Clinical trial NCT01327612
Conditions: Advanced Solid Tumors Carcinoid Colorectal Cancer Locally Advanced Lymphoma Metastatic Cancer Non-Small Cell Lung Cancer Sarcoma Solid Tumors
Keywords: AMG 655 AMG 479 Apoptosis Monoclonal Antibody Tumor Necrosis Factor Insulin-like Growth Factor Bevacizumab Modified FOLFOX6 mFOLFOX6 FOLFOX Lymphoma Trail Receptor ganitumab conatumumab
Sponsor: Amgen
Start date: 2011-03-03; Completion date: 2020-02-05
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this protocol is to allow continued treatment with conatumumab and/or ganitumab, with or without chemotherapy, to participants who completed a separate Amgen-sponsored conatumumab or ganitumab study without disease progression whose previous studies were closed.

Detailed description:

Arms: arm 1: Participants will continue to receive conatumumab every 2 weeks (Q2W) or every 3 weeks (Q3W) at the same dose and regimen as at the conclusion of the parent study. arm 2: Participants will receive conatumumab and ganitumab by intravenous infusion at the same dose and regimen as at the conclusion of the parent study. arm 3: Participants will continue to receive ganitumab Q3W or every 4 weeks (Q4W) at the same dose and regimen as at the conclusion of the parent study. arm 4: Participants will continue to receive conatumumab by intravenous infusion in addition to modified FOLFOX6 chemotherapy with or without bevacizumab.
Interventions: intervention 1: Modified FOLFOX6 intervention 2: Conatumumab intervention 3: Ganitumab intervention 4: Bevacizumab
Intervention descriptions: intervention 1: The mFOLFOX6 regimen is a combination therapy of oxaliplatin 85 mg/m² administered as a 2-hour intravenous (IV) infusion on day 1 and leucovorin 400 mg/m² racemate or 200 mg/m² levo-leucovorin administered as a 2-hour infusion on day 1, followed by a loading dose of 5-fluorouracil (5-FU) 400 mg/m² IV bolus administered on day 1, then 5-FU 2400 mg/m² via ambulatory pump administered for a period of 46 to 48 hours every 14 days. intervention 2: Administered by intravenous infusion Q2W or Q3W. intervention 3: Administered by intravenous infusion Q3W or Q4W. intervention 4: Administered at a dose of 5 mg/kg by intravenous infusion on day 1 of each 14 day cycle.

Protocol documents:
Prot_000.pdf: 
Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 1 of 80
CONFIDENTIAL
Title:  A Phase 2 Open Label Extension Study of Conatumumab and AMG 479
AMG 655 (Conatumumab) and AMG 479
Amgen Protocol Number 20101116
EudraCT number: 2010-022270-14
Clinical Study Sponsor:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320
Phone: +1 (805) 447-1000
Key Sponsor Contact:
 MD
Clinical Research Senior Medical Scientist
Amgen Inc.
Phone:
E-mail
Global Clinical Trial Manager
DOCS International UK Ltd
Phone: 
E-mail:
Date:
Amendment 1: 
07 September 2010
25 May 2011
Amendment 2:
25 January 2012
Amendment 3:
20 December 2012
Amendment 4:
20 November 2013
Amendment 5:
11 April 2017
Confidentiality Notice
This document contains confidential information of Amgen Inc.
This document must not be disclosed to anyone other than the study staff and members 
of the independent ethics committee/institutional review board.  
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  for US sites, 1- 800-77-AMGEN; for all other 
countries, insert the local toll-free Medical Information number or Amgen’s general 
number in the US (1-805-447-1000).  For all other study-related questions, continue to 
contact the Key Sponsor Contact.
Approved
NCT Number: NCT01327612
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 2 of 80
CONFIDENTIAL
Investigator’s Agreement
I have read the attached protocol entitled A Phase 2 Open Label Extension Study of
Conatumumab and AMG 479, dated 11 April 2017, and agree to abide by all provisions 
set forth therein.
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice and applicable regulations/guidelines.
I agree to ensure that Financial Disclosure Statements will be completed by:

me (including, if applicable, my spouse [or legal partner] and dependent children)

my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children)
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status.
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation
without the prior written consent of Amgen Inc. 
Signature
Name of Principal Investigator
Date (DD Month YYYY)
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 3 of 80
CONFIDENTIAL
Protocol Synopsis
Title:  A Phase 2 Open Label Extension Study of Conatumumab and AMG 479
Study Phase:  2
Indication:  Subjects who have completed a separate Amgen-sponsored conatumumab or 
AMG 479 study and will continue treatment according to the parent study.
Primary Objective:  To provide ongoing treatment with:

conatumumab therapy, with or without co-therapy (chemotherapy with and without 
bevacizumab, or AMG 479) for subjects who are eligible, according to the parent study, to 
receive their next dose of conatumumab, or

AMG 479 therapy alone, for subjects who are eligible, according to the parent study, to 
receive their next dose of AMG 479.
Secondary Objective(s):  To evaluate the safety profile, including adverse events and serious 
adverse events, of:

conatumumab, with or without co-therapy, or

AMG 479 alone.  
Hypotheses:  The purpose of this study is to provide a mechanism for subjects to continue to 
receive treatment with conatumumab and/or AMG 479. 
Study Design
This is a Phase 2 multi-center, open-label study that permits subjects who have completed a 
separate Amgen-sponsored conatumumab or AMG 479 study to continue treatment with 
conatumumab, with or without co-therapy (chemotherapy with and without bevacizumab, or 
AMG 479), or with AMG 479 therapy alone.  Subjects who have not progressed on a separate 
Amgen protocol are eligible to participate in this trial.  
In this extension study, conatumumab and AMG 479 study drugs will be administered at the 
same dose level and schedule that the subject received at the conclusion of the parent 
conatumumab, or AMG 479 study, accommodating any subjects who were maintained on a 
reduced dose level or different schedule of administration in their parent study.  
Subjects will be evaluated before every cycle of conatumumab or AMG 479 therapy at the study 
clinic.  These study visits will include a standard of care clinical assessment which includes 
collection of vital signs, adverse events, concomitant medications, and laboratory samples and 
results.  Radiological assessments to evaluate disease extent (with change compared to nadir 
from the parent protocol) should be performed at regular intervals, at a minimum once every 
6 (± 1) months or more frequently if clinically indicated (starting from their last scan on the parent 
protocol), per standard of care (SOC) at each facility.
Reasons for study discontinuation will include progressive disease, intolerance to investigational 
product(s), and/or need for additional systemic anticancer treatment.  When a subject 
discontinues the study for any reason, a safety follow-up visit will be completed at least 
30 (+ 3) days after the last dose of protocol-specified therapy.  
Primary and Secondary Endpoints

Adverse events

Serious adverse events

Vital signs

Clinical laboratory tests

Tumor response

Disease progressions and deaths
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 4 of 80
CONFIDENTIAL
Sample Size:  The sample size is dependent upon the number of subjects that transition into this 
study from separate Amgen conatumumab or AMG 479 studies.  The sample size is estimated to 
be approximately 15 subjects.
Summary of Subject Eligibility Criteria
Inclusion Criteria
To be enrolled in this study, subjects must be currently enrolled in a prior Amgen-sponsored 
conatumumab or AMG 479 study, and are eligible according to the parent study to receive their 
next dose of conatumumab (with or without co-therapy) or AMG 479 alone. 
Subjects must have their eligibility assessed for this study and be enrolled within 30 days of their 
last treatment on the parent protocol.
Exclusion Criteria
Discontinued from a conatumumab or AMG 479 study due to an adverse event, including 
intolerance to conatumumab or AMG 479, respectively.
Subjects determined to have disease progression during their participation in the parent Amgen 
study.
Amgen Investigational Product Dosage and Administration
The starting dose and frequency of conatumumab will be determined based on the dose and 
frequency administered during the parent study. 
Conatumumab will be administered by IV infusion.  The dose of conatumumab will be calculated 
based on the subject’s actual body weight during the study day 1 assessment and the dose must 
be recalculated if actual body weight changes by 10%.  Investigators may recalculate the doses 
more frequently based on institutional guidelines.
Subjects previously enrolled in Study 20070411 will receive conatumumab and/or AMG 479 per 
parent protocol.  AMG 479 18 mg/kg will be administered IV Q3W, unless discontinued during 
treatment on parent protocol.  Subjects previously enrolled in Study 20050118 will receive 
AMG 479 monotherapy at a dosed of 20 mg/kg IV Q3W or Q4W per parent protocol. There will be 
no individual AMG 479 dose reductions, except as outlined below in Table 5, Thrombocytopenia 
without Bleeding.
The dose (infusion volume) of AMG 479 will be calculated based on the subject’s actual body 
weight during the study day 1 assessment.  The dose will not need to be recalculated unless the 
actual body weight changes by 10%.  Investigators may recalculate the dose of AMG 479 more 
frequently according to institutional guidelines.
AMG 479 will be administered through a peripheral line or indwelling catheter using a 
nonpyrogenic, low protein binding filter with a 0.2- or 0.22- micron pore size in-line filter infusion 
set-up.  
Non Amgen Non-investigational Product Dosage and Administration
Subjects previously enrolled in Study 20060464 subjects will be treated with mFOLFOX6 and 
bevacizumab on each of the 14 day (+ 3 days) treatment cycles before infusion of conatumumab 
(2 or 10 mg/kg Q2W, based on their dose from study 20060464).
Modified FOLFOX6 regimen is a combination therapy of oxaliplatin (85 mg/m2) administered as a 
2-hour infusion on day 1; leucovorin (400 mg/m2 racemate or 200 mg/m2 levo-leucovorin) 
administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m2) IV 
bolus administered on day 1, then 5-FU (2,400 mg/m2) via ambulatory pump administered for a 
period of 46-48 hours every 14 days (+ 3 days).
Administration of mFOLFOX6 chemotherapy will commence on day 1 of each treatment cycle 
and end with a continuous IV infusion of 5-FU.  For the purpose of this protocol, the 
administration of continuous IV infusion of 5 FU will commence after conatumumab infusions.  
A new cycle of mFOLFOX6 treatment will be repeated every 2 weeks (+ 3 days).
Bevacizumab will be administered at a dose of 5 mg/kg by intravenous infusion on day 1 of each 
14 day cycle (+ 3 days).  Institutional standards for bevacizumab infusion times may be used.
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 5 of 80
CONFIDENTIAL
Control Group:  N/A
Procedures
Eligibility Assessment for Continued Treatment

Review of inclusion and exclusion criteria

Medical history and concomitant medications

Vital signs, physical exam and height

Pregnancy test as applicable
Treatment and Follow-up Procedures

Recording of adverse events and concomitant medications

Vital signs and weight

Laboratory samples: including hematology, chemistry, amylase, lipase, coagulation, 
urinalysis, glucose as appropriate

Samples for anti-conatumumab antibodies, samples for anti-AMG 479 antibodies as 
appropriate

Radiological assessments to evaluate disease extent (with change compared to nadir from 
the parent protocol) should be performed at regular intervals, at a minimum once every
6 (± 1) months or more frequently if clinically indicated (starting from their last scan on the 
parent protocol), per standard of care (SOC) at each facility 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and Appendix A.
Statistical Considerations:  
The studies preceding this open label extension are sufficiently different to preclude pooling of 
data over the studies.  Since the number of subjects enrolled per parent study will be low most of 
the data will be shown in listings.  A limited number of summary tables will be produced when the 
number of subjects makes this sensible.
The final analysis of this study will be performed at the end of the study ie, when all the subjects 
have completed or had the opportunity to complete the Day 60 Follow-up visit. The data may be 
summarized and listed before the final analysis to support Regulatory filings.
Subject disposition (number screened, enrolled into the study, receive conatumumab and/or 
AMG 479, withdraw from the study) will be summarized.  
Demographics (age, sex, race) and tumor type will be listed.
For a full description of statistical analysis methods, please refer to Section 10.
Sponsor/Licensee: Amgen Inc.
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 6 of 80
CONFIDENTIAL
Study Design and Treatment Schema
S
C
R
E
E
N
I
N
G
E
N
R
O
L
L
M
E
N
T
Monotherapy 
Treatment 
Conatumumab Q2W 
or Q3W
OR
AMG 479 Q3W or 
Q4W
Combination 
Treatment 
Conatumumab Q2W 
or Q3W + Ongoing 
co-therapy
S
A
F
E
T
Y
F
O
L
L
O
W
-
U
P
D
A
Y
6
0
F
O
L
L
O
W
-
U
P
E
N
D
O
F
S
T
U
D
Y
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 7 of 80
CONFIDENTIAL
Study Glossary
Abbreviation or Term
Definition/Explanation
5-FU
5-fluorouracil
ADL
activities of daily living
Adverse Event
Any event that occurs after the start of study treatment.  These will 
be collected for all enrolled subjects.
ALT (SGPT)
alanine aminotransferase (serum glutamic-pyruvic transaminase)
ANC
absolute neutrophil count
AST (SGOT)
aspartate aminotransferase
Baseline Value
The “baseline value” is the value measured on study Day 1 before 
first administration of study specified treatment.  For 
variables/assessments not scheduled to be performed on study 
Day 1 or that are missing at baseline, the baseline value is the 
value from the screening period measured closest to study Day 1.
BUN
blood urea nitrogen
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Co-therapy
Defined as either chemotherapy (including bevacizumab) or 
AMG 479. This definition applies to subjects who are eligible to 
receive conatumumab in combination with co-therapy according to 
the parent study.   
Day 60 Follow-up Visit
The study visit at 60 days (14 days) after last dose of 
protocol-specified therapy.
Disease Progression
Refers to radiographic progression or clinical progression
DR5
Death receptor 5
eCRF
electronic case report form
End of Study 
When all the subjects have completed or had the opportunity to 
complete the Day 60 Follow-up visit 
GCP
Good Clinical Practice
G-CSF
granulocyte-colony-stimulating factor
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IGF-1R
type I insulin-like growth factor receptor 
IgG1 
immunoglobulin G, type 1
Investigational product
Refers to either conatumumab or AMG 479
IRB
institutional review board
INR
international normalization ratio
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 8 of 80
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
IP
investigational product
IV
intravenous
LLN
lower limit of normal
LV
leucovorin
On-Study Death
Any death that occurs after receiving protocol specified therapy 
through 30 days after the last dose of IP.  Any on-study death will 
be reported as a serious adverse event. 
Parent Study
refers to protocol under which subjects received their initial 
treatment with conatumumab
PK
pharmacokinetics
PLT
platelets
PTT
prothrombin time
Q2W
every two weeks
Q3C
every three cycles
Q8C
every eight cycles
SAE
serious adverse event
SAER
Serious Adverse Event Report 
Safety Follow-up 
(30 Day Safety 
Follow-up Visit)
The study visit at 30 days (+ 3 days) after last dose of 
protocol-specified therapy.
Screen Failure
A subject who signs an informed consent but fails to enroll in the 
study.
SOC
Standard of care
Study Day 1
The day that the first dose of study specified treatment is 
administered. 
Study End
When all the subjects have completed or had the opportunity to 
complete the Day 60 Follow-up visit
Study end for each 
subject
The date the subject withdraws consent from the study, completes 
or has the opportunity to complete the Day 60 follow-up visit or 
dies.
Study Start
The study will start when the first subject has been enrolled.
Study Week 1
The 7-day period beginning with study Day 1 through study Day 7.
TNF
tumor necrosis factor
TRAIL
tumor necrosis factor (TNF)-related apoptosis-inducing ligand
ULN
upper limit of normal
WBC
white blood cell
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 9 of 80 
Table of Contents 
Protocol Synopsis ............................................................................................................. 3 
Study Glossary .................................................................................................................. 7 
1. 
OBJECTIVES ......................................................................................................... 13 
1.1 
Primary ....................................................................................................... 13 
1.2 
Secondary .................................................................................................. 13 
2. 
BACKGROUND AND RATIONALE ........................................................................ 13 
2.1 
Disease ....................................................................................................... 13 
2.2 
Amgen Investigational Product Background ............................................... 13 
2.2.1 
Conatumumab Background ........................................................ 13 
2.2.1.1 
Death Receptor 5 and Cancer ................................. 13 
2.2.1.2 
Conatumumab Clinical Experience .......................... 14 
2.2.1.3 
Conatumumab Pharmacokinetics ............................ 16 
2.2.2 
AMG 479 Background ................................................................ 16 
2.2.3 
AMG 479 Clinical Experience ..................................................... 17 
2.2.4 
Safety and Efficacy Summary .................................................... 18 
2.3 
Rationale .................................................................................................... 19 
2.4 
Clinical Hypotheses .................................................................................... 19 
3. 
EXPERIMENTAL PLAN ......................................................................................... 19 
3.1 
Study Design .............................................................................................. 19 
3.2 
Number of Centers ..................................................................................... 20 
3.3 
Number of Subjects .................................................................................... 20 
3.4 
Estimated Study Duration ........................................................................... 20 
3.4.1 
Study Duration for Participants ................................................... 20 
3.4.2 
End of Study ............................................................................... 21 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 21 
4.1 
Inclusion Criteria ......................................................................................... 21 
4.1.1 
Disease Related ......................................................................... 21 
4.2 
Exclusion Criteria ........................................................................................ 21 
4.2.1 
Disease Related ......................................................................... 21 
4.2.2 
General ....................................................................................... 21 
5. 
SUBJECT ENROLLMENT ..................................................................................... 22 
6. 
TREATMENT PROCEDURES ............................................................................... 23 
6.1 
Conatumumab ............................................................................................ 23 
6.1.1 
Conatumumab Dosage, Administration, and Schedule .............. 23 
6.1.1.1 
Subjects Receiving Conatumumab in 
Monotherapy ............................................................ 24 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 10 of 80
CONFIDENTIAL
6.1.1.2
Subjects Receiving Conatumumab in 
Combination With AMG 479 (Transferring 
From Parent Protocol 20070411) ............................25
6.1.1.3
Subjects Receiving Conatumumab in 
Combination With mFOLFOX6 and 
Bevacizumab (Transferring From Parent 
Protocol 20060464).................................................25
6.1.2
Conatumumab Premedication ...................................................25
6.1.3
Conatumumab Toxicity Management ........................................26
6.1.3.1
ALT or AST Elevations............................................26
6.1.3.2
Serum Amylase or Lipase Elevation........................27
6.1.3.3
Non-hematologic Toxicities .....................................28
6.1.3.4
Hematologic Toxicities ............................................29
6.2
AMG 479...................................................................................................29
6.2.1
AMG 479 Dosage, Administration, and Schedule ......................29
6.2.1.1
AMG 479 Dosage and Schedule (for 
Subjects Transferring From Protocol 
20070411)...............................................................30
6.2.1.2
AMG 479 Dosage and Schedule (for 
Subjects Transferring From Protocol 
20050118)...............................................................31
6.2.2
AMG 479 Premedication ...........................................................31
6.2.3
AMG 479 Toxicity Management.................................................31
6.2.3.1
General Criteria.......................................................31
6.2.3.2
Dosing Adjustments of AMG 479 Alone or 
AMG 479 in Combination with 
Conatumumab.........................................................32
6.2.3.3
AMG 479 Related Non-hematologic 
Adverse Events (Excluding Hyperglycemia 
and Elevation of Transaminases) ............................37
6.2.3.4
Anti-coagulation Management.................................37
6.2.3.5
AMG 479 Related Infusion Reactions......................37
6.2.3.6
AMG 479 Hearing Loss...........................................38
6.2.4
Bisphosphonates.......................................................................38
6.3
Subjects Receiving Conatumumab in Combination With 
mFOLFOX6/Bevacizumab (Transferring From Parent 
Protocol 20060464)...................................................................................39
6.3.1
mFOLFOX6 Regimen................................................................39
6.3.1.1
mFOLFOX6 Regimen Premedication......................40
6.3.1.2
mFOLFOX6 Dose Levels ........................................40
6.3.2
mFOLFOX6 Dose Modification..................................................41
6.3.3
Discontinuation of mFOLFOX6..................................................44
6.3.4
Supportive Therapy for mFOLFOX6 Chemotherapy..................44
6.3.4.1
Growth Factors........................................................44
6.3.4.2
Oral Cryotherapy.....................................................45
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 11 of 80
CONFIDENTIAL
6.3.4.3
Hypersensitivity.......................................................45
6.3.4.4
Pharyngolaryngeal Dysesthesias ............................45
6.4
Bevacizumab (Transferring From Parent Protocol 20060464)...................45
6.4.1
Bevacizumab Dosage, Administration and Schedule.................45
6.4.2
Bevacizumab Premedication .....................................................46
6.4.3
Bevacizumab Toxicity Management ..........................................46
6.4.4
Bevacizumab Dosage Adjustment.............................................46
6.4.5
Discontinuation of Components of 
mFOLFOX6/Bevacizumab.........................................................46
6.5
Concomitant Therapy................................................................................49
6.6
Excluded Medications or Procedures During Study Period........................49
6.7
Metastases Interventional Therapy............................................................49
6.8
Multiple Toxicity.........................................................................................50
7.
STUDY PROCEDURES .......................................................................................50
7.1
General Study Procedures ........................................................................50
7.2
Eligibility Assessment for Continued Treatment ........................................50
7.3
Treatment Period ......................................................................................51
7.4
Day 30 Safety Follow-up Visit....................................................................52
7.5
Day 60 Follow-up Visit...............................................................................53
8.
REMOVAL AND REPLACEMENT OF SUBJECTS...............................................53
8.1
Removal of Subjects .................................................................................53
8.2
Replacement of Subjects ..........................................................................54
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING.......................54
9.1
Adverse Events.........................................................................................54
9.1.1
Definition of Adverse Events......................................................54
9.1.2
Reporting Procedures for Adverse Events.................................55
9.2
Serious Adverse Events............................................................................57
9.2.1
Definition of Serious Adverse Events.........................................57
9.2.2
Reporting Procedures for Serious Adverse Events....................57
9.3
Pregnancy and Lactation Reporting ..........................................................59
10.
STATISTICAL CONSIDERATIONS......................................................................61
10.1
Study Endpoints........................................................................................61
10.2
Sample Size Considerations .....................................................................61
10.3
Access to Individual Subject Treatment Assignments by Amgen 
or Designees.............................................................................................61
10.4
Planned Methods of Analysis ....................................................................61
10.4.1
General Approach/Considerations.............................................61
10.4.2
Analysis of Key Study Endpoints ...............................................62
10.4.2.1
Safety Endpoints.....................................................62
10.4.2.2
Tumor Response, Disease Progression 
and Deaths..............................................................62
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 12 of 80
CONFIDENTIAL
11.
REGULATORY OBLIGATIONS............................................................................63
11.1
Informed Consent......................................................................................63
11.2
Independent Ethics Committee/Institutional Review Board........................64
11.3
Subject Confidentiality...............................................................................64
11.4
Investigator Signatory Obligations.............................................................65
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS..................................................65
12.1
Protocol Amendments and Study Termination ..........................................65
12.2
Study Documentation and Archive ............................................................65
12.3
Study Monitoring and Data Collection .......................................................66
12.4
Investigator Responsibilities for Data Collection........................................67
12.5
Language..................................................................................................67
12.6
Publication Policy......................................................................................67
12.7
Compensation...........................................................................................68
13.
REFERENCES.....................................................................................................69
14.
APPENDICES ......................................................................................................70
List of Tables
Table 1.  Summary of Clinical Studies ...........................................................................14
Table 2.  Clinical Studies With AMG 479 by Tumor Type ..............................................17
Table 3.  Conatumumab Dose Interruption Guidelines for Increases in ALT 
and AST Levels ......................................................................................27
Table 4.  Conatumumab Product Dose Interruption Guidelines for Increases 
in Serum Amylase or Lipase Levels........................................................28
Table 5.  Conatumumab and AMG 479 Dosing Modifications for Hematologic 
Toxicity Based on Hematology Counts ≤3 Days Prior to a New 
Cycle ......................................................................................................33
Table 6.  Conatumumab and AMG 479 Dosing Modifications for 
Non-hematologic Toxicity Based on Toxicity ≤3 Days Prior to 
a New Cycle ...........................................................................................35
Table 7.  mFOLFOX6 Dose Reductions - Non-neurological Toxicity..............................41
Table 8.  mFOLFOX6 Dose Modification Guidelines......................................................42
Table 9.  Dose Modification Guidelines Oxaliplatin-associated Neurotoxicity.................44
Table 10.  Bevacizumab Treatment Delays and Instructions .........................................47
Table 11.  Summary of Analytes Measured at Baseline / During the Study ...................50
List of Appendices
Appendix A.  Schedule of Assessments ........................................................................71
Appendix B.  Additional Safety Assessment Information................................................73
Appendix C.  Sample Serious Adverse Event Form.......................................................75
Appendix D.  Pregnancy Notification Worksheet............................................................79
Appendix E.  Lactation Notification Worksheet ..............................................................80
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 13 of 80
CONFIDENTIAL
1.
OBJECTIVES
1.1
Primary
To provide ongoing treatment with:

conatumumab therapy, with or without co-therapy (chemotherapy with and without 
bevacizumab, or AMG 479), for subjects who are eligible, according to the parent 
study, to receive their next dose of conatumumab, or  

AMG 479 therapy alone for subjects who are eligible, according to the parent study, 
to receive their next dose of AMG 479.
1.2
Secondary
To evaluate the safety profile, including adverse events and serious adverse events, of:

conatumumab, with or without co-therapy, or 

AMG 479 alone.  
2.
BACKGROUND AND RATIONALE
2.1
Disease
This protocol will include subjects previously enrolled in Amgen-sponsored 
conatumumab and AMG 479 studies with different solid tumors, including, but not limited 
to, colorectal cancer (CRC), non small cell lung cancer (NSCLC), soft tissue sarcoma 
(STS), non-Hodgkin’s lymphoma (NHL), pancreatic cancer, and ovarian cancer.
2.2
Amgen Investigational Product Background 
2.2.1
Conatumumab Background 
2.2.1.1
Death Receptor 5 and Cancer
Apoptosis or programmed cell death is an evolutionarily conserved process for removing 
unwanted cells from the body.  Dysregulation of this process contributes to many 
diseases including cancer.  Tumor necrosis factor (TNF)-related apoptosis-inducing 
ligand (TRAIL) receptor 2 (TR-2, death-receptor 5 [DR5]) is a member of the tumor 
necrosis factor super-family of receptors.  TRAIL is the natural ligand for DR5; TRAIL 
binding to DR5 initiates an intracellular caspase cascade and induces apoptosis in many 
human transformed cell lines but not most normal cells (Kelly and Ashkenazi, 2004).
TRAIL receptor agonists have been demonstrated to induce apoptosis in a variety of 
cancer cell lines with little toxicity to normal cells.  There is also evidence that they may
act cooperatively with existing cancer therapies, including targeted agents.  These 
findings suggest that stimulating DR5 could be useful for cancer therapy in combination 
with a range of existing anti-tumor therapies on a wide variety of tumor types.
Approved 
 
 


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2.2.1.2
Conatumumab Clinical Experience
As of 18 June 2010, approximately 973 subjects have been enrolled in 10 ongoing 
clinical trials of conatumumab; 80 have received monotherapy and 749 have received 
conatumumab (or conatumumab-placebo) in combination with chemotherapy and/or 
other biologic agents.
A brief description and status of each study in the conatumumab clinical development 
program are provided in Table 1.  For details regarding the safety and efficacy of 
conatumumab indications, please refer to the latest edition of conatumumab IB.
Table 1.  Summary of Clinical Studies
Study 
Number
Study Title
Study Status
Dosea
Enrollmentb
Conatumumab Administered as Monotherapy
20050171
A Phase 1, 
Open-Label, Dose 
Escalation Study 
Evaluating the Safety, 
Tolerability and 
Pharmacokinetics of 
Conatumumab in 
Subjects with Advanced 
Tumors
Ongoing; 
primary 
analysis 
complete
Part 1: 0.3, 1, 3, 10, or 
20 mg/kg IV Q2W
Part 2: 20 mg/kg IV Q2W
Part 1: 22
Part 2: 15
20060246
A Phase 1, 
Open-Label, Dose 
Escalation Study 
Evaluating the Safety, 
Tolerability and 
Pharmacokinetics of 
Conatumumab in 
Japanese Subjects with 
Advanced Tumors
Ongoing; 
primary 
analysis 
complete
3, 10, or 20 mg/kg IV 
Q2W
18
Conatumumab Administered in Combination with Chemotherapy
20060323
A Phase 1b/2 Study to 
Evaluate the Safety and 
Efficacy of 
Conatumumab or 
AMG 479 in 
Combination with 
Gemcitabine as 
First-Line Therapy for 
Metastatic Pancreatic 
Cancer
Ongoing; 
preliminary 
data
Part 1: 3 or 10 mg/kg IV 
Q2W in combo with 
gemcitabine
Part 2: conatumumab 
10 mg/kg IV Q2W, 
AMG 479 12 mg/kg IV 
Q2W, or 
conatumumab-placebo 
in combination with 
gemcitabine
Part 1: 13
Part 2: 125
Page 1 of 3
a   Refers to conatumumab dose unless otherwise noted.
b  As of the data cutoff date of 09 July 2009
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Table 1.  Summary of Clinical Studies
Study 
Number
Study Title
Study Status
Dosea
Enrollmentb
Conatumumab Administered in Combination with Chemotherapy (continued)
20060295
A Phase 1b/2 Study of 
Conatumumab in 
Combination with 
Paclitaxel and 
Carboplatin for the 
First-Line Treatment of 
Advanced Non-Small 
Cell Lung Cancer
Ongoing; 
primary 
analysis 
complete
Part 1: 5 or 15 mg/kg IV 
Q3W in combination with 
paclitaxel/ carboplatin
Part 2: conatumumab 
(15 mg/kg), 
conatumumab (3 mg/kg), 
or 
conatumumab-placebo 
IV Q3W in combination 
with 
paclitaxel/carboplatin
Part 1: 12
Part 2: 172
20060464
A Phase 1b/2 Study of 
Conatumumab in 
Combination with 
Modified FOLFOX6 and 
Bevacizumab for the 
First-Line Treatment of 
Subjects with 
Metastatic Colorectal 
Cancer
Ongoing; 
preliminary 
data
Part 1: 3 or 10 mg/kg IV 
Q2W in combination with 
mFOLFOX6/ 
bevacizumab
Part 2: conatumumab 
(10 mg/kg), 
conatumumab (2 mg/kg), 
or conatumumab 
placebo IV Q2W in 
combination with 
mFOLFOX6 and 
bevacizumab
Part 1: 12
Part 2: 186
20060324
A Phase 1b/2 Study of 
Conatumumab in 
Combination With 
Doxorubicin for the 
First-Line Treatment of 
Locally Advanced or 
Metastatic, 
Unresectable Soft 
Tissue Sarcoma
Ongoing; 
preliminary 
data
Part 1: 15 mg/kg IV Q3W 
in combination with 
doxorubicin
Part 2: conatumumab 
(15 mg/kg), or placebo 
IV Q3W in combination 
with doxorubicin
Part 1: 6
Part 2: 128
20060340
A Phase 1b Study to 
Evaluate the Safety and 
Tolerability of 
Conatumumab in 
Combination with 
Bortezomib or 
Vorinostat in Subjects 
with Relapsed or 
Refractory Lymphoma
Ongoing; 
preliminary 
data
Part 1: 1.5, 5 or 
15 mg/kg IV Q3W in 
combination with 
bortezomib or vorinostat
Part 2: dose selected in 
part 1 in combination 
with bortezomib
Part 1: 27
Page 2 of 3
a   Refers to conatumumab dose unless otherwise noted.
b  As of the data cutoff date of 09 July 2009
Approved 
 
 


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Table 1.  Summary of Clinical Studies
Study 
Number
Study Title
Study Status
Dosea
Enrollmentb
Conatumumab Administered in Combination with Chemotherapy (continued)
20060579
A Phase 2, double-blind 
Study to Evaluate the 
Safety and Efficacy of 
FOLFIRI in 
Combination With 
AMG 479 or 
Conatumumab Versus 
FOLFIRI for the 
Second-line Treatment 
of KRAS-mutant 
Metastatic Colorectal 
Carcinoma
Ongoing; 
preliminary 
data
10 mg/kg IV Q2W + 
AMG 479 placebo in 
combination with 
FOLFIRI, AMG 479 
12 mg/kg + 
conatumumab placebo 
IV Q2W in combination 
with FOLFIRI, or 
conatumumab placebo + 
AMG 479 placebo in 
combination with 
FOLFIRI
8
Conatumumab Administered in Combination with Other Biologic Agents
20060332
A Phase 1b/2 Study of 
Conatumumab in 
Combination with 
Panitumumab in 
Subjects with 
Metastatic Colorectal 
Cancer
Ongoing; 
primary 
analysis 
complete
Part 1: 10 mg/kg IV Q2W 
in combination with 
6 mg/kg panitumumab IV 
Q2W
Part 2: 10 mg/kg IV Q2W 
in combination with 
panitumumab
Part 1: 6
Part 2: 47
20070411
A Phase 1b/2, Dose 
Escalation Study of 
Conatumumab in 
Combination with 
AMG 479 in Subjects 
with Advanced, 
Refractory Solid 
Tumors
Ongoing; 
preliminary 
data
Part 1: 1, 3 or 15 mg/kg 
IV Q3W in combination 
with AMG 479 18 mg/kg
Part 2: 15 mg/kg IV Q3W 
in combination with 
AMG 479
Part 1: 9
Page 3 of 3
a   Refers to conatumumab dose unless otherwise noted.
b  As of the data cutoff date of 09 July 2009
2.2.1.3
Conatumumab Pharmacokinetics
Based on noncompartmental analysis of all available PK data, conatumumab exhibited 
doselinear kinetics in the range from 0.3 to 20 mg/kg.  The overall mean (median) 
half-life was 12 (10.7) days.  Therefore, the human PK profile supports intravenous 
administration once every 2 to 3 weeks in subjects with cancer.
2.2.2
AMG 479 Background 
Most human cancers express the type I insulin-like growth factor receptor (IGF-1R; 
Sachdev and Yeel, 2007; Macaulay, 1992; Werner and LeRoith, 1996).  Tumor growth 
and survival is supported by IGF-1R signaling through stimulation of cell survival 
pathways that allow tumor cells to resist the apoptosis-inducing activity of 
Approved 
 
 


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chemotherapeutics, radiation, and antihormone therapy.  IGF-1R signaling inhibition has 
been shown to slow tumor growth in human xenografts.  Moreover, IGF-1R inhibition has 
been shown to potentiate the anti-tumor effects of chemotherapy, radiation therapy, 
biologic and hormonal therapeutic agents in preclinical xenograft models.  AMG 479, a 
fully human monoclonal antibody (IgG1) against human IGF-1R, was developed to 
inhibit survival and proliferative signals that are driven by IGF-1 and IGF-2.  Treatment of 
human tumors with AMG 479 alone or in combination with other anti-cancer therapy 
should inhibit tumor growth and invasion.
2.2.3
AMG 479 Clinical Experience
Table 2.  Clinical Studies With AMG 479 by Tumor Type
Protocol 
No.
Description
Status
Monotherapy Study in Mixed Solid Tumors
20050118
A Phase 1, Open-Label, Dose Finding Study Evaluating the Safety 
and Pharmacokinetics of AMG 479 in Subjects with Advanced Solid 
Tumors 
Ongoing
20060245
A Phase 1, Open-label, Dose Escalation Study Evaluating the Safety, 
Tolerability, and Pharmacokinetics of AMG 479 in Japanese Subjects 
with Advanced Solid Tumors
Ongoing
Monotherapy Study in Ewing’s Family Tumors
20060283
A Phase 2 Study of AMG 479 in Relapsed or Refractory Ewing’s 
Family Tumors and Desmoplastic Small Round Cell Tumors 
Ongoing
Combination Study in Mixed Solid Tumors
20060134
A Phase 1b, Open-Label Study to Evaluate the Safety, Tolerability, 
and Pharmacokinetic of AMG 479 with Biologics or Chemotherapy in 
Adult Subjects with Advanced Solid Tumors 
Ongoing
20070411
A Phase 1b/2 Open Label, Dose Escalation Study of AMG 655 in 
Combination With AMG 479 in Subjects With Advanced, Refractory 
Solid Tumors
Ongoing
Combination Study in Pancreatic Cancer
20060323
A Phase 1b/2 Study to Evaluate the Safety and Efficacy of AMG 655 
or AMG 479 in Combination With Gemcitabine as First-line Therapy 
for Metastatic Pancreatic Cancer 
Ongoing
Page 1 of 2
Approved 
 
 


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Table 2.  Clinical Studies With AMG 479 by Tumor Type
Protocol 
No.
Description
Status
Combination Study in Breast Cancer
20060362
An International, Randomized, Double-blind, Placebo-controlled, 
Phase 2 Study of AMG 479 with Exemestane or Fulvestrant in 
Postmenopausal Women with Hormone Receptor Positive Locally 
Advanced or Metastatic Breast Cancer
Ongoing
Combination Study in Ovarian Cancer
20070080
(TRIO 
014)
A Randomized, Double-blind, Placebo Controlled, Multi-center, Phase 
II Study of Adding AMG 479, a Fully Human Monoclonal Antibody 
Against IGF-1R to First Line Chemotherapy in Patients with Optimally 
Debulked (< 1 cm ) Epithelial Ovarian Cancer.
Ongoing
20070834
(TRIO 
015)
A Multicenter Open Label Phase II Study of the Efficacy and Safety of 
AMG 479, a Fully Human Monoclonal Antibody Against Insulin-like 
Growth Factor Type 1 Receptor (IGF-1R) as Second Line Therapy in 
Patients with Recurrent Platinum-sensitive Ovarian Cancer
Ongoing
Combination Study in Colorectal Cancer
20060447
A Randomized, Phase 1b/2 Trial of AMG 102 or AMG 479 in 
Combination with Panitumumab versus Panitumumab Alone in 
Subjects with Wild-Type  KRAS Metastatic Colorectal Cancer
Ongoing
20060579
A Phase 2, Randomized, Double-blind, Placebo-controlled Study 
Evaluating the Safety and Efficacy of FOLFIRI in Combination With 
AMG 479 or AMG 655 Versus FOLFIRI for the Second-line Treatment 
of KRAS-mutant Metastatic Colorectal Carcinoma
Ongoing
20070820
A Phase 2 Study of Panitumumab Plus Irinotecan Followed by 
Panitumumab Plus AMG 479 in Subjects With Metastatic Colorectal 
Carcinoma Expressing Wild Type KRAS and Refractory to 
Oxaliplatin- or Irinotecan- and Oxaliplatin-containing Regimens to 
Evaluate Mechanisms of Acquired Resistance to Panitumumab
Ongoing
Combination Study in Lung Cancer
20060534
A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with 
Platinum-based Chemotherapy as First-Line Treatment for Extensive 
Stage Small Cell Lung Cancer
Ongoing
20080257
A Phase 1b/ 2 Study of AMG 479 in Combination with Paclitaxel and 
Carboplatin for the First-Line Treatment of Advanced Squamous 
Non-Small Cell Lung Cancer
Ongoing
Page 2 of 2
2.2.4
Safety and Efficacy Summary
Studies across multiple indications have been completed with conatumumab and AMG 
479.  Additional information about the safety and efficacy for both products is available in 
the current Investigator’s Brochure.
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2.3
Rationale
The purpose of this protocol is to allow continued treatment with conatumumab, with or 
without co-therapy, or AMG 479 therapy alone to subjects previously treated with 
conatumumab, with or without co-therapy, or with AMG 479 therapy alone, who have not 
progressed during that treatment. 
2.4
Clinical Hypotheses
The purpose of this study is to provide a mechanism for subjects to continue to receive 
treatment with conatumumab and/or AMG 479. 
3.
EXPERIMENTAL PLAN
3.1
Study Design
This is a Phase 2 multi-center, open-label study that permits subjects who have 
completed a separate Amgen-sponsored conatumumab or AMG 479 study to continue 
treatment with conatumumab, with or without co-therapy (chemotherapy with and without 
bevacizumab, or AMG 479), or with AMG 479 therapy alone.  Subjects who have not 
progressed on a separate Amgen protocol are eligible to participate in this trial.
This study will only be conducted in centers that treated subjects in previous 
conatumumab or AMG 479 studies managed by Amgen Inc.
Subjects must have received conatumumab, with or without co-therapy, or AMG 479
therapy alone on the parent study.  
In this extension study, conatumumab and AMG 479 study drugs will be administered at 
the same dose level and schedule that the subject received at the conclusion of the 
parent conatumumab or AMG 479 study, accommodating any subjects who were 
maintained on a reduced dose level or different schedule of administration in their parent
study.  At the discretion of the investigator, subjects who were receiving conatumumab 
monotherapy on the parent study may switch at the time of starting this study (and only 
at this time) to receive monotherapy at an extended dosing frequency, to a maximum of 
every 3 weeks, if the total weekly dose remains the same as for the parent study.
Subjects will be evaluated before every cycle of conatumumab or AMG 479 therapy at
the study clinic.  These study visits will include a standard of care clinical assessment 
which includes collection of vital signs, adverse events, concomitant medications, and 
laboratory samples and results.  Radiological assessments to evaluate disease extent 
(with change compared to nadir from the parent protocol) should be performed at regular 
intervals, at a minimum once every 6 (± 1) months or more frequently if clinically 
Approved 
 
 


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indicated (starting from their last scan on the parent protocol), per standard of care 
(SOC) at each facility. 
Reasons for study discontinuation will include progressive disease, intolerance to 
investigational product(s), and/or need for additional systemic anticancer treatment.  
When a subject discontinues the study for any reason, a safety follow-up visit will be 
completed at least 30 (+3) days after the last dose of protocol-specified therapy.  This 
visit will include a standard of care clinical assessment, vital sign measurements, 
laboratory tests for blood and urine, adverse event assessment, and concomitant 
medications assessment.  Subjects will also be assessed for anti-conatumumab 
antibody (and anti-AMG 479 antibody, if the subject has received AMG 479) assessment 
60 (14) days after the last administration of protocol-specified therapy.
The overall study design is described by a study schema at the end of the protocol 
synopsis section.
The study endpoints are defined in Section 10.1.
3.2
Number of Centers
The study will be conducted in study sites that treated subjects in previous 
conatumumab or AMG 479 studies in the United States, Europe, and possibly other 
countries.  The number of sites will be determined by the number and location of 
subjects who transition into this study from the separate (parent) Amgen conatumumab 
or AMG 479 studies.
Sites that do not enroll subjects within 3 months of site initiation may be terminated.  
3.3
Number of Subjects
Participants in this clinical investigation shall be referred to as “subjects”.
The sample size is dependent upon the number of subjects that transition into this study 
from separate Amgen conatumumab or AMG 479 studies.  The sample size is estimated 
to be approximately 15 subjects.
3.4
Estimated Study Duration
3.4.1
Study Duration for Participants
The estimated duration of individual subject participation on this trial begins on the date
the subject signs the informed consent for this study and ends when the subject 
completes their Day 60 (immunogenicity) Follow-up visit 60 (14) days after the last 
dose of protocol-specified therapy, unless the subject has started another anti-cancer 
Approved 
 
 


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therapy or withdrawn consent.  The exact duration of each subject’s participation on 
study will vary depending on each subject’s individual clinical response to treatment.  
The end of study for each subject is defined as the date the subject withdraws consent 
from the study, completes or has the opportunity to complete the Day 60 follow-up visit 
or dies.
3.4.2
End of Study
The end of study will occur when all the subjects have completed or had the opportunity 
to complete the Day 60 Follow-up visit.  Amgen reserves the right to terminate the study.
4.
SUBJECT ELIGIBILITY
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (sex, age,
race, date, and outcome of the screening process (eg, enrolled into study, reason for 
ineligibility, or refused to participate).  
Before any study-specific procedure, the appropriate signed and dated written informed 
consent must be obtained (see Section 11.1). 
4.1
Inclusion Criteria
4.1.1
Disease Related
101.
To be enrolled in this study, subjects must be currently enrolled in a prior 
Amgen-sponsored conatumumab or AMG 479 study and are eligible 
according to the parent study to receive their next dose of conatumumab 
(with or without co-therapy), or AMG 479 alone
102.
Subjects must have their eligibility assessed for this study and be enrolled 
within 30 days of their last treatment on the parent protocol
4.2
Exclusion Criteria
4.2.1
Disease Related
201.
Discontinued from a conatumumab or AMG 479 study due to an adverse 
event, including intolerance to conatumumab or AMG 479, respectively
202.
Subjects determined to have disease progression during their participation in 
the parent Amgen study
4.2.2
General
203.
Woman or man with partner of childbearing potential not consenting to use 
adequate contraceptive precautions ie, double barrier contraceptive methods 
(eg, diaphragm plus condom), or abstinence during the course of the study 
and for 6 months after the last dose of protocol-specified therapy 
administration 
204.
Subject is pregnant or breast feeding, or planning to become pregnant within 
6 months after the last dose of protocol-specified therapy administration
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205.
Male subject with a pregnant partner who is not willing to use a condom 
during treatment and for an additional 6 months after the last dose of 
protocol-specified therapy administration
206.
Subject has previously entered this study
207.
Subject will not be available for protocol-required study visits, to the best of 
the subject and investigator’s knowledge
208.
Subject has any kind of disorder that, in the opinion of the investigator, may 
compromise the ability of the subject to give written informed consent and/or 
to comply with all required study procedures
5.
SUBJECT ENROLLMENT
Before subjects may be entered into the study, Amgen requires a copy of the site’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other subject information and/or recruitment 
material, if applicable (see Section 11.2).  The informed consent form must be signed 
and personally dated by the subject or by the subject’s legally acceptable representative 
and by the person who conducted the informed consent discussion before any study 
procedures specific for this study occur (procedures that are part of routine care are not 
considered study specific procedures). 
A subject is considered enrolled once all eligibility criteria are met and the site has 
received an Enrollment Confirmation fax/email from Amgen.  All subjects who enroll will 
be assigned a unique subject identification number by the Amgen study team; this 
unique subject ID will be obtained when the site study staff sends the completed 
Enrollment Confirmation Form to Amgen for review.  The unique number will consist of 
11 digits; digits 1 to 3 represent the last 3 digits of the protocol, 4 to 8 the site number, 
and 9 to 11 the subject number at the site.  For example, the first subject enrolled at site 
50505 for protocol 20101116 would be assigned 11650505001.  This number will be 
used to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.  The subject identification number must remain 
constant throughout the entire clinical study; it must not be changed. 
All efforts should be made to ensure that subjects do not have an interruption of 
conatumumab or AMG 479 treatment, and combination therapy as appropriate, when 
transferring from the parent Amgen protocol to this protocol.  Subjects should receive 
first dose of conatumumab, and applicable combination therapy if any, or AMG 479 
alone, according to the schedule on the parent protocol (interval includes cycle 
frequency plus dose delays due to toxicities).  If for any reason, the subject is not able to 
Approved 
 
 


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continue their treatment per their prior schedule, Amgen approval should be obtained 
prior to dosing.
6.
TREATMENT PROCEDURES
Conatumumab and AMG 479 will be the only Investigational Products (IPs) administered 
in this study. 
Subjects will receive the same regimen they were receiving at the conclusion of their 
parent Amgen-sponsored study.  If 1 or more co-therapy drugs were permanently 
discontinued or dose-reduced on the parent study, their resumption or re-escalation will 
not be allowed on this study for that particular subject.  If a co-therapy is only being 
temporarily held on the parent protocol, resuming it will be allowed according to standard 
of care guidelines.
Dose adjustments for subjects receiving treatment have been adapted from the parent 
protocols.
6.1
Conatumumab
Conatumumab will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures. Refer to the Investigational Product 
Instruction Manual for details regarding packaging, labeling, storage, and dispensing of 
conatumumab. 
6.1.1
Conatumumab Dosage, Administration, and Schedule
The starting dose and frequency of conatumumab will be determined based on the dose 
and frequency administered during the parent study. 
Conatumumab will be administered by IV infusion through a peripheral line or indwelling 
catheter with an infusion set-up. In-line filter is not required.  The dose of conatumumab
will be calculated based on the subject’s actual body weight during the study day 1 
assessment and the dose must be recalculated if actual body weight changes by 10%.  
Investigators may recalculate the doses more frequently based on institutional 
guidelines.
If a subject misses a conatumumab dose, the dose will not be made up at a later date 
and the subject will remain on the original dosing schedule.
Conatumumab preparation will be administered by an IV infusion over a 60 (15) 
minutes period.  If the dose administration was well tolerated during the parent protocol, 
administrations may be made over a 30 (10) minutes infusion period.  Infusion time 
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can be extended to a maximum of 120 minutes for subjects unable to tolerate the 
60 minute infusion.
Conatumumab should not be mixed with, or administered as an infusion simultaneously 
with other medicinal products.  An experienced and qualified staff member will perform 
the placement of the IV access, establishment of an IV line, and administration of the 
investigational product.  The infusion line should be flushed with at least 5.0 mL of 0.9% 
normal saline or 5% dextrose before and after the investigational product administration 
to avoid mixing with other drug products or IV solutions.  Conatumumab should not be 
administered as an IV push injection.  If the investigational product extravasates during 
the IV administration, the infusion must be stopped immediately.  The subject may 
develop a reddened area around the site of the infiltration, which is caused by 
accumulation of the investigational product in the surrounding tissues (ie, depot effect).  
A physician or medical staff involved in study evaluation must be available during the 
administration of the investigational product to assess and treat adverse events that may 
arise during dosing.  Subjects will be monitored in the clinic throughout their infusion for 
any signs of adverse events and for at least 60 minutes after their infusion if previous 
doses of conatumumab were not well tolerated. 
The date, start and end times, and volume of each conatumumab infusion (volume of 
conatumumab plus volume of diluent) will be recorded in the subject’s medical record 
and electronic case report form (eCRF).  Refer to the Investigational Product Instruction 
Manual for details regarding packaging, labeling, storage, preparation and dispensing of 
conatumumab.
6.1.1.1
Subjects Receiving Conatumumab in Monotherapy 
Subjects currently receiving conatumumab monotherapy will continue doing so at the 
same dose.  The dose range in the parent protocols is from 0.3 mg/kg Q2W to 15 mg/kg 
Q3W.  Subjects will be allowed to switch from a Q2W dosing to a Q3W dosing if they so 
desire and their physician is in agreement, but only at the start of this study.  In this 
case, the actual dose to be administered every 3 weeks will be recalculated in order to 
deliver the same weekly dose, according to the formula:
Q3W dose (in mg/kg) = Q2W dose (in mg/kg) x 1.5
Such change in dosing frequency should be communicated to Amgen’s study team.
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6.1.1.2
Subjects Receiving Conatumumab in Combination With AMG 479 
(Transferring From Parent Protocol 20070411)
Subjects transitioning from the 20070411 protocol will continue receiving AMG 479 
18 mg/kg Q3W in combination with conatumumab at 1, 3, or 15 mg/kg Q3W.
Conatumumab should be given on day 1 of each cycle after completion of the AMG 479 
infusion, unless otherwise specified, allowing 30 minutes between the end of the 
AMG 479 infusion and the start of the conatumumab infusion to assess potential 
toxicities from AMG 479.  If no toxicities were observed with previous doses, the time 
interval between the AMG 479 infusion and the conatumumab infusion will be at the 
Investigator’s discretion. 
6.1.1.3
Subjects Receiving Conatumumab in Combination With mFOLFOX6 
and Bevacizumab (Transferring From Parent Protocol 20060464)
All subjects will be treated with mFOLFOX6 and bevacizumab on each of the 14 day 
(+ 3 days) treatment cycles before infusion of conatumumab (2 or 10 mg/kg Q2W, based 
on their dose from study 20060464).
mFOLFOX6 and bevacizumab will be obtained by each center from commercial sources.  
Study personnel will follow the institutional standard operating procedures for handling 
mFOLFOX6 and bevacizumab.  For additional detail and full prescribing information 
please see the most recent local version of the label for the products.
6.1.2
Conatumumab Premedication
This section applies to all subjects, irrespective of whether they are receiving 
conatumumab in monotherapy or in combination with AMG 479 or chemotherapy.
No specific premedication is required for routine conatumumab infusions.  If during or 
after any infusion a reaction occurs, pre-medication may be used for subsequent 
conatumumab infusions.  Subjects, who experience any serious infusion reaction (eg, 
dyspnea, chest tightness, fever, rigors or hypotension) during conatumumab 
administration will have the infusion stopped.  Continuation of drug administration will be 
based on the severity and resolution of the event and will be at the discretion of the 
investigator.  Treatment for an infusion reaction may include methylprednisolone, 
ranitidine, diphenhydramine, atropine, epinephrine, or other drugs, depending on the 
severity of the reaction.  Premedication (eg, antihistamines or corticosteroids) may be 
considered for subsequent administrations in subjects who develop an infusion reaction, 
at the discretion of the investigator.  Suspected infusion reactions should be reported as 
an adverse event.  All subjects who experience such an event will be followed for safety.
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 26 of 80
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6.1.3
Conatumumab Toxicity Management
This section applies to all subjects, irrespective of whether they are receiving 
conatumumab in monotherapy or in combination with AMG 479 or chemotherapy.
Subjects should be assessed clinically for toxicity before each dose using the National 
Cancer Institute (NCI) CTCAE version 3.0 (Appendix B).  Complete blood count with 
differential and chemistry panels including glucose and liver function laboratory tests 
(ALT, AST, alkaline phosphatase, and bilirubin) must be obtained 3 days before the 
dose of conatumumab on Day 1 of each cycle, and the results must be checked before 
each treatment.  Amylase and Lipase values must be obtained at every cycle thereafter 
as close as possible to the scheduled dosing date.  Dosing will occur only if these test 
values are acceptable per protocol guidelines (see Sections 6.1.3.1 to 6.1.3.4).
Any adverse event deemed related to conatumumab requiring a dose hold of more than 
42 days will result in conatumumab being permanently discontinued.
If conatumumab administration does not commence within 3 days of the per protocol 
administration date due to an adverse event deemed related to conatumumab, the dose 
will be considered a missed dose, and conatumumab administration may resume at the 
next planned dosing date if the criteria outlined below are met.  A missed dose will not 
be made up.
If an unscheduled interruption of conatumumab administration occurs, not due to toxicity 
events, the study site personnel should notify the sponsor at the earliest possible time.
There will be no conatumumab dose reductions or escalations in this study. 
6.1.3.1
ALT or AST Elevations
The rules for conatumumab dosing interruptions in response to ALT and AST elevations
are provided in Table 3.
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 27 of 80
CONFIDENTIAL
Table 3.  Conatumumab Dose Interruption Guidelines for Increases in ALT and 
AST Levels
AST or ALT 
Elevation
Conatumumab 
dose
Outcome
Conatumumab 
Dose Modification
Grade 1 or 2
No change
-
No change 
Grade 3 or 4a
Hold
Improve to Grade 1 or baseline
Restart full dose 
No improvement b
Discontinue 
a Not related to conatumumab.  Conatumumab should be withheld if the change in AST/ALT is > 5 x ULN 
and 10 x ULN, and is related to conatumumab.  Conatumumab should be discontinued if the change in 
AST/ALT is > 10 x ULN and is related to conatumumab.
b  No improvement to Grade 1 or the subject’s baseline within 28 days of onset.
ALT = alanine aminotransferase, AST = aspartate aminotransferase
Subjects who develop conatumumab-related elevation of either AST or ALT > 10 ULN 
will permanently discontinue conatumumab. 
For subjects who develop an AST or ALT elevation related to conatumumab which does 
not require discontinuation of investigational product (ie, AST/ALT elevation > 5 x ULN 
and 10 x ULN), treatment with conatumumab will be withheld until the level of ALT or 
AST has returned to grade 1 or the subject’s baseline within 28 days of onset as 
described in Table 3.
Attribution to conatumumab for the abnormal liver function test criteria in the context of 
oncology patients needs to be considered carefully.  There should be no evidence of 
obstruction, such as elevated alkaline phosphatase in gall bladder or bile duct disease, 
progression of malignancy, or other explanation (viral hepatitis, alcoholic or autoimmune 
hepatitis, other hepatotoxic drugs).
6.1.3.2
Serum Amylase or Lipase Elevation
Amylase and lipase values must be obtained at every cycle as close as possible to the 
scheduled dosing date.  Before conatumumab administration the investigator or 
designee will review the subject’s previous amylase and lipase values and will follow the 
dose interruption guidelines in Table 4 to determine treatment suitability.  Results from 
present cycle’s amylase and lipase tests are not required to be available prior to dosing.  
The investigator can use previous cycle’s amylase and lipase values if present cycle’s 
results are not available before dosing.  Dosing modifications based on present cycle’s 
amylase and/or lipase values will apply to the next treatment cycle.
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 28 of 80
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Table 4.  Conatumumab Product Dose Interruption Guidelines for Increases in 
Serum Amylase or Lipase Levels
Amylase or Lipase 
Elevation
Conatumumab 
dose
Outcome
Conatumumab 
Dose Modification
Grade 1, 2 or 3‡
No change
-
No change 
Grade 4a
Hold
Improve to Grade 2 or 
baseline
Restart full dose 
No improvement b
Discontinue 
‡ Results from present cycle’s amylase and lipase tests are not required to be available prior to dosing.  The 
investigator can use previous cycle’s amylase and lipase values if present cycle results are not available 
before dosing. Dosing modifications based on present cycle’s amylase and/or lipase values will apply to the 
next treatment cycle.
a Conatumumab must be discontinued if a Grade 4 event is related to conatumumab persists for > 28 days.
b No improvement to Grade 2 or the subject’s baseline within 28 days of onset.
Subjects experiencing Grade 4 elevation of amylase and/or lipase related to
conatumumab will have conatumumab withheld and serum amylase and lipase 
monitored until the amylase and/or lipase values resolve to Grade 2 or the subject’s 
baseline.
Any Grade 4 amylase or lipase elevation deemed related to conatumumab requiring a 
dose hold of more than 28 days will result in conatumumab being permanently 
discontinued.
6.1.3.3
Non-hematologic Toxicities 
Any Grade 3 or higher non-hematologic adverse event (other than  AST, ALT, lipase or 
amylase elevation) deemed related to conatumumab will result in conatumumab being
withheld until symptoms resolve to Grade 1 or subject’s baseline within 28 days of 
onset.  Exceptions to this rule are anorexia, nausea, vomiting, stomatitis/mucositis, 
diarrhea, fatigue, and pulmonary embolism that will lead to conatumumab being withheld 
only if following criteria are met: 

Grade 3 or higher anorexia, nausea, vomiting, stomatitis/mucositis, or diarrhea not 
manageable despite maximum supportive care

Grade 3 fatigue persists more than 7 days

Symptomatic pulmonary embolism (incidental asymptomatic pulmonary embolism or 
deep vein thrombosis will not lead to conatumumab being withheld)
Any Grade 3 or higher non-hematologic adverse event (other than AST, ALT, lipase or 
amylase elevation) as defined above deemed related to conatumumab requiring a dose 
hold of more than 28 days will result in conatumumab being permanently discontinued.
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 29 of 80
CONFIDENTIAL
6.1.3.4
Hematologic Toxicities
Any Grade 3 or higher hematologic adverse event deemed related to conatumumab will 
result in conatumumab being withheld until symptoms resolve to Grade 1 or subject’s 
baseline with 28 days of onset.  Exceptions to this rule are anemia, neutropenia, and 
thrombocytopenia that will lead to conatumumab being withheld only if following criteria 
are met:

Grade 4 anemia

Grade 3 or 4 neutropenia with fever > 38.5C

Grade 4 neutropenia or thrombocytopenia > 7 days
Any Grade 3 or higher hematologic adverse event deemed related to conatumumab 
requiring a dose hold of more than 28 days as defined above will result in conatumumab 
being permanently discontinued.
6.2
AMG 479
AMG 479 will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study distribution procedures. Upon the appropriate approvals being 
received, AMG 479 will be manufactured and packaged by Amgen, and labelled 
and distributed by NantCell using NantCell clinical study distribution procedures.  
Subsequent to this, and subject to the appropriate approvals being in place, 
AMG 479 will be manufactured, packaged, labelled, and distributed by NantCell,
using NantCell clinical study distribution procedures.  Refer to the Investigational 
Product Instruction Manual for details regarding packaging, labeling, storage, and 
dispensing of AMG 479.  
6.2.1
AMG 479 Dosage, Administration, and Schedule
The starting dose and frequency of AMG 479 will be determined based on the dose and 
frequency administered during the parent study. 
The dose (infusion volume) of AMG 479 will be calculated based on the subject’s actual 
body weight during the study day 1 assessment.  The dose will not need to be 
recalculated unless the actual body weight changes by 10%.  Investigators may 
recalculate the dose of AMG 479 more frequently according to institutional guidelines.
AMG 479 will be administered by IV infusion through a peripheral line or indwelling 
catheter using a nonpyrogenic, low protein binding filter with a 0.2- or 0.22-micron pore 
size in-line filter infusion set-up.  
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 30 of 80
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AMG 479 will be administered by an IV infusion over a 60 (15) minutes period.  If the 
dose administration was well tolerated during the parent study, AMG 479 may be given 
over 30 (10) minutes.  Infusion times can be extended to a maximum of 120 minutes 
for subjects deemed unable to tolerate the 60 minutes infusion. 
AMG 479 should not be mixed with, or administered as an infusion simultaneously with 
other medicinal products.  The infusion line should be flushed with at least 5.0 mL of 
0.9% normal saline before and after the investigational product administration to avoid 
mixing with other drug products or IV solutions.  AMG 479 should not be administered as 
an IV push injection.
If the AMG 479 extravasates during the IV administration, the infusion must be stopped 
immediately.  The subject may develop a reddened area around the site of the 
infiltration, which is caused by accumulation of AMG 479 in the surrounding tissues (ie, 
depot effect).  
An experienced and qualified staff member will perform the placement of the IV access, 
establishment of an IV line, and administration of the investigational product.  A 
physician or medical staff involved in study evaluation must be available during the 
administration of the investigational product to assess and treat adverse events that may 
arise during dosing.  If previous doses were well tolerated, subsequent post-infusion 
monitoring is not required.  
Date, start and end times, and volume of each AMG 479 infusion (volume of AMG 479
plus volume of diluent) will be recorded in the subject’s medical record and eCRF. 
Refer to the AMG 479 Investigational Product Instruction Manual for details regarding 
packaging, labeling, storage, preparation and dispensing of AMG 479.
6.2.1.1
AMG 479 Dosage and Schedule (for Subjects Transferring From 
Protocol 20070411)
Subjects previously enrolled in Study 20070411 will receive conatumumab and/or 
AMG 479 per parent protocol.  AMG 479 18 mg/kg will be administered IV Q3W, unless 
discontinued during treatment on parent protocol.  There will be no individual AMG 479 
dose reductions, except as outlined below in Table 5, Thrombocytopenia without 
Bleeding.
If no toxicities were observed during the infusion period on the parent study, the time 
interval between the AMG 479 infusion and the conatumumab infusion for subsequent 
cycles will be at the investigator’s discretion.  If toxicities were observed during the 
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 31 of 80
CONFIDENTIAL
infusion period on the parent study, allow 30 minutes between the end of the AMG 479 
infusion and the start of the conatumumab infusion to assess potential toxicities from 
AMG 479.
6.2.1.2
AMG 479 Dosage and Schedule (for Subjects Transferring From 
Protocol 20050118)
Subjects previously enrolled in Study 20050118 will receive AMG 479 monotherapy per 
parent protocol. AMG 479 20 mg/kg will be administered IV Q3W.  At the discretion of 
the investigator, subjects who have been on the parent study for more than 48 months 
without progression or unacceptable toxicity may continue receiving AMG 479 on an 
extended dosing frequency, to a maximum of Q4W (± 3 days).  Once the extended 
dosing frequency is selected, the dosing schedule must remain the same throughout the 
study. There will be no individual AMG 479 dose reductions, except as outlined below in 
Table 5, Thrombocytopenia without Bleeding.
6.2.2
AMG 479 Premedication
No specific premedication is required for routine AMG 479 infusions.  If during or after 
any infusion a reaction occurs, pre-medication may be used for subsequent AMG 479 
infusions.  Subjects, who experience any serious infusion reaction (eg, dyspnea, chest 
tightness, fever, rigors or hypotension) during AMG 479 administration will have the 
infusion stopped.  Continuation of drug administration will be based on the severity and 
resolution of the event and will be at the discretion of the investigator.  Treatment for an 
infusion reaction may include methylprednisolone, ranitidine, diphenhydramine, atropine, 
epinephrine, or other drugs, depending on the severity of the reaction.  Premedication 
(eg, antihistamines or corticosteroids) may be considered for subsequent administrations 
in subjects who develop an infusion reaction, at the discretion of the investigator.  
Suspected infusion reactions should be reported as an adverse event.  All subjects who 
experience such an event will be followed for safety.
6.2.3
AMG 479 Toxicity Management
This section applies subjects receiving AMG 479 alone or in combination with 
conatumumab.
6.2.3.1
General Criteria
The NCI CTCAE v3.0 grading scale (Appendix B) will be used as a guide for grading 
adverse events.  All adverse events will be documented on the adverse event eCRF.  
If AMG 479 is held due to AMG 479 related toxicities, conatumumab should also be held
if administered in combination with AMG 479, in accordance with protocol guidelines 
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 32 of 80
CONFIDENTIAL
(Table 5 and Table 6).  In the event AMG 479 is held for more than 42 days for related 
toxicity, AMG 479 will be permanently discontinued.  Treatment with conatumumab 
should continue Q3W after AMG 479 has been discontinued due to AMG 479 related 
toxicity.  In the event that treatment with conatumumab is discontinued for any reason 
prior to disease progression, AMG 479 treatment should continue.  If conatumumab has 
been permanently discontinued and/or AMG 479 is the only agent administered, in case 
of AMG 479-related toxicities AMG 479 treatment should be delayed by 1 week 
interval(s) until recovery, in accordance with protocol guidelines.  Subjects missing 2 
consecutive scheduled administrations of AMG 479, not due to AMG 479 related toxicity, 
must have the case reviewed by the Amgen Medical Director to determine if this subject 
can resume AMG 479.  A missed dose of AMG 479 will not be made up.  
6.2.3.2
Dosing Adjustments of AMG 479 Alone or AMG 479 in Combination 
with Conatumumab
Subjects should be assessed clinically for toxicity prior to administration of 
protocol-specified treatment using the CTCAE v3.0 grading scale (Appendix B).  
Complete blood count with differential and chemistry panels including liver function 
laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) and glucose must be 
obtained 3 days before the first dose of protocol-specified treatment on day 1 of each 
cycle, and the results must be evaluated before each planned infusion.  Dosing will 
occur only if these test values are acceptable, as outlined below (Table 5 and Table 6).  
In addition to dosage adjustments and dose delays, toxicities will be managed according 
to local institutional and all other applicable guidelines.  If multiple or overlapping 
toxicities occur, the most stringent dose modification criteria must be followed.  
There will be no intra-subject dose reductions or escalations for conatumumab.  There 
will be no individual AMG 479 dose reductions, except as outlined below in Table 5 for 
thrombocytopenia without bleeding.  
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 33 of 80
CONFIDENTIAL
Table 5.  Conatumumab and AMG 479 Dosing Modifications for Hematologic 
Toxicity Based on Hematology Counts ≤3 Days Prior to a New Cycle
Toxicity
Action to be taken
Thrombocytopenia WITHOUT Bleeding
Thrombocytopenia 
Grade 2
No AMG 479 or conatumumab dosing modifications
Thrombocytopenia 
Grade 3 b
Delay AMG 479 and conatumumab by 1 week interval(s) until recovery 
to grade 2, or baseline (+ 10%). a
AMG 479
First episode:
If thrombocytopenia is deemed related to AMG 479, then permanently 
dose reduce AMG 479 by 50%.
Second and subsequent episodes:
No further dose reductions of AMG 479 will occur; resume AMG 479 at 
the investigator’s discretion. 
Conatumumab
Resume previous dose.  If conatumumab is the only agent 
administered, then resumption of conatumumab treatment is at the 
investigator’s discretion. 
Thrombocytopenia 
Grade 4 b
Delay AMG 479 and conatumumab by 1 week interval(s) until recovery 
to grade 2, or baseline (+ 10%). a
AMG 479
First episode:
Permanently dose reduce AMG 479 by 50%. b
Second and subsequent episodes:
Permanently discontinue AMG 479.  
Conatumumab
Resume previous dose.
Permanently discontinue conatumumab if grade 4 thrombocytopenia is 
deemed related to conatumumab or to the combination of 
conatumumab with AMG 479 and lasts > 7 days. 
If conatumumab is the only agent administered, then
-  resumption of conatumumab treatment is at the investigator’s 
discretion; 
-  permanently discontinue conatumumab if grade 4 thrombocytopenia 
lasts > 7 days. 
Page 1 of 2
The CTCAE v3.0 grading scale (Appendix B) will be used for grading toxicity.
a conatumumab and/or AMG 479 will be permanently discontinued if held for more than 42 days due to 
related toxicity.
b Subjects on therapeutic anticoagulation treatment (eg, full dose coumadin or low molecular weight 
heparin) while receiving AMG 479, who develop concurrent grade 3 or 4 thrombocytopenia will 
permanently discontinue AMG 479.
c Exceptions: 
(i)    except Iymphocytopenia
(ii)   except anemia
(iii)  neutropenia only if grade 3 or 4 with fever > 38.5C, or if grade 4 > 7 days 
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 34 of 80
CONFIDENTIAL
Table 5.  Conatumumab and AMG 479 Dosing Modifications for Hematologic 
Toxicity Based on Hematology Counts ≤3 Days Prior to a New Cycle
Toxicity
Action to be taken
Thrombocytopenia WITH Bleeding
Thrombocytopenia 
Grade 1
No conatumumab or AMG 479 dosing modifications
Thrombocytopenia 
Grade 2
Delay AMG 479 and conatumumab by 1 week interval(s) until recovery 
from bleeding, then resume previous doses of AMG 479 and of 
conatumumab. a
Thrombocytopenia 
Grade 3 b
AMG 479
Permanently discontinue AMG 479.
Conatumumab
Delay conatumumab by 1 week interval(s) until recovery from bleeding
a, then resume previous dose 
Permanently discontinue conatumumab in case of grade 3 
thrombocytopenia with grade > 1 bleeding related to conatumumab or 
to the combination of conatumumab with AMG 479. 
Permanently discontinue conatumumab, if conatumumab is the only 
agent administered. 
Any Other Hematologic Toxicity c
Grade 2
No AMG 479 or conatumumab dosing modifications 
Grade 3
First episode:
Delay AMG 479 and/or conatumumab by 1 week interval(s) until 
recovery to grade 2, or   baseline (+ 10%), then resume previous 
doses of  AMG 479 and of conatumumab. a, c 
Second and subsequent episodes of the same event:
Delay AMG 479 and conatumumab by 1 week interval(s) until recovery 
to grade 2 or   baseline (+ 10%). a, c 
AMG 479
Permanently discontinue AMG 479 in case of recurrent grade 3 
hematologic toxicity related to AMG 479. c 
Conatumumab
Permanently discontinue conatumumab in case of recurrent grade 3 
hematologic toxicity related to conatumumab or to the combination of 
conatumumab with AMG 479. c
Page 2 of 2
The CTCAE v3.0 grading scale (Appendix B) will be used for grading toxicity.
a conatumumab and/or AMG 479 will be permanently discontinued if held for more than 42 days due to 
related toxicity.
b Subjects on therapeutic anticoagulation treatment (eg, full dose coumadin or low molecular weight 
heparin) while receiving AMG 479, who develop concurrent grade 3 or 4 thrombocytopenia will 
permanently discontinue AMG 479.
c Exceptions: 
(i)    except Iymphocytopenia
(ii)   except anemia
(iii)  neutropenia only if grade 3 or 4 with fever > 38.5C, or if grade 4 > 7 days 
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 35 of 80
CONFIDENTIAL
Table 6.  Conatumumab and AMG 479 Dosing Modifications for Non-hematologic
Toxicity Based on Toxicity ≤3 Days Prior to a New Cycle
Toxicity
Action to be taken
Serum Amylase or Lipase Elevations ‡
  Grade 3
No AMG 479 or conatumumab dosing modifications
  Grade 4 
Delay AMG 479 and/or conatumumab by 1 week interval(s) until recovery to 
grade 2, or   baseline (+ 10%), then resume previous doses of AMG 479 
and of conatumumab. a
Permanently discontinue conatumumab if grade 4 amylase or lipase 
elevation persists > 7 days.
Hepatotoxicity: Serum AST or ALT Elevations 
  Grade 1 or 2
  (5 x ULN)
No AMG 479 or conatumumab dosing modifications
  Grade 3 or 4
  (> 5 x ULN) 
Delay AMG 479 and/or conatumumab by 1 week interval(s) until recovery to 
grade 2 or baseline (+ 10%), then resume previous doses of AMG 479 
and of conatumumab a
AMG 479
Permanently discontinue AMG 479 in case of recurrent grade 3 toxicity 
related to AMG 479; or if AST or ALT is > 10 x ULN related to AMG 479.
Conatumumab
Permanently discontinue in case of recurrent grade 3 toxicity related to 
conatumumab; or if AST or ALT is > 10 x ULN related to conatumumab.
Hyperglycemia (Glucose Elevations)
  Grade 2
No AMG 479 and conatumumab dosing modifications c
Page 1 of 2
The CTCAE v3.0 grading scale (Appendix B) will be used for grading toxicity.
‡ Results from amylase and lipase tests are not required to be available prior to dosing.  The investigator 
can use previous cycle’s amylase and lipase values if present cycle results are not available before 
dosing.  Dosing modifications based on present cycle’s amylase and/or lipase tests will apply to the next 
treatment cycle.
a conatumumab and/or AMG 479 will be permanently discontinued if held for more than 42 days due to 
related toxicity.  
c Manage hyperglycemia per local institutional guidelines.  
d Exceptions: The following adverse events do not require dosing modifications, unless:
(i)   Grade 3 fatigue persists for > 7 days, or grade 4 fatigue; b
(ii)  Grade 3 or 4 anorexia, nausea, vomiting, stomatitis/mucositis or diarrhea
       despite maximum supportive care; b
(iii) Symptomatic pulmonary embolism. b
e Refer to Table 5 for management of Grade 2 infection in the presence of neutropenia
(ANC < 1.5 x 109/L) at any time.
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 36 of 80
CONFIDENTIAL
Table 6.  Conatumumab and AMG 479 Dosing Modifications for Non-hematologic
Toxicity Based on Toxicity ≤3 Days Prior to a New Cycle
Toxicity
Action to be taken
  Grade 3
If hyperglycemia is deemed related to AMG 479, delay AMG 479 and
conatumumab by 1 week interval(s) until hyperglycemia resolves to 
grade 2, or baseline (+ 10%), then resume full dose a, c
Permanently discontinue AMG 479 in case of 
- recurrent grade 4 hyperglycemia related to AMG 479 c, d; or
- hyperglycemia with life-threatening consequences (ketoacidosis or
  hyperosmolar non-ketotic coma). c
Permanently discontinue conatumumab in case of hyperglycemia with 
life-threatening consequences (ketoacidosis or hyperosmolar non-ketotic 
coma), if deemed related to conatumumab, or if conatumumab is the only 
agent administered. c
Any Other Non-Hematologic Toxicity (other than infusion reactions and hearing loss)
   Grade 2 
No AMG 479 and/or conatumumab dosing modifications e
   Grade 3 
Delay AMG 479 and/or conatumumab by 1 week interval(s) until recovery to 
grade 2, or baseline (+ 10%), then resume full dose of AMG 479 and of 
conatumumab. a, d, e
   Grade 4  
First episode:
Delay AMG 479 and/or conatumumab by 1 week interval(s) until recovery to 
grade 2, or   baseline (+ 10%), then resume previous doses of AMG 479 
and of conatumumab. a,d,e 
Second and subsequent episodes of the same event:
Delay AMG 479 and/or conatumumab by 1 week interval(s) until recovery to 
grade 2, or baseline (+ 10%), then resume previous doses of AMG 479 
and/or of conatumumab. a,d,e,
AMG 479
Permanently discontinue AMG 479 in case of recurrent grade 3 
non-hematologic toxicity related to AMG 479. d,e
Conatumumab
Permanently discontinue conatumumab in case of recurrent grade 3 
non-hematologic toxicity related to conatumumab. d,e
Page 2 of 2
The CTCAE v3.0 grading scale (Appendix B) will be used for grading toxicity.
‡ Results from amylase and lipase tests are not required to be available prior to dosing.  The investigator 
can use previous cycle’s amylase and lipase values if present cycle results are not available before 
dosing.  Dosing modifications based on present cycle’s amylase and/or lipase tests will apply to the next 
treatment cycle.
a conatumumab and/or AMG 479 will be permanently discontinued if held for more than 42 days due to 
related toxicity. 
c Manage hyperglycemia per local institutional guidelines.  
d Exceptions: The following adverse events do not require dosing modifications, unless:
(i)   Grade 3 fatigue persists for > 7 days, or grade 4 fatigue; b
(ii)  Grade 3 or 4 anorexia, nausea, vomiting, stomatitis/mucositis or diarrhea
      despite maximum supportive care; b
(iii) Symptomatic pulmonary embolism. b
e Refer to Table 5 for management of Grade 2 infection in the presence of neutropenia
(ANC < 1.5 x 109/L) at any time.
Approved 
 
 


Product:  Conatumumab and AMG 479
Protocol Number:  20101116
Date:  11 April 2017
Page 37 of 80
CONFIDENTIAL
6.2.3.3
AMG 479 Related Non-hematologic Adverse Events (Excluding 
Hyperglycemia and Elevation of Transaminases)
Any grade 4 non-hematologic adverse event (except grade 4 hyperglycemia, and 
transaminase elevations, as discussed below) deemed related to AMG 479 will result in 
the permanent discontinuation of AMG 479.  Subjects who are diagnosed with a 
symptomatic pulmonary embolism on study treatment must permanently discontinue 
AMG 479.  Subjects who are diagnosed with an asymptomatic pulmonary embolism, 
which has been incidentally diagnosed by CT or other imaging modality, must be 
managed per local regional guidelines and can remain on study treatment at the 
discretion of the investigator (see Section 6.2.3.4 for on study anti-coagulation 
management guidelines).
Any grade 3 non-hematologic adverse event deemed related to AMG 479 will result in 
AMG 479 being withheld until symptoms resolve to grade 1 or to the subject’s baseline 
grade. 
6.2.3.4
Anti-coagulation Management
Subjects requiring initiation of therapeutic anti-coagulation treatment while on study 
treatment (eg, for deep venous thrombosis or asymptomatic pulmonary embolism) will 
have AMG 479 and/or conatumumab withheld until the therapeutic anti-coagulation 
treatment is stable (eg, on coumadin with an INR of 2 to 3 for at least 14 days). Subjects 
who remain on full dose low molecular heparin (without Coumadin) as therapeutic 
anti-coagulation may restart AMG 479 and/or conatumumab at the discretion of the 
investigator.
Subjects on therapeutic anti-coagulation treatment while being treated with AMG 479 
who develop concurrent grade 3 or 4 thrombocytopenia regardless of relationship to 
AMG 479 will permanently discontinue AMG 479.
6.2.3.5
AMG 479 Related Infusion Reactions
Investigational product pre-medication is not required for routine infusions.  Investigators 
should monitor subjects for signs and symptoms of infusion reactions.  Any subject who 
experiences a grade 4 infusion reaction must permanently discontinue AMG 479.  
Subjects, who experience a grade 3 infusion reaction during AMG 479 administration,
will have the AMG 479 infusion stopped and the remainder of that AMG 479 infusion will 
not be administered.  Continuation of subsequent AMG 479 dosing after a grade 3 
infusion reaction will be based on the severity and resolution of the event, and the 
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grade 3 infusion reaction must be reviewed by the Amgen medical monitor to determine 
if the subject can resume AMG 479.
If an AMG 479 infusion is interrupted because of a grade 1 or 2 infusion reaction, the 
infusion may be restarted after resolution of the event and stabilization of the subject, 
with total infusion time up to 120 minutes.  If a subject is unable to complete an 
AMG 479 infusion on the day of the infusion due to an infusion reaction, then the 
remainder of the infusion will not be made up on subsequent days.
At the discretion of the investigator, treatment for an infusion reaction may include 
solumedrol (50 to 80 mg IV bolus or equivalent), ranitidine 50 mg IV bolus (or 
equivalent), diphenhydramine 50 mg IV bolus (or equivalent).  AMG 479 pre-medications 
are recommended for subjects who have previously experienced an AMG 479 related 
infusion reaction.  The AMG 479 pre-medication that will be used is at the discretion of 
the investigator; however, it is recommended that the investigator consider using any of 
the following AMG 479 pre-medication for future infusions: dexamethasone or 
solumedrol, ranitidine, diphenhydramine or equivalents.  Investigational product 
pre-medications must be recorded in the eCRF.  Subjects treated with steroids while on 
study should be monitored closely for hyperglycemia, as the combination of steroids and 
AMG 479 may increase this risk.
Investigators should decrease the AMG 479 infusion rate by 50% (eg, increase the 
AMG 479 infusion duration from 30 to 60 minutes) in subjects who have previously had a 
grade 3 AMG 479 infusion reaction.  For subjects who have had a grade 1 or 2 AMG 479 
infusion reaction, decreasing the AMG 479 infusion rate is at the discretion of the 
investigator.  Suspected infusion reactions should be reported as an adverse event.  All 
subjects who experience such an event will be followed for safety.
6.2.3.6
AMG 479 Hearing Loss
Subjects experiencing hearing loss will be managed as per local regional medical 
guidelines.  If hearing loss cannot be clearly attributed to another cause (eg, acoustic 
trauma), investigators should permanently discontinue AMG 479 in subjects who 
experience severe (grade 3) hearing loss.
6.2.4
Bisphosphonates
Bisphosphonates (eg, pamidronate or zoledronic acid) may be used in subjects with 
documented bone metastases, according to standard of care, the most recent version of 
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the label for the product, in the region in which it is approved, and all applicable 
guidelines.  
6.3
Subjects Receiving Conatumumab in Combination With 
mFOLFOX6/Bevacizumab (Transferring From Parent 
Protocol 20060464)
Subjects transitioning from the 20060464 study who are on mFOLFOX6/bevacizumab in 
combination with conatumumab will continue to receive the same regimen with the same 
doses and timing.  The components of the mFOLFOX6 regimen and bevacizumab will 
be administered per standard of care, according to the PI’s clinical judgment and 
institutional guidelines. 
All other protocol-required drugs including, mFOLFOX6 and bevacizumab, that are 
commercially available are not provided by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these drugs.  
All subjects will be treated with mFOLFOX6 and bevacizumab on each of the 14 day 
(+ 3 days) treatment cycle before infusion of conatumumab.
6.3.1
mFOLFOX6 Regimen
Modified FOLFOX6 regimen is a combination therapy of oxaliplatin (85 mg/m2) 
administered as a 2-hour infusion on day 1; leucovorin (400 mg/m2 racemate or 
200 mg/m2 levo-leucovorin) administered as a 2-hour infusion on day 1; followed by a 
loading dose of 5-FU (400 mg/m2) IV bolus administered on day 1, then 5-FU 
(2,400 mg/m2) via ambulatory pump administered for a period of 46-48 hours every 
14 days (+ 3 days).
Administration of mFOLFOX6 chemotherapy will commence on day 1 of each treatment 
cycle and end with a continuous IV infusion of 5-FU.  For the purpose of this protocol, 
the administration of continuous IV infusion of 5 FU will commence after conatumumab
infusions. 
A new cycle of mFOLFOX6 treatment will be repeated every 2 weeks (+ 3 days) but may 
not be administered to the subject if the ANC < 1.0 x 109 cells/L; or if the platelet count is 
< 75 x 109/L; if stomatitis, or diarrhea have not recovered to grade 1; or if fatigue has 
not recovered to grade 2.  Up to a 6 week delay is allowed in the initiation of a new 
cycle of treatment for resolution of toxicities.  A treatment delay of one component of the 
mFOLFOX6 regimen (ie, 5-FU/leucovorin or oxaliplatin) results in a similar delay of the 
other component to allow both therapies to be given together on day 1 of each 2-week 
cycle.  Any delay to the start of mFOLFOX6 or bevacizumab will result in the same delay 
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to the bevacizumab and conatumumab so that all treatments are given together.  Study 
procedures associated with each cycle of therapy will also be delayed accordingly.  If 
conatumumab is held due to toxicities, mFOLFOX6 and bevacizumab should continue 
as planned and the conatumumab will be restarted at the next cycle of chemotherapy, so 
long as the toxicities have reduced in accordance with protocol guidelines.  
If parameters are not met by the scheduled dosing date, blood tests and/or clinical 
evaluations should occur at least weekly to monitor these parameters.  The guideline in 
Section 6.3.2 will be followed for mFOLFOX6/bevacizumab delay and dosing 
resumption.
In the event that mFOLFOX6 chemotherapy or any of its components administration is 
permanently discontinued for any reason prior to disease progression, bevacizumab and 
conatumumab may continue. Investigational product infusions should remain on a once 
every 14 days (+ 3 days) schedule until the subject develops disease progression or is 
unable to tolerate conatumumab.
If mFOLFOX6 chemotherapy interruption is 6 weeks from the previous cycle, and the 
subject has recovered from toxicity, as specified above, and the subject’s disease has 
not progressed, mFOLFOX6 chemotherapy should be restarted at doses according to 
Table 7, Table 8, and Table 9.  If mFOLFOX6 chemotherapy interruption is > 6 weeks, 
but the subject has recovered from toxicity and the subject’s disease has not 
progressed, the case should be reviewed by the sponsor study team in conjunction with 
the investigator to determine the appropriateness of treatment resumption.
6.3.1.1
mFOLFOX6 Regimen Premedication
5-FU and oxaliplatin may be emetogenic.  Prior to the administration of mFOLFOX6, 
pre-medication with antiemetics, such as serotonin (5HT3) antagonists (ie, ondansetron, 
or granisetron) with or without dexamethasone may be used at the investigator’s 
discretion or according to institutional standards.
6.3.1.2
mFOLFOX6 Dose Levels
Subjects should be closely monitored for mFOLFOX6 toxicity.  Doses of 5-FU and 
oxaliplatin may be adjusted depending on an individual subject’s tolerance.  The dose of 
leucovorin will remain fixed at 400 mg/m2 racemate (d,l-leucovorin), or 200 mg/m2 
l-leucovorin). Table 7, Table 8, and Table 9 indicate recommended dose levels and 
modification guidelines for oxaliplatin and 5-FU for non-neurological and neurological 
toxicity.
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6.3.2
mFOLFOX6 Dose Modification
Table 7 describes the recommended dose reductions for non-neurological toxicity.
Table 7. mFOLFOX6 Dose Reductions - Non-neurological Toxicity
Starting Dose
(mg/m2)
Dose Level – 1
(mg/m2)
Dose Level- 2
(mg/m2)
Oxaliplatin
85
65
50
5-FU Bolus
400
320
260
5-FU infusion
2,400
1,900
1,500
Table 8 describes the recommended dose modifications at the start of each subsequent 
course of therapy.  All dose modifications should be based on the worst preceding 
toxicity.  The dose of LV will not be adjusted due to toxicity.  It should remain at 
400 mg/m² racemate (or 200 mg/m2 l-LV) for all courses.  LV will be given immediately 
prior to each 5-FU dose; thus, if 5-FU is delayed, LV will be delayed.
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Table 8. mFOLFOX6 Dose Modification Guidelines
Toxicity
NCI Gradea (Value)
Dose Level for Subsequent 
Cycles Based on Interval 
Toxicityb
At Time of Retreatment
No toxicity
Maintain dose level
Maintain dose level
Neutropenia (ANC)
If ANC < 1.0 x 109/L at 
start of cycle, hold and 
check weekly then treat 
based on interval toxicity.
If ANC < 1.0 x 109/L after 
4 weeks, discontinue 
therapy.
Grade 1 (ANC <LLN - 1.5 x 
109/L )
Maintain dose level
Grade 2 (ANC <1.5 x 109/L -
1.0 x 109/L)
Maintain dose level
Grade 3 (ANC <1.0 x 109/L -
0.5 x 109/L)
Decrease both 5-FU & OXAL 
1 dose levelc
Grade 4 (ANC < 0.5 x 109/L)
Decrease both 5-FU & OXAL 
1 dose levelc
Thrombocytopenia
If PLT < 75.0 x 109/L at 
start of cycle, hold and 
check weekly then treat 
based on interval toxicity.
If PLT < 75.0 x 109/L after 
4 weeks, discontinue 
therapy.
Grade 1 (PLT < LLN - 75.0 x 
109/L)
Maintain dose level
Grade 2 (PLT < 75.0 x 109/L 
- 50.0 x 109/L)
Maintain dose level
Grade 3 (PLT < 50.0 x 109/L 
- 25.0 x 109/L)
Decrease both 5-FU & OXAL 
1 dose level
Grade 4 (PLT < 25.0 x 
109/L)
Decrease both 5-FU & OXAL 
1 dose level
Neutropenic feverc,d
ANC <1.0 x 109/L (ie 
Grade 3 or 4 neutropenia) 
fever 38.5°C
Decrease both 5-FU & OXAL 
1 dose level
Other hematologic toxicities
Dose modifications for leukopenia at the start of subsequent 
courses of therapy and at time of retreatment are also based 
on NCI toxicity criteria (CTC Version 3.0) and are the same 
as recommended for neutropenia above.
Page 1 of 2
a National Cancer Institute Common Toxicity Criteria (CTC Version 3.0).
b Refers to initial dose used in previous course.
c At the investigator’s discretion, G-CSF should be used, and considered for use in subsequent cycles, 
according to standard of care, the most recent version of the product label in the region in which it is 
approved, and all applicable guidelines.  G-CSF should not be administered in the period between 
24 hours before and 24 hours after the administration of cytotoxic chemotherapy.  Given the short 
(14 day) interval between treatment cycles, pegylated G-CSF should not be used. At the investigator’s 
discretion, in subsequent cycles, treatment with oxaliplatin and 5-FU may be resumed at the dose used 
prior to the hematological toxicity, if ANC levels have returned to 1.0 x 109/L, and if all other criteria are 
met.
d In case of febrile neutropenia (ie, ANC < 1.0 x 109/L with fever 38.5C) or grade 2 infection at any time, 
G-CSF should be used according to all applicable guidelines.
e For mucositis/stomatitis decrease only 5-FU, not Oxaliplatin.
f Exceptions: alopecia, fatigue, anorexia, nausea/vomiting (if can be controlled by antiemetics), viral 
infections.
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Table 8. mFOLFOX6 Dose Modification Guidelines
Toxicity
NCI Gradea (Value)
Dose Level for Subsequent 
Cycles Based on Interval 
Toxicityb
At Time of Retreatment
Diarrhea
Grade 1
Maintain dose level
If Grade 2 diarrhea at start 
of cycle, hold and check 
weekly then treat based 
on interval toxicity.
If Grade 2 diarrhea after 
4 weeks, discontinue 
therapy.
Grade 2
Maintain dose level
Grade 3
Decrease both 5-FU & OXAL 
1 dose level
Grade 4
Decrease both 5-FU & OXAL 
1 dose level
Other nonhematologic 
toxicitiese,f
Dose modifications for other nonhematologic toxicities at the 
start of subsequent courses of therapy, and at time of 
retreatment are also based on NCI toxicity criteria (CTC 
version 3.0) and are the same as recommended for diarrhea 
above.
The dose of LV will not be adjusted due to toxicity.  It should remain at 400 mg/m² racemate (or 
200 mg/m2 l-LV) for all courses.  LV will be given immediately prior to each 5-FU dose; thus, if 
5-FU is delayed, LV will be delayed.
Page 2 of 2
a National Cancer Institute Common Toxicity Criteria (CTC Version 3.0).
b Refers to initial dose used in previous course.
c At the investigator’s discretion, G-CSF should be used, and considered for use in subsequent cycles, 
according to standard of care, the most recent version of the product label in the region in which it is 
approved, and all applicable guidelines.  G-CSF should not be administered in the period between 
24 hours before and 24 hours after the administration of cytotoxic chemotherapy. Given the short 
(14 day) interval between treatment cycles, pegylated G-CSF should not be used. At the investigator’s 
discretion, in subsequent cycles, treatment with oxaliplatin and 5-FU may be resumed at the dose used 
prior to the hematological toxicity, if ANC levels have returned to 1.0 x 109/L, and if all other criteria are 
met.
d In case of febrile neutropenia (ie, ANC < 1.0 x 109/L with fever 38.5C) or grade 2 infection at any time, 
G-CSF should be used according to all applicable guidelines.
e For mucositis/stomatitis decrease only 5-FU, not Oxaliplatin.
f Exceptions: alopecia, fatigue, anorexia, nausea/vomiting (if can be controlled by antiemetics), viral 
infections.
Table 9 describes the recommended dose modifications of oxaliplatin based on the 
duration of oxaliplatin-associated neurotoxicity.
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Table 9. Dose Modification Guidelines Oxaliplatin-associated Neurotoxicity
Toxicity (Grade)
Duration of Toxicity
Persistent
(Not Resolved 
Between 
Cycles)
1 - 7 Days
> 7 and < 14 Days
Paresthesias/dysesthesiasa of 
short duration that resolve and 
do not interfere with function 
(Grade 1)
No Change
No Change
No Change
Paresthesias/dysesthesiasa 
interfering with function, but not 
activities of daily living (ADL)
(Grade 2)
No Change
No Change
Decrease to 
65 mg/m2 or 
Hold until 
toxicity is 
< Grade 2
Paresthesias/dysesthesiasa with 
pain or with functional 
impairment that also interfere 
with ADL (Grade 3)
1st time: Decrease 
to 65 mg/m2
2nd time: Decrease 
to 40 mg/m2
STOP
STOP
Persistent paresthesias 
/dysesthesias that are disabling 
or life-threatening (Grade 4)
STOP
STOP
STOP
Pharyngo-laryngeal 
dysesthesias
Increase duration 
of infusion to 
6 hours
Increase duration 
of infusion to 
6 hours
Increase 
duration of 
infusion to 
6 hours
a May be cold-induced
Subjects who discontinue oxaliplatin due to associated neurotoxicity should continue all 
other first-line treatment components of the regimen (5-FU/leucovorin, bevacizumab, 
and conatumumab).  This modified first-line therapy will continue until one of the 
following occurs: disease progression, unacceptable adverse events, death, or the 
withdrawal of consent by the subjects.
6.3.3
Discontinuation of mFOLFOX6
Oxaliplatin and 5-FU/leucovorin will be administered until subjects develop disease 
progression, intolerability to each component, or withdrawal of consent.
Reintroducing mFOLFOX6 after permanent discontinuation will not be allowed as part of 
the first line treatment aspects of this trial.
6.3.4
Supportive Therapy for mFOLFOX6 Chemotherapy
6.3.4.1
Growth Factors
For low white blood cell counts, granulocyte-colony-stimulating factor (G-CSF) should be 
used in subjects with serious neutropenic complications such as febrile neutropenia, 
tissue infections, sepsis syndrome, fungal infection, etc.  G-CSF should be used and 
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administered according to the product label or applicable guidelines.  G-CSF should not 
be administered in the period between 24 hours before and 24 hours after the 
administration of cytotoxic chemotherapy.  Given the short (14 day) interval between 
treatment cycles, pegylated G-CSF is not recommended.
For chemotherapy-induced anemia, erythropoiesis stimulating agents should be used 
and administered according to the product label or applicable guidelines.
6.3.4.2
Oral Cryotherapy
Subjects receiving oxaliplatin should not receive oral cryotherapy (ie. ice for mucositis 
prophylaxis) on Day 1 of each treatment cycle as this may exacerbate 
laryngopharyngeal dysesthesia caused by oxaliplatin.
6.3.4.3
Hypersensitivity
Platinum hypersensitivity can cause dyspnea, bronchospasm, itching and hypoxia.  
Appropriate treatment may include supplemental oxygen, standard epinephrine, 
corticosteroid, antihistamine therapy, bronchodilators or vasopressors.  Platinum 
hypersensitivity is a rare event and should be treated promptly.
6.3.4.4
Pharyngolaryngeal Dysesthesias
Oxaliplatin may cause discomfort in the larynx or pharynx associated with dyspnea, 
anxiety and difficulty swallowing.  This discomfort is exacerbated by cold.  Appropriate 
therapy may include the use of antihistamine therapy, bronchodilators, cold avoidance or 
monitoring.
6.4
Bevacizumab (Transferring From Parent Protocol 20060464)
Please see package insert of bevacizumab for the most current storage and preparation 
instructions.
6.4.1
Bevacizumab Dosage, Administration and Schedule
Bevacizumab must be prepared by a healthcare professional using aseptic technique 
according to the most current label.
Bevacizumab will be administered at a dose of 5 mg/kg by intravenous infusion on day 1 
of each 14 day cycle (+ 3 days). Institutional standards for bevacizumab infusion times 
may be used.
In the event that bevacizumab is discontinued for any reason prior to disease 
progression, mFOLFOX6 and conatumumab should continue on a once every 14 days 
(+ 3 days) schedule until disease progression or intolerance to the study therapy.
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The highest dose tested in humans (20 mg/kg of body weight, IV) was associated with 
severe migraine in several subjects. Overdose with this product have not been reported. 
If body weight changes exceed 10% of the baseline weight the bevacizumab dose will 
need to be re-calculated.
6.4.2
Bevacizumab Premedication
Any pre-medication for bevacizumab should be administered at the investigator’s 
discretion and must be recorded in the appropriate electronic case report form.
6.4.3
Bevacizumab Toxicity Management
General toxicities associated with bevacizumab therapy (Avastin labeling text, 2009) 
include bleeding, arterial clots (which could lead to stroke and heart attack), bowel 
perforation, wound healing difficulties, and hypertension. Gastrointestinal perforation 
complicated by intra-abdominal abscesses or fistula formation and in some instances 
with fatal outcome, occurs at an increased incidence in subjects receiving bevacizumab. 
If bevacizumab is held due to toxicities, mFOLFOX6 and conatumumab should continue 
as planned and bevacizumab will be restarted at the next cycle of chemotherapy, so 
long as the toxicities have reduced in accordance with the protocol guidelines. Subjects 
will then resume bevacizumab treatment at the same dose and schedule.
See Table 10 for management of bevacizumab related toxicities.
For any subject experiencing grade 3 or 4 toxicity that persists for > 6 weeks or recurs 
after a dose delay, bevacizumab will be discontinued permanently.
6.4.4
Bevacizumab Dosage Adjustment
Reintroducing bevacizumab therapy after permanent discontinuation will not be allowed 
as part of the first-line treatment aspects of this trial.  Bevacizumab should not be 
initiated for at least 28 days following major surgery. The surgical incision should be 
fully healed prior to initiation of bevacizumab. The half life of bevacizumab is estimated 
to be 20 days. Treatment should be suspended prior to elective surgery.
6.4.5
Discontinuation of Components of mFOLFOX6/Bevacizumab
Subjects who have intolerance to single or multiple components of the first-line treatment 
regimen (eg, oxaliplatin due to neurotoxicity), should continue all other first-line 
treatment components of the regimen (eg, 5-FU/leucovorin, bevacizumab, and 
conatumumab) on a once every 14 days (+ 3 days) schedule.  This modified first-line 
therapy will continue until one of the following occurs: disease progression, 
unacceptable adverse events, death, or the withdrawal of consent by the subjects.
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Table 10.  Bevacizumab Treatment Delays and Instructions
Page 1 of 2
a If coagulation disorders develop secondary to other medical conditions, hold bevacizumab until the INR and PTT return to grade 1.
b New or worsening grade 2 events.  (Therapy may be continued for grade 2 conditions present at baseline that have not worsened.)
c Subjects who develop brief, reversible, exercise-induced claudication (grade 2) not attributable to arterial thromboembolic events may continue on study.
d Refer to grading criteria listed for the appropriate adverse event in the Infection Section of the CTCAE v 3.0.
e Refer to Dermatology/Skin Section of the CTCAE v 3.0.
f Determination of “clinically significant” is at the physician’s discretion and applies to those adverse events that can be attributed to   bevacizumab and are not related 
to chemotherapy.
Adverse Event
Grade CTCAE 
v3.0
Action to be Taken
Acute infusion reaction eg, 
fever, chills, headache, 
nausea (see 
Syndrome-Cytokine 
reaction, see CTCAE v 3.0 
Appendix B)
or
Allergic 
reaction/hyper-sensitivity 
(eg, fever, rash, urticaria, 
bronchospasm)
1, 2 or 3
If infusion-related or allergic reactions occur, pre-meds should be given with the next dose and the 
infusion time should be increased by 30 minutes.   If infusion-related AEs occur with the 30-min 
infusion, all subsequent doses should be given over 60 10 min (with pre-meds).  If infusion-related 
AEs occur with the 60-min infusion, all subsequent doses should be given over 90 15 min (with 
pre-meds).
For subjects with grade 3 reactions, the bevacizumab infusion should be stopped and not restarted 
on that day.  At the physician’s discretion, bevacizumab may be permanently discontinued or 
re-instituted with pre-medications and at a rate of 90 15 min.  If the reaction occurred at the 90-min 
rate, initially challenge at a slower infusion rate and gradually increase to 90 minutes.  When 
bevacizumab is re-instituted, the subject should be monitored, per physician’s usual practice, for a 
duration comparable to duration of reaction.
4
Permanently discontinue bevacizumab.
Hemorrhage a
3 or 4
Permanently discontinue bevacizumab.
Thrombosis/thrombus/ 
embolism-venous 
(including vascular access 
device)
2 or 3
Hold bevacizumab until resolution by clinical assessment or Doppler.
If the planned duration of full-dose anticoagulation is < 2 weeks, hold bevacizumab until 
anticoagulation is complete.
If the planned duration of full-dose anticoagulation is 2 weeks, bevacizumab may be resumed 
during anticoagulation if no grade 3 or 4 hemorrhage event occurred while on therapy and:
If stable dose of warfarin (or other anticoagulant), INR must be in range (usually between 2 and 3); or
If unfractionated heparin, PTT must be in therapeutic range.
Discontinue bevacizumab if thromboembolic events worsen or recur after resuming therapy.
4
Permanently discontinue bevacizumab.
Visceral or peripheral 
arterial ischemia
2b,c, 3 or 4
Permanently discontinue bevacizumab.
Cardiac 
ischemia/infarction
2b, 3 or 4
Permanently discontinue bevacizumab.
 
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Table 10.  Bevacizumab Treatment Delays and Instructions 
Page 2 of 2 
a  If coagulation disorders develop secondary to other medical conditions, hold bevacizumab until the INR and PTT return to ≤ grade 1. 
b  New or worsening grade 2 events.  (Therapy may be continued for grade 2 conditions present at baseline that have not worsened.) 
c  Subjects who develop brief, reversible, exercise-induced claudication (grade 2) not attributable to arterial thromboembolic events may continue on study. 
d  Refer to grading criteria listed for the appropriate adverse event in the Infection Section of the CTCAE v 3.0. 
e  Refer to Dermatology/Skin Section of the CTCAE v 3.0. 
f  Determination of “clinically significant” is at the physician’s discretion and applies to those adverse events that can be attributed to   bevacizumab and are not related 
to chemotherapy. 
Adverse Event 
Grade CTCAE 
v3.0 
Action to be Taken 
CNS ischemia 
2b, 3 or 4 
Permanently discontinue bevacizumab. 
GI perforation including GI 
leak and GI fistula 
≥ 1 
Permanently discontinue bevacizumab. 
Intra-abdominal abscess d 
3 
Hold bevacizumab until resolved. 
4 
Permanently discontinue bevacizumab. 
Complication, 
non-infectious-wound 
dehiscence e 
1 
Hold bevacizumab for at least 1 month.  If, in the physician’s opinion, substantial healing has taken 
place within 1-3 months, bevacizumab may be resumed.  If wound dehiscence recurs, permanently 
discontinue bevacizumab. 
2, 3, or 4 
Permanently discontinue bevacizumab. 
Proteinuria 
2 (only if 
> 2 g/24 hrs)  
or 3 
Hold bevacizumab until proteinuria improves to < 2 g of protein in a 24-hour urine collection.  
Re-check 24-hour urine protein every 2-4 weeks.  If proteinuria does not improve to < 2 g/24 hrs 
within 3 months, permanently discontinue bevacizumab. 
4 
Permanently discontinue bevacizumab. 
Hypertension 
3 
Bevacizumab may be continued in conjunction with standard anti-hypertensive therapy at physician 
discretion.  Bevacizumab should be held for uncontrolled or symptomatic hypertension present on the 
day that the bevacizumab dose is to be given.  If BP is not controlled with medication within 1 month, 
permanently discontinue bevacizumab. 
4 
Permanently discontinue bevacizumab. 
Other clinically significant 
(AEs)f 
3 
Hold until AE has resolved to grade ≤ 1. 
4 
Permanently discontinue bevacizumab. 
CONFIDENTIAL  
 
 
 
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6.5
Concomitant Therapy
Throughout the study, investigators may prescribe any concomitant medication or 
treatment deemed necessary to provide adequate supportive care except for those listed 
above.  
All prescribed and non-prescription concomitant medications that are administered, 
ingested, applied, or injected on an ongoing basis from the start of study treatment (or 
planned start of treatment in the case of subjects who have their first treatment delayed 
for any reason), as well as changes in such concomitant medication, and any new 
concomitant medication taken while the subject is on study should be recorded on the 
appropriate eCRF.  Concomitant medications should be recorded until the Day 30 Safety 
Follow-up Visit or until 30 days after the last dose of protocol-specified treatment, 
whichever is later.  Concomitant medications for medically significant adverse events, 
which are ongoing at the end of study treatment and considered related to study 
treatment, should be followed until the adverse event is resolved or considered stable.   
6.6
Excluded Medications or Procedures During Study Period
The following therapies and treatments should not be administered while receiving 
protocol specified therapy during the study:

Any investigational agent or other anti-tumor treatment (both standard and 
investigational)

Chemotherapy, radiation therapy (except palliative radiation), hormone directed 
cancer therapy, or tumor directed antibody therapy other then therapy specified in 
this protocol

Concurrent use of herbal medications or treatments

Elective major surgeries during the study through 30 days after the last dose of 
protocol specified therapy.  Subjects that undergo any unexpected major surgery 
during the course of the study must discontinue study treatment immediately and the 
study site should in turn notify the sponsor as soon as possible.  Such cases will be 
reviewed by the Sponsor to determine whether the subject will be allowed to resume 
study treatment.
6.7
Metastases Interventional Therapy
Subjects that undergo interventional therapy for metastases (eg, surgical resection, 
radiofrequency ablation or cryotherapy) during the course of the study will do so 
according to standard institutional practice.  Study treatment should be discontinued and 
the study site should in turn notify the sponsor as soon as possible.  Such cases will be 
reviewed by the Sponsor to determine whether the subject will be allowed to resume 
study treatment.
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6.8
Multiple Toxicity
If multiple or overlapping toxicity occurs, the most stringent dose modification criteria 
should be followed.
7.
STUDY PROCEDURES
7.1
General Study Procedures 
Refer to the Schedule of Assessments (see Appendix A) for an outline of procedures 
required at each visit.  Blood samples for hematology, chemistry, and coagulation should 
be collected and submitted to the accredited local laboratory on the day of collection.  
Blood samples for antibody analyses should be shipped to Amgen (see Laboratory 
Manual and Appendix A).
Blood for antibody samples will be collected according to the schedule described in 
Sections 7.3 to 7.5 and Appendix A.
A summary of analytes to be tested in the study is provided in Table 11.
Table 11.  Summary of Analytes Measured at Baseline / During the Study
Chemistry
Coagulation Urinalysis
Hematology
Other Labs
Sodium
PTT
Specific gravity RBC
Pregnancy Test
Potassium
INR
pH
Hemoglobin
Anti-conatumumab antibodies
Chloride
Blood
Platelets
Anti-AMG 479 antibodies
Albumin
Protein 
WBC
HgbA1c*
Calcium
Glucose
ANC
Magnesium
Differentials
Phosphorus
Neutrophils
Glucose
Lymphocytes
BUN 
Monocytes
Creatinine
Eosinophils
Uric acid
Basophils
Creatine Kinase
Total bilirubin
Alk phosphatase
AST (SGOT)
ALT (SGPT)
Amylase 
Lipase
* HgbA1c required for subjects with diabetes (Type 1 or Type 2) receiving AMG 479
7.2
Eligibility Assessment for Continued Treatment
Subjects must have their eligibility assessed for this study and be enrolled within 30 days 
of their last treatment on the parent protocol.  Subjects will not be given the opportunity 
to be reassessed for eligibility should criteria not initially be met. 
The eligibility assessment begins when the subject signs the IEC/IRB approved informed 
consent form and continues until study enrollment.  A signed and dated IEC/IRB 
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informed consent (see Section 5) must be obtained before any specific procedures are 
performed.  Only eligible subjects will be enrolled into this study.
The following eligibility assessments must be performed prior to enrollment:

Review of inclusion/exclusion criteria

Review of concomitant medications

Review of medical history

Physical exam including height

Vital signs: resting pulse, respiration and temperature measurements, resting blood 
pressure (after subject has been seated for at least 5 minutes)

Serum or urine pregnancy tests for female subjects of childbearing potential (within 
3 days before enrollment)
If for any reason, the subject is not able to continue their treatment according to 
schedule, Amgen Sponsor approval should be obtained.
7.3
Treatment Period
Study day 1 is defined as the first day that protocol specific treatments begin.  A cycle is 
defined as either 14 (+3) or 21 (3) days for conatumumab or 21 (3) days or 
28 (± 3) days for AMG 479, respectively, (plus time to recover from toxicity if required), 
as per parent protocol.  If Investigator decides to change the cycle duration from 2 to 
3 weeks (for conatumumab) or 3 to 4 weeks (for AMG 479 if administered alone), this 
must be decided prior to first dose and documented on the eCRF.  The new cycle 
duration should remain the same throughout the duration of the protocol (allowing for 
time to recover from toxicity as required).
The following procedures will be performed up to 3 days before each investigational 
product(s) infusion unless otherwise indicated (Note: If baseline physical exam, vital 
signs, weight, and laboratory tests are performed within 7 days of Cycle 1 they do not 
need to be repeated at Cycle 1):

Recording of concomitant medications, including those continuing from the parent 
protocol

Recording all non-serious and serious adverse events beginning at the start of study 
treatment (or planned start of treatment in the case of subjects who have their first 
treatment delayed for any reason), including those continuing from the parent 
protocol

All serious adverse events must be reported to Amgen within 24 hours following the 
investigator’s knowledge of the event (see Section 9.2.2)

Vital signs (resting pulse, respiration and temperature measurements, resting blood 
pressure [after subject has been seated for at least 5 minutes]) and weight 
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
Collection of samples for local laboratory assessment (see Table 11):

Hematology panel with 5 part differential 

Comprehensive chemistry panel including sodium, potassium, chloride, albumin, 
calcium, magnesium, phosphorus, glucose, BUN, creatinine, creatine kinase, uric 
acid, total bilirubin, alkaline phosphatase, AST, ALT 

Amylase and lipase 

Urinalysis consisting of specific gravity, pH, blood, protein and glucose

Coagulation: PTT and INR 

For subjects with diabetes (Type 1 or Type 2) who are receiving AMG 479, 
sample for HgbA1c collected at Cycle 1 and Cycle 3, and every 3 cycles 
thereafter (ie, C6, C9, etc). 

Collection of antibody samples, prior to infusion, for shipment to Amgen (refer to 
laboratory manual for detailed instructions):

Blood for anti-conatumumab antibody analyses collected every 8 cycles

For subjects receiving AMG 479 alone or in addition to conatumumab, blood for 
anti-AMG 479 antibody analyses collected every 8 cycles

Infusion of investigational product(s) on Day 1 of each cycle; 

For subjects receiving conatumumab refer to Section 6.1.1 for specifics on 
Dosage, Administration and Schedule

For subjects receiving infusion of AMG 479 alone or in addition to conatumumab, 
refer to Section 6.2.1 for specifics on dosage, administration and schedule

For subjects receiving FOLFOX6 plus bevacizumab in addition to conatumumab, 
refer to Sections 6.3.1 and 6.4.1 for specifics on dosage, administration and 
schedule

Radiological assessments to evaluate disease extent (with change compared to 
nadir from the parent protocol) should be performed at regular intervals, at a 
minimum once every 6 (± 1) months or more frequently if clinically indicated (starting 
from their last scan on the parent protocol), per standard of care (SOC) at each 
facility
7.4
Day 30 Safety Follow-up Visit
Upon discontinuation of protocol-specified therapy, subjects will undergo the Safety 
Follow-up Visit assessment approximately 30 (+ 3) days after the last administration of 
conatumumab or AMG 479 if administered alone.  NOTE: For subjects also receiving 
AMG 479 in combination with conatumumab, this visit occurs once both conatumumab 
and AMG 479 have been discontinued (see Section 6.2.3.1).
The following procedures will be performed:

Recording of concomitant medications

Review and recording of adverse events (see Section 9.1.2)
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
Reporting of all serious adverse events to Amgen within 24 hours following the 
investigator’s knowledge of the event (see Section 9.2.2)

Clinical evaluation, including physical exam

Vital signs: including pulse, respiration rate, temperature and blood pressure and 
weight

Blood sample collection for local laboratory assessments (refer to Table 11 for 
analyte descriptions)

Hematology panel with differentials

Comprehensive chemistry panel including sodium, potassium, chloride, albumin, 
calcium, magnesium, phosphorus, glucose, BUN, creatinine, creatine kinase, uric 
acid, total bilirubin, alkaline phosphatase, AST, ALT 

Amylase and lipase

Coagulation: PTT and INR

Urinalysis consisting of specific gravity, pH, blood, protein and glucose

For subjects with diabetes who are receiving AMG 479, collect blood sample for 
HgbA1c 

Serum or urine pregnancy tests for female subjects of childbearing potential 

Additional blood collection for anti-conatumumab antibody analyses and/or, blood 
collection for anti-AMG 479 antibody analyses 
7.5
Day 60 Follow-up Visit
Obtain serum samples for anti-conatumumab antibody analyses and/or anti-AMG 479 
antibody analyses, at 60 (14) days after the date of the last administration of 
protocol-specified therapy, unless the subject has started another systemic anti-cancer 
therapy.
NOTE: If a subject tests positive for the development of anti-conatumumab or 
anti-AMG 479 neutralizing antibodies, serum samples will be taken every 12 (2) weeks 
from the time the site is notified by Amgen that a subject tested positive for neutralizing 
antibodies until antibody levels return to baseline (or become negative), start of new 
anti-cancer therapy, or up to 1 year from the last dose of protocol-specified therapy, 
whichever occurs first.
8.
REMOVAL AND REPLACEMENT OF SUBJECTS
8.1
Removal of Subjects
Subjects have the right to withdraw fully from the study at any time and for any reason 
without prejudice to his or her future medical care by the physician or at the institution.
Withdrawal of full consent for this study means that the subject does not wish to receive 
further investigational treatment and does not wish to or is unable to continue further 
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study participation; subject data up to withdrawal of consent will be included in the 
subject’s study data.  Any subject may withdraw full consent to participate in the study at 
any time during the study.  The investigator will discuss with the subject appropriate 
procedures for withdrawal from the study.  
There will be no partial consent withdrawal in this study.
Should a subject (or a legally acceptable representative) request or decide to withdraw 
from the study, all efforts will be made to complete and report the observations as 
thoroughly as possible up to the date of withdrawal.  All information should be reported 
on the applicable CRFs.  
Reasons for removal from protocol-specified product(s) or observation might include:

withdrawal of full consent

administrative decision by the investigator or Amgen

pregnancy in a female subject (report on Pregnancy Notification Worksheet; see
Appendix D)

pregnancy in female partner of a male subject if he is unwilling to use a condom 
during treatment and for 6 months after the end of treatment (report pregnancy on 
Pregnancy Notification Worksheet; see Appendix D)

ineligibility

significant protocol deviation

subject noncompliance

adverse event

disease progression

requirement for alternative therapy

protocol-specified criteria

other safety concern by the investigator or Amgen 

death
8.2
Replacement of Subjects
There will be no replacement of subjects. 
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING
9.1
Adverse Events
9.1.1
Definition of Adverse Events
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
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The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.  
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates the pre-existing medical condition (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome.  A pre-existing condition that has not 
worsened during the study, and involves an intervention such as elective cosmetic 
surgery or a medical procedure while on study is not considered an adverse event.  
Disease progression of the primary tumor itself is not considered an adverse event; 
however, signs and symptoms of disease progression may be recorded as adverse 
events or serious adverse events.  If a new primary tumor malignancy appears, it will be 
considered an adverse event.
Deaths due to progressive disease during treatment until the Safety Follow-up Visit or 
30 days after the last dose of protocol specified therapy, whichever is later, should be 
recorded as due to the primary tumor.
Interventions for pretreatment conditions (eg, elective cosmetic surgery) or medical 
procedures that were planned before study enrollment are not considered adverse 
events.  
9.1.2
Reporting Procedures for Adverse Events
The investigator is responsible for ensuring that all adverse events (as defined in 
Section 9.1 and as further specified below) observed by the investigator or reported by 
the subject that occur after the start of study treatment (or planned start of treatment in 
the case of subjects who have their first treatment delayed for any reason) through the 
Safety Follow-up Visit or 30 days post the last dose of protocol-specified therapy are 
collected and reported using the applicable CRF (eg, Adverse Event Summary CRF).  In 
addition, adverse events that were continuing at the end of the parent study must be 
recorded and followed through to the stop date or the Safety Follow-up Visit.  Adverse 
events should also be collected and recorded in the subject’s medical records and 
serious adverse events should be recorded on the Serious Adverse Event Report 
(SAER) form.  These adverse events will include the following:

All serious adverse events (as defined in Section 9.2.1) that occur after the start of 
study treatment (or planned start of treatment in the case of subjects who have their 
first treatment delayed for any reason) through to the Safety Follow-up Visit or 
30 days after the last dose of protocol-specified therapy, whichever is later. 
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
All non-serious adverse events (as defined in Section 9.1.1) beginning at the start of 
study treatment (or planned start of treatment in the case of subjects who have their 
first treatment delayed for any reason) through to the Safety Follow-up Visit or 
30 days after the last dose of protocol-specified therapy, whichever is later. 
The investigator must assign the following adverse event attributes:

Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms),

Dates of onset and resolution,

Severity [and/or toxicity per protocol],

Assessment of relatedness to conatumumab (and/or AMG 479 if applicable), and

Action taken.
The adverse event severity grading scale used will be the Common Terminology Criteria 
for Adverse Events (CTCAE) version 3.0. The severity grading scale used in this study 
is described in Appendix B.
The investigator must assess whether the adverse event is possibly related to the
investigational product(s) and/or other study drugs.  This relationship is indicated by a 
“yes” or “no” response to the question:  Is there a reasonable possibility that the event 
may have been caused by the investigational product(s) and/or other study drugs?
The investigator must assess whether the adverse event is possibly related to any 
study-mandated procedure or activity.  This relationship is indicated by a “yes” or “no” 
response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study procedure/activity”?
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a change from the 
subject’s baseline values.  In general, abnormal laboratory findings without clinical 
significance (based on the investigator's judgment) should not be recorded as adverse 
events.  However, laboratory value changes that require treatment or adjustment in 
current therapy are considered adverse events.  Where applicable, clinical sequelae (not 
the laboratory abnormality) should be recorded as the adverse event.
The investigator’s clinical judgment will be used to determine whether a subject should 
be removed from treatment or from the study due to an adverse event.  A subject, or 
subject’s parent/legal guardian, may also voluntarily withdraw from treatment due to an 
adverse event.  If the subject withdraws full consent, the subject should be encouraged 
to undergo, at a minimum, the Safety Follow-up Visit.  
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9.2
Serious Adverse Events
9.2.1
Definition of Serious Adverse Events
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria:

fatal,

life threatening (places the subject at immediate risk of death),

requires in-patient hospitalization or prolongation of existing hospitalization,

results in persistent or significant disability/incapacity,

congenital anomaly/birth defect, and/or

other medically important serious event.
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).  
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, and blood dyscrasias, drug-induced liver 
injury events that necessitate an emergency room visit, outpatient surgery, or other 
events that require other urgent intervention.
Since the criteria for CTCAE severity differs from the regulatory criteria for serious 
adverse events, if adverse events correspond to grade 4 “life threatening” CTCAE 
severity criteria (eg, laboratory abnormality reported as grade 4 without manifestation of 
life threatening status), it will be left to the investigator’s judgment to also report these 
abnormalities as serious adverse events. For any adverse event that applies to this 
situation, comprehensive documentation of the event’s severity status must be recorded 
in the subject’s medical record.
9.2.2
Reporting Procedures for Serious Adverse Events
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur from the start of study treatment (or 
planned start of treatment in the case of subjects who have their first treatment delayed 
for any reason)  through to the Safety Follow-up Visit or 30 days after the last dose of 
protocol-specified therapy, whichever is later, are recorded in the subject’s medical 
record and are reported to Amgen via a Serious Adverse Event Report (SAER) form.  
The SAER must be submitted to Amgen within 24 hours of following the investigator’s 
knowledge of the event.  See Appendix C for a sample of the SAER form.
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After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event to Amgen within 24 hours following 
the investigator’s knowledge of the event.  Serious adverse events reported outside of 
the protocol-required reporting period will be captured within the safety database as
clinical trial cases for the purposes of expedited reporting.
New information relating to a previously (while subject was treated on the parent study) 
reported serious adverse event must be recorded on an SAER form using the subject’s 
ID and protocol number from the parent study. New serious adverse events occurring 
after the start of study 20101116 treatment (or planned start of treatment in the case of 
subjects who have their first treatment delayed for any reason) must be recorded on an 
SAER using the subject’s ID and protocol number from this study.  All changes to SAER 
forms must be sent to Amgen within 24 hours following the investigator’s knowledge of 
the new information.  The investigator may be asked to provide additional follow-up 
information, which may include a discharge summary or extracts from the medical 
record.  Information provided on the SAER form must be consistent with that recorded 
on the applicable CRF (eg, Adverse Event Summary CRF).
Hospitalization for events requiring anticipated protocol-specified procedures, such as
hospitalization for administration of chemotherapy or central line insertion and elective 
hospitalizations are not considered serious adverse events.  However, if an adverse 
event occurs during the hospital visit for one of these procedures and meets the 
definition of serious, then it must be reported as a serious adverse event. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen and included on the
Serious Adverse Event Report Form as well as the appropriate CRF.
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions (SUSARs) as required to regulatory authorities, investigators/institutions, and 
IRBs/ECs in compliance with all reporting requirements according to local regulations 
and good clinical practice.
The investigator should notify the appropriate IRB/EC/head of the medical institution of 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures and statutes.
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9.3
Pregnancy and Lactation Reporting
Details of all pregnancies and/or lactation in female subjects and, if indicated, 
female partners of male subjects will be collected after the start of study treatment 
and until 6 months after the end of treatment.
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of 
learning of the pregnancy and/or lactation.
Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events.
Collection of Pregnancy Information
Female Subjects Who Become Pregnant

Investigator will collect pregnancy information on any female subject who 
becomes pregnant while taking protocol-required therapies through 
6 months after the end of treatment.

Information will be recorded on the Pregnancy Notification Worksheet
(Appendix D). The worksheet must be submitted to Amgen Global Patient 
Safety within 24 hours of learning of a subject’s pregnancy.  (Note: Sites 
are not required to provide any information on the Pregnancy Notification 
Worksheet that violates the country or regions local privacy laws.)

After obtaining the female subject’s signed authorization for release of 
pregnancy and infant health information, the investigator will collect 
pregnancy and infant health information and complete the pregnancy 
questionnaire for any female subject who becomes pregnant while taking 
protocol-required therapies through 6 months after the end of treatment of 
the study drug.  This information will be forwarded to Amgen Global Patient
Safety. Generally, infant follow-up will be conducted up to 12 months after 
the birth of the child (if applicable).

Any termination of pregnancy will be reported to Amgen Global Patient 
Safety, regardless of fetal status (presence or absence of anomalies) or 
indication for procedure.

While pregnancy itself is not considered to be an adverse event or serious 
adverse event, any pregnancy complication or report of a congenital 
anomaly or developmental delay, fetal death, or suspected adverse 
reactions in the neonate will be reported as an adverse event or serious 
adverse event. Note that an elective termination with no information on a 
fetal congenital malformation or maternal complication is generally not 
considered an adverse event, but still must be reported to Amgen as a 
pregnancy exposure case.

If the outcome of the pregnancy meets a criterion for immediate 
classification as a serious adverse event (eg, female subject experiences a 
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spontaneous abortion, stillbirth, or neonatal death or there is a fetal or 
neonatal congenital anomaly) the investigator will report the event as a 
serious adverse event.

Any serious adverse event occurring as a result of a poststudy pregnancy 
which is considered reasonably related to the study treatment by the 
investigator, will be reported to Amgen Global Patient Safety as described 
in Appendix C.  While the investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of a serious 
adverse event through spontaneous reporting.

Any female subject who becomes pregnant while participating will 
discontinue study treatment.
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time 
of Enrollment

In the event a male subject fathers a child during treatment, and for an 
additional 6 months after discontinuing protocol-required therapies, the 
information will be recorded on the Pregnancy Notification Worksheet.  The 
worksheet must be submitted to Amgen Global Patient Safety within 
24 hours of the site’s awareness of the pregnancy.  (Note: Sites are not 
required to provide any information on the Pregnancy Notification 
Worksheet that violates the country or regions local privacy laws.)

The investigator will attempt to obtain a signed authorization for release of 
pregnancy and infant health information directly from the pregnant female 
partner to obtain additional pregnancy information.  After obtaining the 
female partner’s signed authorization for release of pregnancy and infant 
health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and 
complete the pregnancy questionnaires.  This information will be 
forwarded to Amgen Global Patient Safety.

Generally, infant follow-up will be conducted up to 12 months after the birth 
of the child (if applicable).

Any termination of the pregnancy will be reported to Amgen Global Patient 
Safety regardless of fetal status (presence or absence of anomalies) or 
indication for procedure.
Collection of Lactation Information

Investigator will collect lactation information on any female subject who 
breastfeeds while taking protocol-required therapies through 6 months 
after the end of treatment.

Information will be recorded on the Lactation Notification Worksheet 
(Appendix E) and submitted to Amgen Global Patient Safety within 
24 hours of the investigator’s knowledge of event.

Study treatment will be discontinued if female subject breastfeeds during 
the study as described in exclusion criterion 204 (see Section 4.2).

With the female subjects signed authorization for release of mother and 
infant health information, the investigator will collect mother and infant 
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health information and complete the lactation questionnaire on any female 
subject who breastfeeds while taking protocol-required therapies through 
6 months after the end of treatment after discontinuing protocol-required 
therapies.
10.
STATISTICAL CONSIDERATIONS
10.1
Study Endpoints
The endpoints for this study include:

Adverse events

Serious adverse events

Vital signs

Clinical laboratory tests

Tumor response

Disease progressions and deaths
10.2
Sample Size Considerations
The sample size for this study cannot be determined prospectively, as it is contingent on 
the number of subjects still receiving conatumumab or AMG 479 on the parent studies.  
The sample size is estimated to be approximately 15 subjects.
10.3
Access to Individual Subject Treatment Assignments by Amgen or 
Designees
This is an open-label study.  All study team members, investigators, and subjects will 
have access to study treatment information.
10.4
Planned Methods of Analysis
10.4.1
General Approach/Considerations
The studies preceding this open label extension are sufficiently different to preclude 
pooling over the studies.  Since the number of subjects enrolled per parent study will be 
low most of the data will be shown in listings.  A limited number of summary tables will 
be produced when the number of subjects makes this sensible.
The final analysis of this study will be performed at the end of the study ie, when all the 
subjects have completed or had the opportunity to complete the Day 60 Follow-up 
visit. The data may be summarized and listed before the final analysis to support 
Regulatory filings.
Subject disposition (number screened, enrolled into the study, receive conatumumab
and/or AMG 479, withdraw from the study) will be summarized.  
Demographics (age, sex, race) and tumor type will be listed.
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10.4.2
Analysis of Key Study Endpoints
10.4.2.1
Safety Endpoints
Analyses of safety will be carried out for all subjects who enrolled into this study.
All reported adverse events will be assigned to a system organ class and preferred term 
within a system organ class according to the Medical Dictionary for Regulatory Activities 
(MedDRA) version 13.0 or later.  The adverse events (all, serious, and related) will be 
listed by subject, system organ class, preferred term, and severity.  Further listings will 
show events that were continuing at the end of the parent study, on-study deaths, 
serious and significant adverse events, including early withdrawals due to adverse 
events.
Adverse events will be reported up to 30 days after last dose of investigational product.  
Listings will be provided for hematology, chemistry, and urinalysis parameters, as well as 
for vital sign variables.  Listings will be provided for baseline pre-study measurements, 
minimum observed on-study measurement, maximum observed on-study measurement 
and last observed measurement (including change from baseline to each).
10.4.2.2
Tumor Response, Disease Progression and Deaths
Analyses of tumor response, disease progression and deaths will be carried out for all 
subjects who enrolled into this study.
Listings will be provided for tumor response, disease progression, and deaths.  
Overall survival is the time, in months, from randomization into the parent study to the 
day of death.  Subjects who have not died while on the study or are lost to follow-up will 
be censored at the date of last contact.  Subjects who withdraw consent will be censored 
on the date of withdrawal.
Progression-free survival is the time, in months, from randomization/enrollment into the 
parent study to the first observation of disease progression or death due to any cause.  
For the progression-free survival analysis the following censoring strategies for missing 
dates of disease progression will be used:

If a subject’s disease has not progressed and the subject is alive, progression-free 
survival will be censored at the last date they are known to be progression-free (ie, 
the last tumor evaluation date).  

If a subject has no tumor evaluation in either the parent study or the extension study, 
progression-free survival will be censored at the date of randomization into the 
parent study.
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
Subjects who withdraw consent to participate in the study prior to progression will be 
censored at their last evaluable tumor assessment.
If sufficient subjects enrolled from parent studies then Kaplan-Meier plots of progression 
free survival and overall survival will be shown for each parent study.  
11.
REGULATORY OBLIGATIONS
11.1
Informed Consent
An initial generic informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template will be 
communicated by letter from the Amgen study manager to the investigator.  The written 
informed consent document should be prepared in the language(s) of the potential 
patient population.
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any 
investigational products are administered.  A legally acceptable representative is an 
individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study.  
The investigator is also responsible for asking the subject if the subject agrees to have 
his/her primary care physician informed of the subject’s participation in the clinical study.  
If the subject agrees to such notification, the investigator shall inform the subject’s 
primary care physician of the subject’s participation in the clinical study.
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician should be documented in the subject’s medical 
records, and the informed consent form should be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  The original signed informed consent form should be 
retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject or legally acceptable representative.
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
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subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  
11.2
Independent Ethics Committee/Institutional Review Board
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IEC/IRB for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product(s).
The investigator must submit and, where necessary, obtain approval from the IEC/IRB
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator should notify the IEC/IRB/head of the medical institution of 
deviations from the protocol or serious adverse events occurring at the site and other 
adverse event reports received from Amgen, in accordance with local procedures.
The investigator will be responsible for obtaining annual IEC/IRB approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IEC/IRB continuance of approval must be sent to Amgen.
11.3
Subject Confidentiality
The investigator must ensure that the subject’s confidentiality is maintained:  

On the eCRFs or other documents submitted to Amgen, subjects should be identified 
by a subject identification number only, with a complete and accurate date of birth on 
the demographics eCRF.  

On Serious Adverse Event forms submitted to Amgen, subjects should be identified 
by their initials and a subject identification number only.  

Documents that are not for submission to Amgen (eg, signed informed consent 
forms) should be kept in strict confidence by the investigator.
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IEC/IRB direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit named representatives to have access to 
his/her study-related records, including personal information, without violating the 
confidentiality of the subject.
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11.4
Investigator Signatory Obligations
Each clinical study report should be signed by the investigator or, in the case of 
multicenter studies, the coordinating investigator.
The coordinating investigator, identified by Amgen, will either be:

a recognized expert in the therapeutic area

an investigator who provided significant contributions to either the design or 
interpretation of the study

an investigator contributing a high number of eligible subjects
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS
12.1
Protocol Amendments and Study Termination
Protocol amendments, except where necessary to eliminate an immediate hazard to 
subjects, must be made only with the prior approval of Amgen.  Agreement from the 
investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The IEC/IRB must be informed of all amendments and 
give approval.  The investigator/institution must send a copy of the approval letter from 
the IEC/IRB to Amgen.
Both Amgen and the investigator reserve the right to terminate the investigator’s 
participation in the study.  Amgen reserves the right to terminate the study.  The 
investigator should notify the IEC/IRB/head of the medical institution in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.
12.2
Study Documentation and Archive
The investigator should maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form.
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  Elements should include:
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
Subject files containing completed eCRF, informed consent forms, and subject 
identification list

Study files containing the protocol with all amendments, investigator’s brochure, 
copies of prestudy documentation, and all correspondence to and from the IEC/IRB
and Amgen

If kept, proof of receipt/delivery sheet, Investigational Product Accountability Record, 
Return of Investigational Product for Destruction, Final Investigational Product 
Reconciliation Statement (if applicable), and all drug-related correspondence
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available.
Retention of study documents will be governed by the Clinical Trial Agreement.
12.3
Study Monitoring and Data Collection
The Amgen representative and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected.
The Amgen monitor is responsible for verifying the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the eCRFs.
The investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing eCRFs, 
are resolved.
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) 
and review of study-related records will occur to evaluate the study conduct and 
compliance with the protocol, ICH GCP, and applicable regulatory requirements.
Data capture for this study is planned to be electronic:

All source documentation supporting entries into the electronic CRFs (eCRFs) must 
be maintained and readily available.

Updates to electronic CRFs will be automatically documented through the software’s 
“audit trail”.
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
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review will be performed on subject data received at Amgen.  During 
this review, subject data will be checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries are created in the EDC system database 
for site resolution and subsequently closed by the EDC system or by Amgen 
reviewer.

The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature will indicate that the investigator inspected or reviewed 
the data on the CRF and the data queries, and agrees with the content.
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.
12.4
Investigator Responsibilities for Data Collection
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Appendix A), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.
12.5
Language
eCRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language.
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  Consult the 
country-specific requirements for language requirements.
12.6
Publication Policy
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several principal investigators and appropriate 
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Amgen staff.  The committee is expected to solicit input and assistance from other 
investigators and Amgen staff as appropriate.  Membership on the committee (both for 
investigators and Amgen staff) does not guarantee authorship—the criteria described 
below should be met for every publication.
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors).
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical 
Study Agreement among the institution, principal investigator, and Amgen will detail the 
procedures for, and timing of, Amgen’s review of publications.
12.7
Compensation 
Subject will be treated and/or compensated for any study-related illness/injury pursuant 
to the information provided in the Compensation for Injury section of the Informed 
Consent Template.  Depending on the type of study, subjects may be compensated for 
other inconveniences not associated with study-related injuries (eg, travel costs).
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13.
REFERENCES
Avastin(Bevacizumab) Final Labeling Text, U.S.  BL 125085/168 Amendment: 
Bevacizumab-Genentech, Inc.  July 2009.
Kelly S, Ashkenazi A.  Targeting death receptors in cancer with Apo2L/TRAIL.  Curr 
Opin Pharmacol. 2004; 4:333-339.
Macaulay VM.  Insulin-like growth factors and cancer.  Br J Cancer.  1992;65: 311-320. 
Sachdev D, Yee D.  Disrupting insulin-like growth factor signaling as a potential cancer 
therapy.  Mol Cancer Ther.  2007;6:1-12.
Werner H, LeRoith D.  The role of the insulin-like growth factor system in human cancer.  
Adv Cancer Res. 1996;68:183-223.
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14.
APPENDICES
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Appendix A.  Schedule of Assessments
Eligibility Assessments
Treatment Period
Follow-up Period
Cycles (Q2W, Q3W, or Q4W)
1
2
3
4
5
6
7
8
Day 30 
Safety 
Follow-up
Day 60 
Follow-up
Days
1
1
1
1
1
1
1
1
30 days
60 days
GENERAL & SAFETY ASSESSMENTS
Informed consent
X
Medical History
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Physical exam
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Height
X
LABORATORY ASSESSMENTS & CONATUMUMAB DOSING
Pregnancy test
Xa
X
Coagulation (PTT, INR) 
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
Serum amylase & lipase
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
HgbA1c b
X
X
X (q3c)
X
Anti-AMG 479 antibodyc
q8c
X
Xe
Anti-conatumumab antibodyd
q8c
X
Xe
Conatumumab infusionf
X
X
X
X
X
X
X
X
CHEMOTHERAPY & OTHER BIOLOGICS DOSING
AMG 479 infusiong
X
X
X
X
X
X
X
X
Leucovorin, Oxaliplatin & 5-FU Bolus Infusion h
X
X
X
X
X
X
X
X
Bevacizumab Infusion i
X
X
X
X
X
X
X
X
5-FU 46-48 Hour Ambulatory Infusionj
X
X
X
X
X
X
X
X
RADIOLOGICAL ASSESSMENTS
Staging k
SOC
Footnote defined on the next page
 
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a Pregnancy test within 3 days before enrollment.
b HgbA1c will be collected for diabetic subjects who are receiving AMG 479 at cycle 1, cycle 3 and every 3 cycles thereafter (ie, C6, C9, etc).
c Anti-AMG 479 antibody will be collected at a frequency of every 8 cycles from study day 1 only for subjects receiving treatment with AMG 479 (subjects who were 
previously on the 20070411 or 20050118 Amgen protocol).  A sample will also be collected at SFU and the Day 60 Follow-up visit, unless another anti-cancer 
therapy has started.
d Anti-conatumumab antibody will be collected at a frequency of every 8 cycles from study day 1.  A sample will also be collected at SFU and the Day 60 Follow-up 
visit, unless another anti-cancer therapy has started.
e Day 60 Follow-up: If a subject tests positive for the development of anti-conatumumab or anti-AMG 479 neutralizing antibodies, serum samples will be taken every 
12 (2) weeks from the time the site is notified by Amgen that a subject tested positive for neutralizing antibodies until antibody levels return to baseline (or become 
negative), start of new anti-cancer therapy, or up to 1 year from the last dose of protocol-specified therapy, whichever occurs first.
f Conatumumab will be administered on day 1 of each 14 (+ 3) or 21 (± 3) day cycle.
g AMG 479 will be administered on day 1 of each 21 (± 3) or 28 (± 3) day cycle.
h Leucovorin, Oxaliplatin & 5-FU Bolus infusion regimen is administered at every cycle (q2w schedule) for subjects with metastatic colorectal cancer who were 
previously receiving this treatment on the 20060464 Amgen protocol.
i Bevacizumab infusion regimen is administered at every cycle (q2w schedule) for subjects with metastatic colorectal cancer who were previously receiving this 
treatment on the 20060464 Amgen protocol.
j 5-FU 46-48 Hour Ambulatory Infusion regimen is administered at every cycle (q2w schedule) for subjects with metastatic colorectal cancer who were previously 
receiving this treatment on the 20060464 Amgen protocol.
k Radiological assessments to evaluate disease extent (with change compared to nadir from the parent protocol) should be performed at regular intervals, at a 
minimum once every 6 (± 1) months or more frequently if clinically indicated (starting from their last scan on the parent protocol), per standard of care (SOC) at each 
facility.
 
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Appendix B. Additional Safety Assessment Information
Adverse Event Severity Scoring System
The Common Terminology Criteria for Adverse Events (CTCAE) is available at the 
following link:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf
Drug-induced Liver Injury Assessment and Monitoring
Reporting:  Regardless of attribution or etiology, in order to monitor for signals of 
protocol-specified therapy induced liver injury, the following events should be reported 
as Serious Adverse Events and recorded on the Adverse Events CRF.
Notify the Sponsor within 24 hours: 

AST or ALT 3 times the upper limit of normal AND with serum bilirubin 2 times 
the upper limit of normal of the reference laboratory

Unexplained AST or ALT > 8 times the upper limit of normal

AST or ALT 3 times the upper limit of normal with clinical signs or symptoms of 
hepatitis (eg, jaundice, right upper quadrant abdominal pain)
If the cause of the liver test abnormalities is apparent and not attributable to 
protocol-specified therapy, adjust dosing per dose modification guidelines in Section 6.
For sustained elevations, submit as additional information to the initial SAE report
For recurrent elevations: 

30 days of the initial SAE report and have the same etiology, report as additional 
information to the original SAE.

30 days or different event, report as new SAE
If the cause of the liver test abnormalities is not known, manage as a potential 
drug-induced liver injury:

Withhold protocol-specified therapy (see Section 6)
Evaluation: consider viral hepatitis A, B, or C, preexisting or acute liver disease, liver 
metastases, fatty liver, or another drug(s) capable of causing the observed injury.  

Perform clinical follow-up, including repeat liver enzymes (AST, ALT, total bilirubin, 
alkaline phosphatase, INR) within 48-72 hours

Consider hepatitis serology, imaging, or other testing required to establish cause 
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
Obtain a more detailed history of: 

symptoms (if applicable) including hypersensitivity type reactions, fatigue, 
nausea, vomiting, fever, or eosinophilia. 

prior and/or concurrent conditions, including use of alcohol, drugs and special 
diets 

concomitant medications (including non-prescription medicines, herbal and 
dietary supplements) 

Follow the subject until all abnormalities return to baseline or normal.  Follow up 
should be for a minimum of 4 weeks after protocol-specified therapy discontinuation.
The potential drug-induced liver injury event and additional information such as medical 
history, concomitant medications and laboratory results must be captured in 
corresponding eCRFs.
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Appendix C.  Sample Serious Adverse Event Form
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Appendix D.  Pregnancy Notification Worksheet
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Appendix E.  Lactation Notification Worksheet
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Amendment 5 
Protocol Title:   
A Phase 2 Open Label Extension Study of Conatumumab and AMG 479 
 
Amgen Protocol Number AMG 655 (Conatumumab) and AMG 479 20101116 
 
Amendment Date: 
11 April 2017 
 
Rationale: 
• 
To describe the two-step transition to NantCell in manufacturing, labeling, and 
distribution of AMG 479. 
• 
To update the Key Sponsor Contacts 
• 
To update Section 9.3, Pregnancy and Lactation Reporting 
• 
To update Appendix C, Sample Serious Adverse Event Form, Appendix D, 
Pregnancy Notification Worksheet, and Appendix E, Lactation Notification 
Worksheet 
CONFIDENTIAL 
 
 
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Description of Changes: 
Section:  Global 
Replace: 
20 November 2013 
With: 
11 April 2017 
Section:  Title Page 
Key Sponsor Contact(s) 
Replace: 
, MD, PhD 
Clinical Research Medical Director 
Amgen Inc. 
Phone:
Fax:
E-mail:
  
With: 
, MD 
Clinical Research Senior Medical Scientist 
Amgen Inc. 
Phone:
E-mail:
 
Replace: 
 
Clinical Research Study Manager 
Amgen Inc. 
Phone:
Fax:
E-mail: 
 
With: 
Global Clinical Trial Manager  
DOCS International UK Ltd 
Phone:
E-mail:
 
Add: 
Amendment 5: 
11 April 2017 
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Section:  6.2 AMG 479 
Add: 
AMG 479 will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study distribution procedures. Upon the appropriate approvals being 
received, AMG 479 will be manufactured and packaged by Amgen, and labelled 
and distributed by NantCell using NantCell clinical study distribution procedures.  
Subsequent to this, and subject to the appropriate approvals being in place, 
AMG 479 will be manufactured, packaged, labelled, and distributed by NantCell, 
using NantCell clinical study distribution procedures.  Refer to the Investigational 
Product Instruction Manual for details regarding packaging, labeling, storage, and 
dispensing of AMG 479. 
Section:  9.3 Pregnancy and Lactation Reporting 
Replace: 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-specified product and for 6 months after end of treatment, the 
pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program within 
7 business days of the site receiving notification of a pregnancy.  Report a pregnancy on 
the Pregnancy Notification Worksheet (Appendix D).  The Pregnancy Surveillance 
Program (PSP) will seek to follow the pregnant woman throughout her pregnancy and 
her baby up to 12 months after birth. 
If a lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, Investigators should monitor for 
lactation cases that occur after the last dose of protocol-specified product through 
6 months after of end of treatment.  
Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
(LSP) within 7 business days of the site receiving notification.  Report a lactation case on 
the Lactation Notification Worksheet (Appendix E). 
With: 
Details of all pregnancies and/or lactation in female subjects and, if indicated, 
female partners of male subjects will be collected after the start of study treatment 
and until 6 months after the end of treatment. 
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If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of 
learning of the pregnancy and/or lactation. 
Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
• 
Investigator will collect pregnancy information on any female subject who 
becomes pregnant while taking protocol-required therapies through 
6 months after the end of treatment. 
• 
Information will be recorded on the Pregnancy Notification Worksheet 
(Appendix D). The worksheet must be submitted to Amgen Global Patient 
Safety within 24 hours of learning of a subject’s pregnancy.  (Note: Sites 
are not required to provide any information on the Pregnancy Notification 
Worksheet that violates the country or regions local privacy laws.) 
• 
After obtaining the female subject’s signed authorization for release of 
pregnancy and infant health information, the investigator will collect 
pregnancy and infant health information and complete the pregnancy 
questionnaire for any female subject who becomes pregnant while taking 
protocol-required therapies through 6 months after the end of treatment of 
the study drug.  This information will be forwarded to Amgen Global Patient 
Safety. Generally, infant follow-up will be conducted up to 12 months after 
the birth of the child (if applicable). 
• 
Any termination of pregnancy will be reported to Amgen Global Patient 
Safety, regardless of fetal status (presence or absence of anomalies) or 
indication for procedure. 
• 
While pregnancy itself is not considered to be an adverse event or serious 
adverse event, any pregnancy complication or report of a congenital 
anomaly or developmental delay, fetal death, or suspected adverse 
reactions in the neonate will be reported as an adverse event or serious 
adverse event. Note that an elective termination with no information on a 
fetal congenital malformation or maternal complication is generally not 
considered an adverse event, but still must be reported to Amgen as a 
pregnancy exposure case. 
• 
If the outcome of the pregnancy meets a criterion for immediate 
classification as a serious adverse event (eg, female subject experiences a 
spontaneous abortion, stillbirth, or neonatal death or there is a fetal or 
neonatal congenital anomaly) the investigator will report the event as a 
serious adverse event. 
• 
Any serious adverse event occurring as a result of a poststudy pregnancy 
which is considered reasonably related to the study treatment by the 
investigator, will be reported to Amgen Global Patient Safety as described 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 5 of 15 
in Appendix C.  While the investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of a serious 
adverse event through spontaneous reporting. 
• 
Any female subject who becomes pregnant while participating will 
discontinue study treatment. 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time 
of Enrollment 
• 
In the event a male subject fathers a child during treatment, and for an 
additional 6 months after discontinuing protocol-required therapies, the 
information will be recorded on the Pregnancy Notification Worksheet.  The 
worksheet must be submitted to Amgen Global Patient Safety within 
24 hours of the site’s awareness of the pregnancy.  (Note: Sites are not 
required to provide any information on the Pregnancy Notification 
Worksheet that violates the country or regions local privacy laws.) 
• 
The investigator will attempt to obtain a signed authorization for release of 
pregnancy and infant health information directly from the pregnant female 
partner to obtain additional pregnancy information.  After obtaining the 
female partner’s signed authorization for release of pregnancy and infant 
health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and 
complete the pregnancy questionnaires.  This information will be 
forwarded to Amgen Global Patient Safety. 
• 
Generally, infant follow-up will be conducted up to 12 months after the birth 
of the child (if applicable). 
• 
Any termination of the pregnancy will be reported to Amgen Global Patient 
Safety regardless of fetal status (presence or absence of anomalies) or 
indication for procedure. 
Collection of Lactation Information 
• 
Investigator will collect lactation information on any female subject who 
breastfeeds while taking protocol-required therapies through 6 months 
after the end of treatment. 
• 
Information will be recorded on the Lactation Notification Worksheet 
(Appendix E) and submitted to Amgen Global Patient Safety within 
24 hours of the investigator’s knowledge of event. 
• 
Study treatment will be discontinued if female subject breastfeeds during 
the study as described in exclusion criterion 204 (see Section 4.2). 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health 
information and complete the lactation questionnaire on any female subject who 
breastfeeds while taking protocol-required therapies through 6 months after the 
end of treatment after discontinuing protocol-required therapies. 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 6 of 15 
Section:  14 - Appendices 
Replace: 
 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 7 of 15 
 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 8 of 15 
With: 
 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 9 of 15 
 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 10 of 15 
 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 11 of 15 
 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 12 of 15 
Section:  Appendix D.  Pregnancy Notification Worksheet 
Replace: 
 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 13 of 15 
With: 
 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 14 of 15 
Section:  Appendix E.  Lactation Notification Worksheet 
Replace: 
 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  11 April 2017 
Page 15 of 15 
With: 
 
CONFIDENTIAL 
 
 
Approved 
 
 


Approved 
 
 
Product:  Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  20 November 2013 
Page 1 of 13 
 
Amendment 4 
Title:  A Phase 2 Open Label Extension Study of Conatumumab and AMG 479 
 
Amgen Protocol Number (Conatumumab and AMG 479) 20101116 
 
Amendment Date: 
20 November 2013 
 
Rationale: 
The protocol was amended primarily to change the interval of tumor scans from 3 to 
6 months (±1 months or more frequently if clinically indicated) in order to reduce the risk 
to subjects due to potential cumulative radiation exposure given that all subjects have 
been on study treatment for 3.5 to 7 years since the initial dose on the Parent Study and 
continue to do well either responding to treatment or are clinically stable. 
In the addition, the following changes have been incorporated into the protocol: 
• 
Update the sponsor contact information. 
• 
Remove the description of the formulation of the conatumumab and AMG 479 
investigational product materials from the protocol since the information is already 
provided to the investigator in the Investigational Product Instruction Manual.  
• 
Allow the investigator to use previous cycle’s amylase and lipase results, if present 
cycle’s results are not available before dosing 
• 
Revision of the reporting language of SAE’s within the Treatment period and Day 30 
Safety Follow Up Visit (sections 7.3 and 7.4) 
• 
Update reasons for removal from protocol-specified product(s) or observation in 
Section 8.1 in accordance with reasons available on the end of study case report 
form.  
• 
Update Section 9.2.2 (Reporting Procedures for SAE) to inform the investigator to 
report SAEs that occurs outside the protocol-specified reporting period per the 
Guidance CT-3. 
• 
Update EAC data capture instructions in Section 12.3 (Study Monitoring and Data 
Collection) to align with the current standard instructions in the Amgen protocol 
template. 
• 
Add Section 12.4 (Investigator Responsibilities for Data Collection) per the latest 
version of the Amgen protocol template 
• 
Update Section 12.6 (Publication Policy) to only reference the International 
Committee Medical Journal Editors (ICMJE) guidelines without specifying a version 
or set of criteria. 
• 
Other administrative corrections were made throughout the protocol.  


Superseded 
 
 
Product: Conatumumab and AMG 479 
Protocol Number:  20101116 
Date:  20 December 2012 
Page 1 
 
 
Amendment 3 
Title:  A Phase 2 Open Label Extension Study of Conatumumab and AMG 479 
 
Amgen Protocol Number (Conatumumab and AMG 479) 20101116 
 
Amendment Date: 
20 December 2012 
Rationale: 
The protocol was amended to incorporate the following changes: 
• 
Update the sponsor contact information. 
• 
Revise the eligibility criteria, patient population, and treatment procedures to allow 2 
ongoing subjects on the AMG 479 20050118 study to rollover into 20101116 study in 
order to continue to receive AMG 479 at the same dose and schedule they were 
receiving at the conclusion of the 20050118 Study. 
• 
SAE Reporting Procedures: 
o Change the SAE reporting timelines from 1 working day to 24 hours of 
discovery to comply with the EU Clinical Trial Guidance on the collection 
of adverse event/reaction arising from clinical trials.  
o Remove the language that requires the investigator to report SAEs 
related to investigational products that occurs outside the 
protocol-specified reporting period since the investigators may use their discretion 
to report any SAE to Amgen after the safety follow-up, whether related to 
investigational product or not.   
o Revise the language related to determination of expectedness for 
expedited reporting of adverse events in clinical trials to ensure better 
alignment with ICH E6 and regulatory agency expectations. 
• 
Add lactation reporting procedures and the Lactation Notification Worksheet. 


Superseded 
 
 
Product:  Conatumumab 
Protocol Number:  20101116 
Date:  25 January 2012 
Page 1 
 
 
Amendment 2 
Protocol Title:  A Phase 2 Open Label Extension Study of Conatumumab 
 
Amgen Protocol Number AMG 655 (Conatumumab) 20101116 
EudraCT number: 2010-022270-14 
 
Amendment Date: 
25 January 2012 
 
Rationale: 
The protocol has been amended for the following reasons: 
• 
To update the conatumumab investigational product information due to the transition 
of the conatumumab clinical supply for this study from material manufactured by 
Process 1 to material manufactured by Process 2.  The change in clinical supply 
eliminates the risk caused by the potential for the Process 1 material to form flake-
like glass particles when stored at -70°C.  Process 2 material is stored and shipped 
at refrigerated conditions, and therefore does not form flake-like glass particles, and 
does not require the use on an in-line filter. 
• 
To remove the requirement for the use of an in-line, nonpyrogenic, low-protein-
binding 0.2- or 0.22-micron filter when administering conatumumab investigational 
product.  Filter use is not required for intravenous infusion of conatumumab Process 
2 material.    
• 
To revise the sample size from approximately 50 to 15 subjects because fewer than 
expected subjects decided to continue treatment on this rollover study. 
• 
To add new section (Section 9.3) to provide instructions for pregnancy reporting.  
• 
To replace Pregnancy Notification Form with current Form. 
• 
To update the sponsor contact information. 
• 
Finally, minor administrative errors in the protocol were corrected. 
 
 
 


Superseded 
 
 
Product:  Conatumumab 
Protocol Number:  20101116 
Date:  25 May 2011 
Page 1 
 
Amendment 1 
Protocol Title:  A Phase 2 Open Label Extension Study of Conatumumab 
 
Amgen Protocol Number: AMG 655 (Conatumumab) 20101116 
 
Amendment Date: 
25 May 2011 
 
Rationale: 
The protocol has been amended for the following reasons: 
• 
The purpose of this protocol amendment is to add a requirement for the use of an 
in-line, nonpyrogenic, low-protein-binding 0.2- or 0.22-micron filter when 
administering AMG 655 and AMG 479 investigational product.  Notification to 
investigators of this requirement was provided in the form of a letter dated 27 May 
2011.  Filter use is being implemented to address a potential risk of formation of 
particles in vials of AMG 655 and AMG 479 investigational product that has been 
exposed to temperatures of -30°C or lower.    
• 
Provide minor procedural clarifications 
• 
Updated sponsor contact information 
 
Section:  Global 
Replace:  07 September 2010 
With:  25 May 2011 
 
Section:  Title page 
Replace:   
, PT 
Clinical Research Study Manager 
Amgen Inc. 
Phone:
Fax:
E-mail: 
 
With:   
 
Clinical Research Study Manager 
Amgen Inc. 
Phone: 
 
Fax: 
 
E-mail: 
 

SAP_001.pdf: 
20101116 
Statistical Analysis Plan, Version 1.1 
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Page 1 of 24 
DOCUMENT NO. FORM-008180 
       EFFECTIVE DATE 04-Oct-2010 
VERSION NO.V 4.0
STATISTICAL ANALYSIS PLAN  
A Phase 2 Open Label Extension Study of Conatumumab 
Protocol Number 20101116 
Version: 1. 1 
Date: 
10 December 2010 
Author:  
 
NCT Number: NCT01327612
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


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TABLE OF CONTENTS 
TABLE OF ABBREVIATIONS ........................................................................................... 5 
1.
INTRODUCTION ...................................................................................................... 6
2.
OBJECTIVES ........................................................................................................... 6
2.1 
Primary ......................................................................................................... 6 
2.2 
Secondary .................................................................................................... 6 
3.
STUDY OVERVIEW ................................................................................................. 6 
3.1 
Study Design ................................................................................................ 6 
3.2 
Sample Size ................................................................................................. 7 
4.
STUDY ENDPOINTS ............................................................................................... 7 
5.
HYPOTHESES AND/OR ESTIMATION ................................................................... 8 
6.
DEFINITIONS ........................................................................................................... 8
7.
ANALYSIS SUBSETS ............................................................................................ 12 
7.1 
All Enrolled Analysis Set ............................................................................. 12 
7.2 
Safety Analysis Set ..................................................................................... 12 
7.3 
Covariates .................................................................................................. 12 
8.
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES .............................. 12 
9.
DATA SCREENING AND ACCEPTANCE ............................................................. 13 
9.1 
General Principles ...................................................................................... 13 
9.2 
Data Handling and Electronic Transfer of Data .......................................... 13 
9.2.1 
Laboratory Ranges ..................................................................... 13 
9.2.2 
Data Extraction from the EDC System ....................................... 13 
9.3 
Handling of Missing and Incomplete Data .................................................. 14 
9.3.1 
Missing data for Safety ............................................................... 14 
9.4 
Outliers ....................................................................................................... 14 
9.5 
Validation of Statistical Analyses ................................................................ 14 
10.
STATISTICAL METHODS OF ANALYSIS ............................................................. 14 
10.1 
General Principles ...................................................................................... 14 
10.2 
Subject Accountability ................................................................................ 15 
10.3 
Important Protocol Deviations .................................................................... 15 
10.4 
Demographic and Baseline Characteristics ................................................ 15 
10.5 
Analysis of Key Study Endpoints ................................................................ 16 
10.5.1 
Tumor Response, Disease Progressions and Deaths ................ 16 
10.5.2 
Safety Endpoints ........................................................................ 16 
10.6 
Protocol-specified Treatment Administration .............................................. 18 
10.7 
Exposure to Concomitant Medication ......................................................... 18 


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10.8 
Physical Examination/Physical Measurements .......................................... 18 
11. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ..................................... 19 
12. 
LIST OF PLANNED TABLES, FIGURES AND LISTINGS [TFLs] .......................... 19 
12.1 
Planned Tables ........................................................................................... 19 
12.2 
Planned Listings ......................................................................................... 19 
13. 
LITERATURE CITATIONS / REFERENCES ......................................................... 22 
14. 
APPENDICES ........................................................................................................ 23 
 


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List of Tables 
Table 10.1.  Laboratory Parameters Measured During the Study  …...……………...16 
 
List of Appendices 
Appendix A.  Handling of Dates, Incomplete Dates for Adverse Events and 
Concomitant Medications
 
 ......................................................................... 24
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF ABBREVIATIONS 
Abbreviation/ Acronym Definition/Explanation 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CTCAE 
 
DMP 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
data management plan 
eCRF 
EDC 
INR 
electronic case report form 
electronic data capture 
international normalization ratio 
IP 
IPD 
investigational product (AMG 655 and/or AMG 479) 
important protocol deviation 
PD 
progressive disease 
PFS 
PLT 
PTT 
SOC 
TLGs 
progression-free survival 
platelets 
prothrombin time 
standard of care 
tables, figures, and listings 
WBC 
white blood cell 


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1. 
INTRODUCTION  
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical analyses 
that have been outlined within the protocol for Conatumumab Study 20101116 dated 07 
September 2010.  The scope of this plan includes the final analysis that is planned and will be 
executed by the Biostatistics department or designee.  
 
2. 
OBJECTIVES  
2.1 
Primary 
To provide ongoing treatment with conatumumab therapy, with or without chemotherapy 
(including bevacizumab) or with or without AMG 479, for subjects who are eligible, according to 
the parent study, to receive their next dose of conatumumab.  
2.2 
Secondary 
To evaluate the safety profile of conatumumab, with or without chemotherapy (including 
bevacizumab) or AMG 479, including adverse events and serious adverse events. 
 
3. 
STUDY OVERVIEW 
3.1 
Study Design 
This is a Phase 2 multi-center, open-label study that permits subjects who have 
completed a separate Amgen conatumumab study to continue treatment with 
conatumumab, with or without chemotherapy or with or without AMG 479. Subjects who 
have not progressed on a separate Amgen protocol are eligible to participate in this trial. 
 
This study will only be conducted in centers that treated subjects in previous conatumumab  
studies managed by Amgen Inc.. 
 
Subjects must have received conatumumab, with or without chemotherapy (including 
bevacizumab) or AMG 479, on the parent study. 
 
In this extension study, conatumumab study drug will be administered at the same dose 
level and schedule that the subject received at the conclusion of the parent 
conatumumab study, accommodating any subjects who were maintained on a reduced 
dose level or different schedule of administration in their parent study. At the discretion 
of the investigator, subjects who were receiving conatumumab monotherapy on the 


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parent study may switch at the time of starting this study (and only at this time) to 
receive monotherapy at an extended dosing frequency, to a maximum of every 3 weeks, 
if the total weekly dose remains the same as for the parent study.  
Subjects will be evaluated before every cycle of conatumumab therapy at the study 
clinic. These study visits will include a standard of care clinical assessment which 
includes collection of vital signs, adverse events, concomitant medications, and 
laboratory samples and results. Radiological assessments to evaluate disease extent 
(with change compared to nadir from the parent protocol) should be performed at regular 
intervals, at a minimum once every 12 weeks, per standard of care (SOC) at each 
facility. 
 
Reasons for study discontinuation will include progressive disease, intolerance to 
investigational product(s), and/or need for additional systemic anticancer treatment. 
When a subject discontinues the study for any reason, a safety follow-up visit will be 
completed at least 30 (+3) days after the last dose of protocol-specified therapy. This 
visit will include a standard of care clinical assessment, vital sign measurements, 
laboratory tests for blood and urine, adverse event assessment, and concomitant 
medications assessment. Subjects will also be assessed for anti-conatumumab 
antibody (and anti-AMG 479 antibody, if the subject has received AMG 479) assessment 
60 (±14) days after the last administration of protocol-specified therapy. 
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
 
3.2 
Sample Size  
The sample size for this study cannot be determined prospectively, as it is contingent on 
the number of subjects still receiving conatumumab on the parent studies. The sample  
size is estimated to be approximately 16 subjects.  
 
4. 
STUDY ENDPOINTS  
The endpoints for this study include: 
• 
 Adverse events 
• 
 Serious adverse events 
• 
 Vital signs 
• 
Clinical laboratory tests 


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• 
Tumor response 
• 
Disease progressions and deaths 
 
5. 
HYPOTHESES AND/OR ESTIMATION 
The main purpose of this study is to provide a mechanism for subjects to continue to receive 
treatment with conatumumab and/or AMG 479. 
 
6. 
DEFINITIONS 
• 
Baseline is defined as the last non-missing assessment prior to the first administration of 
protocol specified treatment in the parent study. Where baseline measurements are taken on 
the same day as the protocol specified treatment and no times are reported it will be assumed 
that these measurements are taken prior to the protocol specified treatment being administered.  
Baseline (of parent protocol) 
• 
A treatment cycle will be calculated as the time from the first administration of protocol specified 
treatment (in the extension study) for the given cycle to the day before the first administration of 
the subsequent cycle.  Cycles are planned to include either a 14 day or 21 (±3) day period (as 
defined in the parent protocol) following the start of the treatment with investigational product 
(IP) in combination with chemotherapy plus additional time, as needed, for the resolution of 
protocol-specified therapy-related toxicities.  If the investigator decides to change the cycle 
duration from 2 to 3 weeks at enrollment, then this must be recorded in the electronic case 
report form (eCRF). The new cycle duration should remain the same throughout the duration of 
the protocol (allowing time to recover from toxicity as required). For the last cycle, this includes 
the time from the first administration of protocol specified treatment in the extension study in the 
last cycle up to and inclusive of the date of the safety follow-up visit (or last contact date of no 
safety follow-up visit exists).  
Cycle 
• 
The cycle start date will be identified as follows: the earliest start date when a treatment 
component was administered in the extension study (ie, actual dose > 0) for the respective 
cycle. 
Cycle Start Date 
 


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• 
Immunogenicity follow-up visit 60 days (± 14 days) after the last dose of protocol-specified 
therapy in the extension study.  
Day 60 Follow-up Visit 
• 
Assessments of progressive disease will be determined by the investigator as per standard of 
care (SOC) at each facility (includes both radiographic and clinical progressions). 
Disease Progression (DP) 
• 
The latest date a subject is known to be alive will be based on the latest of the date variables 
included in all the raw datasets (with the exception of the comments datasets). For dates 
captured on the end of study, safety and day 60 follow-up pages, the date will only be used if the 
reason is not “lost to follow-up”.  
Last Contact Date 
• 
The end of study for a subject is defined as the date the subject withdraws consent from this 
study, completes or has the opportunity to complete the Day 60 Follow-up visit or dies, 
whichever occurs first.  
End of Study  
• 
Subject enrollment into the extension study occurs when the subject has signed the informed 
consent, eligibility criteria has been confirmed and the site has received confirmation of 
enrollment from the sponsor. 
Enrollment (into extension study) 
• 
As per parent protocols, investigational product will include conatumumab and/or AMG 479.  
Investigational Product/Protocol Specified Treatment 
The term ‘Protocol Specified Treatment’ is used to reference the following treatments:  
• 
Conatumumab, AMG 479, bevacizumab, leucovorin, oxaliplatin, 5-FU bolus and 5-FU 
continuous IV infusion. 
• 
Any death that occurs after receiving protocol specified therapy through to 30 days after the last 
dose of protocol specified therapy or safety-follow up visit, whichever is later. The primary cause 
of any on-study death will be reported as a serious adverse event. 
On-Study Death 
 


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• 
Refers to protocols under which a subset of subjects received their initial treatment with 
conatumumab. Subjects who received conatumumab with or without chemotherapy or AMG479 
and have not progressed on the Parent Study are eligible to participate in this trial. 
Parent Study 
• 
The randomization date is defined as the date when the call is made to the IVRS vendor and a 
randomization number is assigned in the parent study. For parent studies that are open-label 
where there is no randomization, the enrollment date in parent study will be used instead. Prior 
to this call the subject must have signed an informed consent and all eligibility criteria should 
have been verified.  
Randomization/enrollment date (in parent study) 
• 
Adverse events will be collected at least throughout the period beginning with the signing of the 
informed consent for this study, until the safety follow-up visit or 30 days after the last 
administration of protocol specified treatment, whichever is the later. Treatment emergent 
adverse events from the parent study will be concatenated with adverse event data from this 
study and will be reported across both protocols.  
Reporting of Adverse Events and Deaths 
The study visit at 30 days (+3 days) after the last dose of protocol-specified therapy. 
Safety Follow-up Visit (30 Day Safety Follow-up Visit) 
• 
A screen failure is defined as a subject who signs the informed consent for this study but does 
not enroll into the study because the subject did not meet the eligibility criteria as defined in 
Section 4.0 of the protocol. 
Screening Failures 
• 
This is the number of days from the date of the first administration of study specified treatment in 
the extension study, inclusive. 
Study Day for Extension Study 
 
Study Day = (Date of Interest - Date of first dose in extension study) + 1 
Study Day 1 is therefore the day that the first dose of study specified treatment is administered 
in the extension study. For dates that occur prior to study day 1, this will be calculated as: 
Study Day = (Date of Interest – Date of first dose in extension study)  


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Therefore, the day prior to study day 1 is -1. 
• 
This is the number of days from the date of the first administration of study specified treatment in 
the parent study, inclusive. 
Study Day for Parent Study 
 
Study Day = (Date of Interest - Date of first dose in parent study) + 1 
Study Day 1 is therefore the day that the first dose of study specified treatment is administered 
in the parent study. For dates that occur prior to study day 1, this will be calculated as: 
Study Day = (Date of Interest – Date of first dose in parent study)  
• 
This is the time interval between the randomization/enrollment date in parent study and the date 
of death. 
Time to Death   
• 
This is the time interval between the randomization/enrollment date in parent study and the date 
of disease progression or death, whichever occurs first. 
Time to Disease Progression   
• 
This is the time interval between the randomization/enrollment date in parent study and the end 
of study date for this extension study. 
Time from Randomization/Enrollment in Parent Study to End of Study   
• 
The time to the end of study is defined as the time interval between the date the subject signs 
the informed consent for this study and the end of study date.   
Time to End of Study   
• 
The time to the end of treatment for each component of protocol specified treatment is defined 
as the time interval between the date of first dose with a component of treatment in the 
extension study and the date the decision was made to end the treatment component in the 
extension study. 
Time to the End of Treatment for Each Component of Protocol Specified Treatment 
• 
A treatment emergent adverse event is defined as an adverse event that occurs or worsens on 
or after the date of the first administration of protocol specified treatment in the parent study 
through 30 days after the last administration of protocol specified treatment in the extension 
Treatment Emergent Adverse Event 


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study or the date of the safety follow-up visit (if this occurs more than 30 days after the last 
administration of protocol specified treatment). 
• 
The treatment phase begins on study day 1 for parent study and continues until the earlier of the 
date the decision to withdraw the subject from all study specified treatment, death, or completion 
of the safety-follow up visit in the extension study. 
Treatment Phase (across parent and extension protocols) 
• 
The treatment phase begins on study day 1 for extension study and continues until the earlier of 
the date the decision to withdraw the subject from all study specified treatment, death, or 
completion of the safety-follow up visit (in the extension study). 
Treatment Phase for Extension Study 
• 
Radiological assessments to evaluate disease extent (relative to the nadir from the parent 
protocol) will be performed at regular intervals, at a minimum once every 12 weeks, per SOC at 
each facility.  The investigator reported response (complete response, partial response, stable 
disease, progressive disease, not evaluable, unknown or not done) collected on the eCRF will 
be used as tumor response data (no confirmation of response is required).  
Tumor Response 
 
7. 
ANALYSIS SUBSETS 
7.1 
All Enrolled Analysis Set 
The All Enrolled Analysis Set will include all subjects enrolled into this extension study. 
7.2 
Safety Analysis Set 
The Safety Analysis Set will include all subjects that received at least one dose of conatumumab 
or AMG479.  
7.3 
Covariates 
Due to the small sample size, the impact of baseline characteristics on study outcomes will not 
be explored, and no subgroup analyses will be performed. 
 
8. 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES 
No interim analysis is planned for this study.   
 


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9. 
DATA SCREENING AND ACCEPTANCE 
9.1 
General Principles 
The objective of the data screening is to assess the quantity, quality and statistical 
characteristics of the data relative to the requirements of the planned analyses.  
9.2 
Data Handling and Electronic Transfer of Data  
Amgen’s Clinical Data Management department will provide all data to be used in the planned 
analyses.  Clinical data from this study will be stored in a single electronic data capture (EDC) 
system, RAVE 5.6.1 or higher. The database will be subjected to edit checks outlined in the 
Clinical Data Management Plan (DMP).   
At a minimum, the following items will be identified for further investigation and resolution by 
CDM: 
• 
Missing disease response data 
• 
Missing dates of disease progression and death 
• 
Outlier lab data  
• 
Missing key baseline data  
• 
Dose administration 
• 
Adverse Events 
Any data inconsistencies or suspicious values will be reviewed and aimed to be resolved before 
the database is locked. 
9.2.1 
Laboratory Ranges 
For the evaluation of abnormal laboratory values and toxicity grading of laboratory parameters, 
the normal ranges included within the database will be used.  Textbook normal ranges will be 
used to calculate CTC-NCI grades for laboratory parameters, with the exception of amylase, 
lipase and creatine kinase which will be entered using local ranges. Additional details regarding 
these ranges are included within the DMP. 
 
9.2.2 
Data Extraction from the EDC System 
The Biostatistics Infrastructure group will set up an automated job in the CDM2SAS interface to 
extract and download data from the EDC system.  The infrastructure group will then provide the 
programming team with Study Data Tabulation Model (SDTM) datasets via the Amgen 
Submission Data File (SDF) system.  SDTM generation will be performed when requested by 
the programming team.  


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9.3 
Handling of Missing and Incomplete Data 
Missing and incomplete data will be identified through programmatic checks and a review of the 
tables and listings created within Biostatistics.  Missing and incomplete data will be identified for 
investigation, and possible resolution, by CDM and Clinical Research Management prior to 
database lock (or prior to a data snapshot).  
 
 
 
 
   
In general, data will be analyzed as retrieved from the study database and no imputation for 
missing data will be performed.  
9.3.1 
Missing data for Safety 
With the exception of adverse event, concomitant medication and disease diagnosis dates, 
missing data for safety endpoints will not be imputed.  Details regarding date imputations can be 
found in appendix A. 
9.4 
Outliers 
Outliers will be identified via the use of descriptive statistics and the review of SDTM and tables, 
figures and listings (TFLs).  Edit checks will be created to specifically look for outlier data as 
indicated in the DMP.   All confirmed outlier data will be included in the analyses presented in 
this statistical analysis plan unless there is sufficient scientific rationale to exclude them. 
9.5 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance with 
current risk-based quality control procedures.   
Tables, figures and listings will be produced with validated standard macro programs where 
standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported versions of 
statistical analysis software, for example the SAS System.   
 
10. 
STATISTICAL METHODS OF ANALYSIS 
10.1 
General Principles 
The studies preceding this open label extension are sufficiently different to preclude 
pooling over the studies. Since the number of subjects enrolled per parent study will be 
low most of the data will be shown in listings. A limited number of summary tables will 
be produced when the number of subjects makes this sensible. 
 
The final analysis of this study will be performed at the end of the study i.e. when all the 


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subjects have completed or had the opportunity to complete the Day 60 Follow-up visit. 
The data may be summarized and listed before the final analysis to support Regulatory 
filings. 
Data from the extension study will be concatenated with data from the parent study for the 
following endpoints: treatment emergent adverse events, exposure to protocol-specified 
treatment, laboratory parameters and vital signs. Summaries and listings will be presented 
grouped by the parent study, unless otherwise stated.  
 
10.2 
Subject Accountability 
The denominators for the percentages in the subject accountability summaries will be the total 
number of subjects enrolled from each parent study. 
Subject disposition (number screened, enrolled into the study, receive study specified products, 
withdrawn from the study and reasons for subjects discontinuing study) will be summarized for 
all enrolled subjects. 
Listings of subject accountability and of subjects who discontinued from the study with the 
reason and timing of discontinuation will be provided using the all enrolled analysis set.  
10.3 
Important Protocol Deviations 
Important Protocol Deviation (IPD) categories will be defined by the study team before the first 
patient visit and updated during the IPD reviews throughout the study prior to database lock. 
These definitions of IPD categories, sub-category codes and descriptions will be used during the 
course of the study.  The final IPD list will be used to produce the List of Subjects with IPDs (see 
section 12.2).   
10.4 
Demographic and Baseline Characteristics 
Demographics (age, sex, race, height, weight) and tumor type will be listed using the all enrolled  
analysis set. 
 
A listing will be provided of new medical history (any new history of an abnormality, disease or 
surgery that was not collected in the parent protocol) using the all enrolled analysis set. 
 
Further listings showing the demographic and baseline characteristics (including prior medical 
and surgical history, prior surgery, prior radiotherapy, prior anti-cancer medications/regimens, and other 


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regional therapies) as collected at baseline of the parent protocol will be presented for all enrolled 
subjects.  
 
10.5 
Analysis of Key Study Endpoints 
10.5.1 
Tumor Response, Disease Progressions and Deaths 
Tumor response, disease progression and deaths will be recorded for all enrolled subjects.  
Since summaries are presented by parent study and the number of subjects enrolled per study 
will be low, listings will be provided for tumor response, disease progression and deaths. Time to 
disease progression or death (whichever occurs first) will be presented as well as time to death 
(refer to section 6 for the definitions).  
Investigator assessed tumor response as per eCRF will be listed for the extension study only (ie 
the time interval between enrollment into extension study and end of study).  
 
10.5.2 
Safety Endpoints 
Safety data will be presented for subjects in the safety analysis set.  
10.5.2.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 13.0 or later will be used to 
code all adverse events to a system organ class and a preferred term.  The severity of adverse 
events will be assigned in accordance with the NCI CTCAE version 3.0 guidelines. 
Treatment emergent adverse event data from the parent study will be concatenated with 
adverse event data from the extension study.  
Treatment emergent adverse events (all, serious and related) will be listed by subject, system 
organ class, preferred term, and severity. Further listings will show treatment emergent adverse 
events with a CTCAE  ≥ 3 by system organ class and preferred term, on-study deaths, serious 
adverse events, and adverse events leading to premature discontinuation from protocol 
specified therapy and/or study. Sponsor defined adverse events of interest will be flagged in the 
listings.  
Adverse events will be reported up to 30 days after last dose of protocol specified therapy or 
safety-follow up visit, whichever is later. 
10.5.2.2 
Laboratory Test Results  
Listings will be provided for hematology, chemistry, and urinalysis parameters.  


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Table 10.1 lists the laboratory parameters measured during the study. Laboratory test results  
in the parent study will be concatenated with the results in the extension study for the  
parameters listed in table 10.1.  
 
Table 10.1 Laboratory Parameters Measured During the Study 
* HgbA1c required for subjects with diabetes (Type 1 or Type 2) receiving AMG 479 
Textbook ranges will be used to calculate CTC-NCI grades for laboratory parameters, with the 
exception of amylase, lipase and creatine kinase which will be entered using local ranges. 
Where normal ranges are available, values outside of the range will be flagged. Severity grades 
for laboratory values will be derived programmatically based on NCI-CTC version 3.0. 
Listings will be provided for baseline measurement in the parent study and all post-baseline 
measurements until the end of study. Further listings will show hematology and clinical 
chemistry assessments with grade 3 and 4 toxicities. 
 
10.5.2.3 
Vital Signs 
Vital sign parameter measurements in the parent study will be concatenated with the vital  
Chemistry  
Coagulation 
Urinalysis 
Hematology 
Sodium 
Other Labs 
INR 
Specific gravity RBC 
Anti-conatumumab 
antibodies 
Potassium 
PTT 
pH 
Hemoglobin 
Pregnancy test 
Chloride 
 
Blood 
Platelets 
Anti-AMG479 antibodies  
Albumin 
 
Protein 
WBC 
HgbA1c* 
Calcium 
 
Glucose 
ANC 
 
Magnesium 
 
 
Differentials 
 
Phosphorus 
 
 
• Neutrophils 
 
Glucose 
 
 
• Lymphocytes 
 
BUN 
 
 
• Monocytes  
 
Creatinine 
 
 
• Eosinophils 
 
Uric acid 
Creatine Kinase 
 
 
• Basophils 
 
Total bilirubin 
 
 
 
 
Alk phosphatase  
 
 
 
AST (SGOT) 
 
 
 
 
ALT (SGPT) 
 
 
 
 
Amylase  
 
 
 
 
Lipase 
 
 
 
 


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sign parameter measurements in the extension study. Listings for each vital sign parameter will 
be provided for baseline measurement in parent study and all post-baseline measurements until 
end of study.   
 
10.6 
Protocol-specified Treatment Administration 
Protocol-specified treatment administration data from parent protocol will be concatenated with 
data from the extension study.  
Listings will be presented using the safety analysis set. 
Listings will be provided for each protocol-specified treatment administration for each subject 
(the total dose administered/infused, dose modifications, if applicable (including dose 
reductions, dose delays, or doses withheld) and the reasons for dose modifications.  
 In addition, a listing of subject box and lot numbers will be provided by parent study. 
 
10.7 
Exposure to Concomitant Medication  
Use of concomitant medications will be grouped by medication class and active ingredient 
according to the most up to date version of the World Health Organization Drug (WHODRUG) 
dictionary implemented by Amgen.  Concomitant medications include those that started on or 
after the day of the first dose of protocol specified treatment (or planned start of treatment in the 
case of subjects who have their first dose delayed for any reason), through 30 days after the last 
administration of protocol specified treatment or safety follow-up visit, which ever comes earlier. 
Listings of all concomitant medications by subject will also be provided by parent study. In 
addition, listing of concomitant medications that were continuing at the end of the parent study 
will be provided. 
 
10.8 
Physical Examination/Physical Measurements 
Listing of weight will be provided for baseline measurement, minimum observed on-study 
measurement, maximum observed on-study measurement and last observed on-study 
measurement, including change from study day -1 in extension study to each of those on-study 
measurements. 
Listing of physical examination at baseline and at follow-up visit will be provided. 


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11. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES  
There are no changes to the protocol-specified analyses.   
 
12. 
LIST OF PLANNED TABLES, FIGURES AND LISTINGS [TFLs] 
Amgen’s Department of Biostatistics standard macros and programs will be used wherever 
possible to create the planned tables, figures and listings.  
For the final analysis, the following TFLs will be provided. 
Table, listing and figure shells will be created and agreed to by the team prior to the final 
analysis.  Standard tables and listings will be used whenever possible. 
Since the number of subjects enrolled per parent study will be low most of the data will be 
shown in listings. 
 
12.1 
Planned Tables 
Category 
Title 
Description 
 Disposition  
Subject Disposition - All 
Enrolled Subjects 
Tabulates the disposition of all enrolled 
subjects, including the number of subjects 
screened, the number of subjects enrolled, 
the number of subjects who received or did 
not receive investigational product by 
parent study.  The reason for investigational 
product discontinuation and the reason for 
study discontinuation will also be 
summarized by parent study. 
[The footnote for the disposition table 
should include the dates for study initiation, 
early study termination (if applicable), and 
study completion, as required for the title 
page of the CSR.] 
 
12.2 
Planned Listings 
Title 
Description 
Study Accounting   
 
 
 
 
 
Listing of the subjects together with the number of doses 
received, time and reason for ending study, reason for 
ending any protocol-specified treatment, time and dates 
for terminations, and completion of safety-follow up, 
grouped by parent study. 
 


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Title 
Description 
 
Screen Failures 
 
 
Medical History 
 
 
Subject Listing of Important 
Protocol Deviations 
 
Listing of subject screen failures and the reason for 
screen failure grouped by parent study. 
 
Listing of subjects with any new medical history not 
recorded in parent protocol grouped by parent study. 
 
Listing of the Important Protocol Deviations with category 
and sub-category codes, and descriptions for each 
subject, grouped by parent study. 
 
 
Listing of Unique Manufacturing Lot 
Numbers  
Listing of the unique Manufacturing Lot Numbers used in 
the study, grouped by parent study (investigational 
product name and concentration). 
Subject Listing of Manufacturing 
Lot Numbers 
 
 
Demographics (at enrollment) 
 
Baseline Demographics  
 
 
 
Prior Medical history 
 
 
 
 
Tumor Response 
 
 
Time to Disease Progression and 
Time to Death 
 
All Adverse Events 
 
 
 
Serious Adverse Events  
 
 
Listing of the subjects administered each Manufacturing 
Lot Number grouped by parent study (investigational 
product name and concentration).   
 
Listing of the subjects together with age, sex, race, 
height, weight and tumor type grouped by parent study. 
 
Listing demographic and baseline characteristics as 
collected at baseline of parent study grouped by parent 
study  
 
Listing of prior medical and surgical history, prior 
surgery, prior radiotherapy, prior anti-cancer 
medications/regimens, and other regional therapies as 
collected at baseline of parent protocol grouped by 
parent study. 
 
Listing of tumor response (CR, PR, SD, PD) for each 
subject grouped by parent study. 
 
Listing of time to disease progression or death 
(whichever occurs first) and time to death grouped by 
parent study. 
 
Listing of treatment-emergent adverse events (verbatim 
and preferred terms, start and stop dates, duration, 
severity, relation and action taken), grouped by parent 
study, subject ID. 
 
Listing of serious treatment-emergent adverse events 
(verbatim and preferred terms, start and stop dates, 
duration, severity, relation and action taken), grouped by 


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Title 
Description 
 
On-study Deaths 
 
 
 
 
Treatment Emergent Adverse 
events with a CTCAE  ≥ 3  
 
 
Discontinuations Due to Adverse 
Events 
 
Clinical laboratory 
 
 
Grade 3 or higher Hematology 
Toxicities 
 
Grade 3 or higher Clinical 
Chemistry Toxicities 
 
Vital Signs 
 
 
 
Protocol specified Treatment 
Administration 
 
 
Concomitant Medication 
 
 
 
Concomitant Medications 
continuing from Parent Study 
 
 
Physical Measurement 
 
 
 
 
parent study, subject ID. 
 
Listing of dates of deaths and last administrations and 
primary cause of deaths, and overall survival grouped by 
parent study, subject ID.    
 
 
Listing of treatment emergent adverse events with a 
CTCAE  ≥ 3 by system organ class and preferred term 
grouped by parent study. 
 
Listing of discontinuations due to adverse events, 
grouped by parent study, subject ID. 
 
Listing of laboratory parameters (including NTC-NCI 
grades) measured at baseline and all post-baseline 
visits, grouped by parent study, subject ID. 
 
Listing of hematology assessments with grade 3 
and 4 toxicities grouped by parent study. 
 
Listing of clinical chemistry assessments with grade 
3 and 4 toxicities grouped by parent study. 
 
Listing of vital sign parameters measured at baseline, 
and all post-baseline visits grouped by parent study, 
subject ID. 
 
Listing of dates, times, days and doses of treatments 
administered and reasons for dose changes, grouped by 
parent study, subject ID. 
 
Listing of concomitant medications (including start and 
stop dates, indication, dose, route, frequency) grouped 
by parent study, subject ID. 
 
Listing of concomitant medications continuing at the end 
of parent study (including start and stop dates, 
indication, dose, route, frequency) grouped by parent 
study, subject ID. 
 
Listing of weight measured at baseline, minimum and 
maximum observed on-study measurement and last 
observed measurement, including change from study 
day -1 for extension study grouped by parent study, 
subject ID. 


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Title 
Description 
Physical Examination 
 
Listing of physical examination at baseline and follow-up 
visit for each subject, grouped by parent study. 
 
13. 
LITERATURE CITATIONS / REFERENCES 
Cox, D. R. and D. Oakes. 1984. Analysis of Survival Data. Chapman and Hall, London. 
 


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14. 
APPENDICES  
 
 


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Appendix A.  Handling of Dates, Incomplete Dates for Adverse Events and Concomitant 
Medications  
Start Date 
Imputation Rules for Partial or Missing Start Dates 
Stop Date 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st dose 
yyyymm 
≥ 1st dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
2 
1 
2 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
3 
1 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
 
1 = Impute the date of first dose 
2 = Impute the first of the month 
3 = Impute January 1 of the year 
4 = Impute January 1 of the stop year 
 
 
Imputation Rules for Partial or Missing Stop Dates 
• 
If the month and year are present, impute the last day of that month but do not exceed 
the subject’s last contact date or final analysis cutoff date.  
• 
If only the year is present, impute December 31 of that year but do not exceed the 
subject’s last contact date or final analysis cutoff date. 
• 
If the stop date is entirely missing, assume the event or medication is ongoing 
If a partial or complete stop date is present and the ‘on-going’ or ‘continuing’ box is checked, 
then it will be assumed that the adverse event or concomitant medication stopped and the stop 
date will be imputed if partial.