2 3 
m m ol/ L 
> 3. 0 - 8. 0 m g/ d L; > 1. 2 3 - 3. 3 0 
m m ol/ L 
> 8. 0 m g/ d L; > 3. 3 0 
m m ol/ L; 


I mal u ma b ( B A X 6 9)
Pa ge 4 8 of 4 8
Statistical A nal ysis Pla n f or Pr ot oc ol I de ntifier: 3 9 1 4 0 1
2 0 1 6 O C T 1 0
L a b P ar a meter 
N CI  C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  ( C T C A E) v 4. 0 3
Gr a de 1
Gr a de 2
Gr a de 3
Gr a de 4
M a g n e si u m
l o w
( H y p o m a g n e s a e mi a)
< L L N - 1. 2 m g/ d L; < L L N - 0. 5 
m m ol/ L
< 1. 2 - 0. 9 m g/ d L; < 0. 5 - 0. 4 
m m ol/ L
< 0. 9 - 0. 7 m g/ d L; < 0. 4 - 0. 3 
m m ol/ L
< 0. 7 m g/ d L; < 0. 3 
m m ol/ L; 
P ot a s si u m hi g h 
( H y p er k al e mi a)
> U L N - 5. 5 m m ol/ L 
> 5. 5 - 6. 0 m m ol/ L 
> 6. 0 - 7. 0 m m ol/ L; 
> 7. 0 m m ol/ L; 
P ot a s si u m l o w*
( H y p o k al e mi a)
< L L N - 3. 0 m m ol/ L 
< L L N - 3. 0 m m ol/ L; 
< 3. 0 - 2. 5 m m ol/ L; 
< 2. 5 m m ol/ L; 
S o di u m hi g h 
( H y p er n atr e mi a)
> U L N - 1 5 0 m m ol/ L 
> 1 5 0 - 1 5 5 m m ol/ L 
> 1 5 5 - 1 6 0 m m ol/ L; 
> 1 6 0 m m ol/ L; 
S o di u m l o w 
( H y p o n atr e mi a)
< L L N - 1 3 0 m m ol/ L
-
< 1 3 0 - 1 2 0 m m ol/ L
< 1 2 0 m m ol/ L; 
Uri c A ci d hi g h* 
( H y p er uri c e mi a)
> U L N - 1 0 m g/ d L ( 0. 5 9 m m ol/ L)  
-
> U L N - 1 0 m g/ d L ( 0. 5 9 
m m ol/ L) 
> 1 0 m g/ d L; > 0. 5 9 
m m ol/ L; 
1) B e c a u s e m a n y i n stit uti o n s h a v e diff er e n c e s f or n or m al r a n g e s of m et a b oli c, l a b or at or y, a n d h e m at ol o g y v al u e s, t h e C T C A E oft e n u s e s t h e t er m s U L N a n d 
L L N i n li e u of a ct u al n u m eri c al v al u e s. I n s o m e c a s e s, a n i n stit uti o n' s L L N mi g ht b e b e y o n d t h e r a n g e s p e ci fi e d f or a Gr a d e 1. I n t hi s c a s e,     t h e i n stit uti o n al 
li mit s of n or m al s h o ul d t a k e pr e c e d e n c e o v er t h e C T C A E v al u e s. F or e x a m pl e, if a n i n stit uti o n' s L L N of l y m p h o c yt e s i s 5 0 0/ m m3 , a l y m p h o c yt e c o u nt of 5 0 1 
at t h at i n stit uti o n w o ul d b e tr a n sl at e d t o a C T C A E Gr a d e 0; a l y m p h o c yt e c o u nt of 4 9 9 w o ul d b e tr a n sl at e d t o a C T C A E Gr a d e 3. B e c a u s e l o c al l a b or at or y 
v al u e s tr u m p C T C A E v 4. 0 3' s r a n g e s, s o m e Gr a d e 1 a n d Gr a d e 2 A E s will n ot e xi st f or a l o c al l a b.
2) C orr e ct e d C al ci u m ( m g/ d L) = T ot al C al ci u m ( m g/ d L) – 0. 8 [ Al b u mi n ( g/ d L) – 4]