Clinical trial NCT00788957
Conditions: Colon Cancer Colorectal Cancer Gastrointestinal Cancer Metastatic Colorectal Cancer Rectal Cancer
Keywords: panitumumab vectibix AMG 102 AMG 479 colon cancer rectal cancer colorectal cancer metastatic colorectal cancer EGFR inhibitor IGF inhibitor c-MET inhibitor
Sponsor: NantBioScience, Inc.
Start date: 2008-10-27; Completion date: 2010-07-23
Enrollment: 177 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a global, multicenter, open-label phase 1b and randomized, double-blinded, 2 part, phase 2 study designed to evaluate the safety and efficacy of rilotumumab or ganitumab in combination with panitumumab versus panitumumab alone in patients with metastatic colorectal cancer whose tumors are wild-type KRAS status.

Detailed description:
This study consisted of 3 parts:

Part 1: determination of the tolerable dose of rilotumumab in combination with panitumumab to be administered in Part 2.

Part 2: Comparison of the safety and efficacy of rilotumumab or ganitumab in combination with panitumumab versus that of panitumumab alone. In Part 2, participants were randomized 1:1:1 into 3 cohorts: 6 mg/kg panitumumab plus 10 mg/kg rilotumumab, 6 mg/kg panitumumab plus 12 mg/kg ganitumab, or 6 mg/kg panitumumab and placebo (panitumumab alone cohort). Panitumumab was administered open-label, and rilotumumab and ganitumab were double-blinded.

Part 3: Exploratory evaluation of the safety and efficacy of the rilotumumab and ganitumab monotherapy following treatment with panitumumab in Part 2. In Part 3, eligible participants who terminated panitumumab treatment in the Panitumumab Alone arm of Part 2 due to disease progression or intolerability could be randomized 1:1 into 2 double-blind cohorts: 10 mg/kg rilotumumab or 12 mg/kg ganitumab.

Participants who permanently discontinued all the investigational products completed a safety follow-up visit 30 days and a follow-up visit 60 days after the last dose of investigational product. Participants were followed for radiographic disease progression and survival every 3 months after the 30-day safety follow-up visit for up to 2 years after the last participant was enrolled in Part 2.

Arms: arm 1: Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision. arm 2: Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision. arm 3: Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision. arm 4: Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision. arm 5: Participants randomized to Panitumumab Alone in Part 2 who had disease progression (radiographic or clinical) or intolerability were re-randomized in Part 3 to receive rilotumumab 10 mg/kg every 2 weeks until disease progression, intolerability, withdrawal, death, or sponsor decision. arm 6: Participants randomized to Panitumumab Alone in Part 2 who had disease progression (radiographic or clinical) or intolerability were re-randomized in Part 3 to receive ganitumab 12 mg/kg every 2 weeks until disease progression, intolerability, withdrawal, death, or sponsor decision.
Interventions: intervention 1: Panitumumab intervention 2: Ganitumab intervention 3: Rilotumumab intervention 4: Placebo
Intervention descriptions: intervention 1: Panitumumab for intravenous infusion intervention 2: Ganitumab for intravenous infusion intervention 3: Rilotumumab for intravenous infusion intervention 4: Placebo intravenous infusion

Protocol documents:
Prot_SAP_000.pdf: 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
Page 1 of 174 
 
 
CONFIDENTIAL 
A
 ®
 
Title:  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 
Panitumumab / AMG 102 / AMG 479 
 
Amgen Protocol Number 20060447 
 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive  
Thousand Oaks, CA 91320-1799 
United States 
Tel:  +1 805-447-1000 
Fax:  +1 805-480-0614 
Key Sponsor Contact (US): 
Shanna Stout 
Clinical Research Study Manager 
Tel: +1 805-447-8580 
Fax: +1 805-480-1291 
Key Sponsor Contact (US 
and Europe) 
Dominic Smethurst 
Medical Director 
1 Sanderson Road  
Uxbridge Business Park 
London 
UB81DH 
Tel: +44 1895 525364 
Fax: +44 1895 525112  
Date: 
22 April 2008 
EudraCT Number: 
2008-001751-21 
 
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:  +1 800-77-AMGEN (for US sites) or +1 800-772-
6436 (for all other countries).  For all other study-related questions, continue to contact 
the Key Sponsor Contact. 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
Page 2 of 174 
 
 
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Investigator’s Agreement 
I have read the attached protocol entitled 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, dated 22 April 2008, 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 FDA regulations/guidelines set forth 
21 CFR Parts 11, 50, 54, 56, and 312 and other 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) 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
Page 3 of 174 
 
 
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Protocol Synopsis 
Title:  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  
Study Phase:  1b/2 
Indication:  wild-type KRAS metastatic colorectal cancer 
This protocol consists of 3 parts.  Part 1 is the dose finding phase 1b portion of the study.  Part 2 
is the phase 2, randomized, three-cohort portion of the study.  Part 3 is an extension of the 
phase 2 (part 2) in which select subjects from part 2 may continue treatment in one of two 
cohorts.  Throughout this protocol synopsis, the various portions of the study will be referred to as 
part 1, 2, or 3. 
Primary Objective:   
Part 1: To identify a tolerable dose of AMG 102 in combination with panitumumab based on the 
incidence of dose-limiting toxicities (DLTs) 
Part 2: To evaluate the efficacy as assessed by the overall objective response rate (ORR) of 
AMG 102 (tolerable dose selected from part 1) in combination with panitumumab and AMG 479 in 
combination with panitumumab versus panitumumab alone 
Secondary Objective(s):  
Part 1: 
 
• 
To evaluate the safety of AMG 102 in combination with panitumumab 
• 
Pharmacokinetics (PK) exposure of AMG 102 and panitumumab when given in 
combination 
Part 2:   
• 
To evaluate the safety and efficacy of AMG 102 (tolerable dose selected from part 1) in 
combination with panitumumab and AMG 479 in combination with panitumumab versus 
panitumumab alone 
• 
PK exposure of AMG 102 and panitumumab when given in combination 
• 
PK exposure of AMG 479 and panitumumab when given in combination 
• 
PK exposure of panitumumab when given alone 
Exploratory Objective(s):   
The exploratory objectives will include, but will not be limited to the following:  
• 
Part 1:  To evaluate the efficacy of AMG 102 in combination with panitumumab 
• 
Part 3:  To evaluate the safety and efficacy of AMG 102 and AMG 479 monotherapy 
following treatment with panitumumab (cohort 3) in part 2 
• 
Pharmacodynamic response of AMG 102 as assessed by hepatocyte growth factor/c-Met 
(HGF/c-Met), pathway markers, tumor apoptosis markers, angiogenic cytokines, and 
other biomarkers (Part 1, 2, and 3) 
• 
Pharmacodynamic response of AMG 479 as assessed by insulin-like growth factor-1 
(IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), and growth hormone 
(Part 2 and 3) 
• 
Correlation between plasma HGF levels or tumor ribonucleic acid (RNA) expression, and 
tumor response (Parts 1, 2, and 3) 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
Page 4 of 174 
 
 
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• 
Effects of tumor genetic variation in pathway genes, cancer genes, drug target genes, 
and other biomarker genes on subject response to investigational product  (Parts 1, 2, 
and 3) 
• 
Effect of genetic variation in cancer genes, drug target genes, drug metabolism genes, 
and other biomarker genes on subject response to investigational product on a subset of 
subjects.  Separate pharmacogenetic informed consent required. (Parts 1, 2, and 3) 
Hypotheses:   
Part 1:  Treatment with AMG 102 in combination with panitumumab will be safe and well 
tolerated.  
Part 2:  Treatment with AMG 102 or AMG 479 in combination with panitumumab will exhibit a 
greater ORR with acceptable safety than treatment with panitumumab alone.   
Part 3:  Hypothesis forming exploratory work will be undertaken to evaluate safety and efficacy 
among those subjects in part 2 that go on to receive AMG 102 or AMG 479 monotherapy in 
part 3. 
Study Design:  This is a global, multicenter, open-label phase 1b and randomized, 
double-blinded two-part phase 2 study designed to evaluate the safety and efficacy of AMG 102 
or AMG 479 in combination with panitumumab versus panitumumab alone in mCRC subjects with 
wild-type KRAS tumor status.   
Panitumumab will be open-label throughout the study (parts 1 and 2).   
Investigational product will be administered every 2 weeks.   
Part 1: 
In part 1, approximately 6 to 18 subjects (6 to 9 subjects at each dose level of AMG 102 
evaluated in combination with panitumumab) will be enrolled to receive open-label AMG 102 in 
combination with panitumumab with the purpose of identifying a tolerable dose of AMG 102 for 
the part 2 portion of the study.   
AMG 102 10 mg/kg will be the starting dose evaluated in combination with panitumumab 6 mg/kg.  
Dose de-escalation of AMG 102 to 5 mg/kg will take place if determined necessary by the study 
team based on the interim safety analysis and incidence of DLTs.  The dose of AMG 102 that is 
determined tolerable in combination with panitumumab in part 1 will be the selected dose used in 
part 2.   
Subjects enrolled in part 1 will not be eligible for randomization in part 2.  
Part 2: 
Panitumumab will be open-label.  AMG 102, AMG 479, and placebo will be blinded and will be 
referred to as blinded investigational product.  In part 2, approximately 126 subjects will be 
randomized in a ratio of 1:1:1 to one of the following three double-blinded treatment groups.  The 
randomization will be stratified for prior chemotherapy regimen: irinotecan or oxaliplatin vs both.  
Cohort 1:   panitumumab 6 mg/kg and AMG 102 (tolerable dose selected from part 1)  
Cohort 2:   panitumumab 6 mg/kg and AMG 479 12 mg/kg  
Cohort 3:   panitumumab 6 mg/kg 
If a tolerable dose of AMG 102 is not identified in part 1, then part 2 will continue with cohorts 2 
and 3 only.  If this occurs, subjects will be randomized in part 2 in a ratio of 1:1 to one of the 
following two double-blinded treatment groups.   
Cohort 2:   panitumumab 6 mg/kg and AMG 479 12 mg/kg  
Cohort 3:   panitumumab 6 mg/kg  


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
Page 5 of 174 
 
 
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Subjects randomized to cohort 3 of part 2 may be eligible to receive treatment with blinded 
investigational product in part 3 (see below). 
Part 3: 
Upon radiographic disease progression per modified RECIST, clinical progression, or intolerability 
to all investigational products, subjects that meet the criteria outlined in protocol Section 4.3 may 
be unblinded via the IVRS by the investigator or designated study staff to determine treatment 
assignment.  Subjects randomized to cohort 3 (ie, panitumumab) of part 2 may be further 
randomized in part 3 in a ratio of 1:1 to one of the following two double-blinded treatment groups.  
The randomization will be stratified for reason for panitumumab discontinuation in part 2: disease 
progression (radiographic or clinical) versus intolerability. 
Cohort 3a: AMG 102 10 mg/kg 
Cohort 3b: AMG 479 12 mg/kg 
The dose of AMG 102 (ie, 10 mg/kg) in part 3 will not be affected by the outcome of the interim 
safety analysis in part 1. 
Investigational product will be administered every 2 weeks (Q2W) until disease progression, 
intolerability, withdrawal, death, or unless otherwise indicated by the study team (see 
investigational product administration details below). 
All subjects that permanently discontinue all investigational products will complete a safety follow-
up visit 30 days (+3 day window) and a follow-up visit 60 days (+14 day window) after the last 
dose of investigational product.   
Subjects will be followed for radiographic disease progression (if not documented previously) and 
survival in the long-term follow-up portion of the study every 3 months (± 28 day window) after the 
30 day safety follow up visit for up to 2 years after the last subject is enrolled in part 2 or 3, 
whichever occurs last. 
 
Primary and Secondary Endpoints:   
Primary Endpoints:   
Part 1:  Subject incidence of DLTs 
Part 2:  Overall ORR 
Secondary Endpoints:  
Parts 2:   
• 
Duration of response 
• 
Time to response 
• 
Disease control 
• 
Progression-free survival  
• 
Overall survival 
• 
Incidence of all AEs and clinical laboratory abnormalities 
• 
Incidence of antibody formation to panitumumab, AMG 102, and AMG 479 
• 
Cmin, Cmax, and AUC for panitumumab and AMG 102 (Part 1) 
• 
Cmin and Cmax for panitumumab, AMG 102, and AMG 479 (Part 2) 
 
Sample Size: 
Part 1:  Approximately 6 to 18 subjects (n = 6 to 9 per dose level of AMG 102 evaluated in 
combination with panitumumab). 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
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Part 2:  Approximately 126 subjects (n = 42 per cohort) 
Part 3:  Subjects from cohort 3 of part 2 will cross over to part 3 (n = 42) 
Summary of Subject Eligibility Criteria:   
Key Inclusion Criteria (Parts 1 and 2) 
• 
Man or woman ≥ 18 years of age 
• 
A life expectancy estimate of ≥ 3 months 
• 
ECOG 0 or 1 
• 
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or 
rectum  
• 
Subjects with wild-type KRAS tumor status confirmed by central laboratory assessment 
• 
Radiographic evidence of disease progression during or following prior treatment with 
irinotecan and/or oxaliplatin based chemotherapy for mCRC  
• 
At least 1 uni-dimensionally measurable lesion ≥ 20 mm in one dimension per modified 
RECIST (CT or MRI) 
• 
Adequate hematology, renal, and hepatic function (see Section 4.1.3) 
• 
Magnesium ≥ lower limit of normal 
• 
Subjects with known diabetes (Type 1 or 2) must have adequate glycemic function, as 
follows: 
- 
Must be controlled with a glycosylated hemoglobin (HgbA1c) of < 8.0% 
- 
Documented fasting blood sugars < 160 mg/dL   
Key Exclusion Criteria (Parts 1 and 2) 
• 
Participation in a phase 3 randomized study of panitumumab in combination with 
chemotherapy, regardless of treatment assignment 
• 
Prior treatment with anti-EGFr inhibitors (eg, panitumumab, cetuximab, erlotinib, 
gefitinib), unless treatment was received in the adjuvant setting ≥ 6 months before 
enrollment 
• 
Prior treatment with c-Met, IGF-IR, or IGF-IIR inhibitors 
• 
Prior treatment with either AMG 102 or AMG 479 
• 
Use of experimental or approved systemic chemotherapy or radiotherapy ≤ 21 days 
before enrollment 
• 
Use of experimental or approved targeted therapies ≤ 30 days before enrollment 
• 
History of prior or concurrent central nervous system (CNS) metastases 
• 
History of other primary cancer, unless: 
- 
Curatively resected non-melanomatous skin cancer 
- 
Curatively treated cervical carcinoma in situ 
- 
Other primary solid tumor treated with curative intent and no known active 
disease present for ≥ 5 years before enrollment 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
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• 
History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence 
of interstitial lung disease on baseline chest computerized tomography (CT) scan 
• 
Clinically significant cardiovascular disease (including myocardial infarction, unstable 
angina, symptomatic congestive heart failure, serious uncontrolled cardiac 
arrhythmia) ≤ 1 year before enrollment 
• 
Active inflammatory bowel disease or other active bowel disease causing chronic 
diarrhea (defined as ≥ grade 2 per CTCAE version 3.0) 
• 
Any co-morbid disease or condition that could increase the risk of toxicity 
(eg, significant ascites, significant pleural effusion) 
• 
Serious or non-healing wound ≤ 35 days before enrollment 
• 
Major surgical procedure ≤ 35 days before enrollment or minor surgical procedure 
≤ 14 days before enrollment.  Subjects must have recovered from surgery related 
toxicities.  Central venous catheter placement, fine needle aspiration, thoracentesis, 
or paracentesis is not considered a major or minor surgical procedure. 
See protocol Section 4.3 for inclusion criteria for part 3. 
Investigational Product Dosage and Administration:   
Investigational product will be diluted in 0.9% sodium chloride.  Investigational product will be 
administered by IV infusion beginning on week 1 and continuing Q2W until disease progression, 
intolerability, withdrawal, death, or unless otherwise indicated by the study team or DRT (see 
Sections 6.7 and 6.8).  Note:  Subjects in cohort 3 of part 2 may be eligible to receive treatment 
with blinded investigational product in part 3 (see Sections 4.3 and 7.2).   
In part 1 and 2, panitumumab will be administered IV by infusion pump through a peripheral line 
or indwelling catheter using a nonpyrogenic, low protein binding 0.2- or 0.22-micron pore size 
in-line filter (obtained by each center) infusion set up over 60 minutes ± 15 minutes.  The infusion 
time should be extended to 90 minutes ± 15 minutes for doses higher than 1000 mg.    
Following completion of the panitumumab infusion and proper flushing of the infusion line, 
AMG 102 (part 1) or blinded investigational product (part 2) will be administered IV over 
60 minutes ± 15 minutes.  Filtration of diluted AMG 102 and AMG 479 is not required.   
If a dose of panitumumab and AMG 102 (part 1) or blinded investigational product (part 2) is well 
tolerated (ie, without any serious infusion-related reactions), then subsequent IV infusions may be 
administered over 30 minutes ± 10 minutes.   
These infusion times also apply to blinded investigational product (ie, AMG 102 or AMG 479) in 
part 3. 
AMG 102 (part 1) and blinded investigational product (part 2) must be stored frozen protected 
from light at a freezer set point of -30°C or -70°C.  Panitumumab must be stored between 2-8°C 
and protected from direct sunlight.   
Control Group:  In part 2, panitumumab will serve as control group.  There will be no control 
group in part 1 or 3. 
Procedures:   
Screening will occur within 35 days before enrollment/randomization. 
During screening, archived paraffin-embedded tumor tissue block or unstained tumor slides will 
be submitted to the central laboratory along with the corresponding pathology report for 
evaluation of KRAS tumor status (wild-type or mutant).  Only subjects with confirmed wild-type 
KRAS tumor status will be eligible for this study (see Section 7.5.1.1).  It is extremely important 
that adequate samples are sent to the central laboratory early in the 35 day screening period to 
allow the central laboratory time to process and analyze the samples, and report the results to the 
study center. 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
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Screening and on-study assessments will be performed such as physical exam, vital signs, 
ECOG, ECG (screening only), and CT or MRI scans of the chest, abdomen, and pelvis. 
Screening and on-study local laboratory tests will be performed including hematology, chemistry, 
carcinoembryonic antigen (CEA, glycosylated hemoglobin (HgbA1c), thyroid stimulating hormone 
(TSH), and urine or serum pregnancy (for women of child-bearing potential). 
During the study, blood samples will be collected for antibody formation, biomarker, and PK 
analyses and submitted to the central laboratory.  Subjects enrolled in part 1 will undergo more 
frequent blood sample collection for PK during weeks 5 – 6.  This will require 4 extra visits. 
During the study, CT or MRI scans of the chest, abdomen, pelvis and all other sites of disease  
will be performed at week 8 (+ 1 week window) and within ± 1 week at weeks 12, 16, 24, 32, 40, 
and 48, and every 12 weeks thereafter until radiographic disease progression or the subject 
begins another anti-cancer treatment. 
Statistical Considerations: Tolerability of AMG 102 in combination of panitumumab will be 
assessed in part 1 based on the subject incidence of DLTs.  A subject will be considered DLT 
evaluable if the subject has received at least 2 doses of panitumumab and AMG 102 as 
scheduled (ie, Week 1 and 3) and has a minimum 4 week (28 days) follow-up for safety or has 
received at lease 1 dose of panitumumab and AMG 102 and has a DLT within the first 4 weeks 
(28 days) on study.   
Overall safety will be evaluated throughout the study including all enrolled subjects who receive at 
least 1 dose of investigational product (Safety Analysis Set).  Efficacy will be evaluated on 
subjects with wild-type KRAS in the Safety Analysis Set.  The primary analysis for the ORR will 
included all enrolled subjects in part 2 in the Safety Analysis set with measurable disease at 
baseline.   
The primary analysis of efficacy in part 2 will include data 24 weeks after the last subject is 
enrolled in part 2.  ORR will be analyzed based on Bayesian methodology.  Historical ORRs from 
4 previous panitumumab trials combined with the response outcome from cohort 3 of the study 
will provide a posterior distribution for the overall panitumumab monotherapy ORR.  A 
combination regimen may be considered promising and possibly warrant further evaluation in a 
larger subsequent study if the posterior probability that the odds ratio (ie, combination versus 
panitumumab alone) is greater than 1 is ≥ 0.90.  Likewise, a combination may not be considered 
promising if the posterior probability that the odds ratio is greater than 1 is ≤ 0.50.   
The primary analysis for part 3 will include data 24 weeks after the last subject is enrolled in 
part 3.   
Final safety and efficacy analyses will include data 24 months after the last subject is enrolled in 
part 2 or in part 3, whichever occurs last.  
Analyses will be separated by parts 1, 2 and 3. 
Sponsor/Licensee:  Amgen Inc. 
 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
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Study Design and Treatment Schema 
 
 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
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15. 
APPENDICES  
Appendix A.  Schedule of Assessments (Part 1 and Part 2) 
 
Screening 
Week 
Study Proceduresa 
-35 
days 
-7 
days 
1 
2 
3 
4 
5 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Hour (D = day) 
 
 
 
 
 
 
D1 
24 
D2 
48 
D3 
96 
D5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Collection windowk 
 
 
 
 
 
 
 
± 4 hrs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent & eligibility review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
Xe 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, height, weight & ECOGb 
Xe 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECGc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of AEs,SAEs,conmedsd 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Hematology 
 
Xe 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
  Chemistryg 
 
Xe 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
  HgbA1c 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
  TSH 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
  CEA 
 
Xe 
 
 
 
 
 
 
 
 
 
 
Xf 
 
 
 
X 
 
 
 
X 
 
 
 
 
  Urine/Serum Pregnancy (-3 days)f 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory Sample Collectionh 
  Tumor Tissuei 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  PK (Part 1)j 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  PK (Part 2)k 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  Biomarker 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product 
Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review dose adjustment criteriam 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product admin.m 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI-Chest, Abdomen, & Pelvis 
Xe 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
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Appendix A.  Schedule of Assessments (continued) 
(Part 1 and Part 2) 
 
Study Proceduresa 
Week 
 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
General Assessments 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, 
& conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsf 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Central Laboratory Sample Collectionh 
   PK (Part 1)j  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
   PK (Part 2)k 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
   Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Investigational Product Administration 
Review dose 
adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product 
administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsn 
CT/MRI - Chest, 
Abdomen, & Pelvis 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Investigator 
Assessment of Tumor 
Response 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
Page 114 of 174 
 
 
CONFIDENTIAL 
A
 ®
 
Appendix A.  Schedule of Assessments (continued) 
(Part 1 and Part 2) 
 
Study Proceduresa 
Week 49 until Radiographic Disease Progression 
Visits repeated every 12 weeks 
(unless otherwise indicated) 
30-Day 
Safety 
Follow-
up Visit 
(+3 day 
window) 
60-Day 
Follow-
up Visit 
(+14 
day 
window) 
LTFU 
(± 28 
day 
window) 
End of 
Studyq 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
11 12
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Review inclusion criteria for part 3 (see 
Section 4.3 & Appendix B) o 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
 
 
 
Local Laboratory Testsf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
   Chemistryg 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Central Laboratory Samplesh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   PK (Part 1)j  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
   PK (Part 2)k  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
   Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
   Antibodieslp 
 
 
 
 
 
 
 
 
 
 
 
X 
Xl 
Xl 
Xp 
 
Investigational Product Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review dose adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Investigational product administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Radiological Assessmentsn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI of Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
Page 115 of 174 
 
 
CONFIDENTIAL 
A
 ®
 
Appendix B.  Schedule of Assessments (Part 3) 
 
Study Proceduresa 
Qualification 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion criteria for part 3 
(see Section 4.3) 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind in IVRS 
Note: only eligible subjects may be randomized in 
part 3 (see Section 7.2) 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   HgbA1c 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA 
X 
 
 
 
 
 
 
 
Xf 
 
 
 
X 
 
 
 
X 
 
 
 
 
Central Laboratory Testsh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Biomarker 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
   Antibodieslp 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review dose adjustment criteriam 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product administrationm 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI - Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Investigator Assessment of Tumor Response 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
Page 116 of 174 
 
 
CONFIDENTIAL 
A
 ®
 
Appendix B.  Schedule of Assessments (continued) 
(Part 3) 
 
Study Proceduresa 
Week 
 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
General Assessments 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, 
& conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsf 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Central Laboratory Sample Collectionh 
   Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Investigational Product Administration 
Review dose 
adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product 
administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsn 
CT/MRI - Chest, 
Abdomen, & Pelvis 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Investigator 
Assessment of Tumor 
Response 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  22 April 2008 
 
Page 117 of 174 
 
 
CONFIDENTIAL 
A
 ®
 
 
Appendix B.  Schedule of Assessments (continued) 
(Part 3) 
 
 
Study Proceduresa 
Week 49 until Radiographic Disease Progression 
Visits repeated every 12 weeks 
(unless otherwise indicated) 
30-Day 
Safety 
Follow-
up Visit 
(+3 day 
window) 
60-Day 
Follow-
up Visit 
(+14 
day 
window) 
LTFU 
(± 28 
day 
window) 
End of 
Studyq 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Local Laboratory Testsf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
   Chemistryg 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Central Laboratory Samplesh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
   Antibodieslp 
 
 
 
 
 
 
 
 
 
 
 
X 
Xl 
Xl 
Xp 
 
Investigational Product Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review dose adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Investigational product administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Radiological Assessmentsn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI - Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 


Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date: 22 April 2008 
 
Page 118 of 174 
 
 
CONFIDENTIAL 
A
 ®
 
Appendix A & B.  Schedule of Assessments Footnotes 
a. Study Procedures.  All treatment procedures must be performed within ± 3 days of the planned visit. 
b. Vital signs, PE, Height, Weight, ECOG.  Vital signs will include BP, resting pulse, respiration rate, and temp.  Height 
will be collected at screening.  See Appendix E for ECOG scale.  For part 3, only ECOG is required at qualification. 
c. ECG.  A 12-lead ECG will be performed at screening and should include HR, QRS, QT, QTc, and PR intervals. 
d. AEs, SAEs, and Concomitant Medications.  AEs, SAEs, and con-meds should be reviewed at each study visit.  
Details including the start and stop dates of all AEs, SAEs, and con-meds will be recorded on the eCRF.  All SAEs 
should be reported to Amgen within 24 hours.  See Section 9 for details. 
e. Standard of Care.  Vitals, PE, ECOG, hematology, chemistry, CEA, pregnancy test, and CT or MRI scans of the chest, 
abdomen, and pelvis will be considered standard of care and may be performed before consent.  However, for 
screening and baseline purposes, they must be performed within the timeframes specified (Section 7.1).   
f. Local Laboratory Analytes.  See Section 7, Table 7-1 for a complete list of laboratory analytes.  The screening 
hematology and chemistry performed ≤ 7 days before enrollment will be used as baseline.  Urine or serum pregnancy 
test must be completed ≤ 3 days before enrollment/randomization.  Blood samples will be collected before each dose of 
investigational product.  The blood samples may be collected up to 3 days before the dose of investigational product as 
long as they are collected no moare than 3 days before the planned visit. 
g. Chemistry.  Glucose (non-fasting) is included as part of the chemistry assessment.  A fasting glucose will replace the 
glucose assessment at screening, weeks 3, 5, 11, 17, and 23. 
h. Central Laboratory Assessments.  Refer to the central laboratory manual(s) provided separately for instructions on 
the collection, processing, and shipment of samples.   
i. Tumor Tissue.  During screening, colorectal tumor tissue (paraffin-embedded block or unstained slides) collected prior 
to enrollment will be submitted to the central laboratory along with the associated pathology report(s) for eligibility 
determination of the subjects KRAS tumor status (ie, wild-type or mutant).  Only subjects with wild-type KRAS tumor 
status will be eligible.  These samples will also be used for exploratory biomarker development (see Section 7.5). 
j. PK Assessments (Part 1).  Subjects enrolled in part 1 will undergo more intensive PK blood sample collection during 
weeks 5 through 6.  This will require 4 extra visits.  For all subjects enrolled in part 1, PK samples will be collected pre-
panitumumab infusion and post-AMG 102 infusion (± 5 min. after end of infusion) at weeks 1, 5, 6, 7, 13, 23, 47, and 
every 6 months thereafter during treatment.  During week 5, PK samples will be collected at week 5, hours 24 (day 2), 
48 (day 3), and 96 (day 5) post-AMG 102 infusion.  A PK sample will also be collected at the 30-day and 60-day follow-
up visit(s).  Note: If a subject is receiving only one of the two investigational products on a day PK is collected, then a 
pre-and post-infusion blood sample will be collected. 
k. PK Assessments (Part 2).  PK samples will be collected pre-panitumumab infusion and post-AMG 102, AMG 479, or 
placebo infusion (± 5 min. after end of infusion) at weeks 1, 3, 5, 7, 13, 23, 47, and every 6 months thereafter during 
treatment.  A PK sample will also be collected at the 30-day and 60-day follow-up visit(s). Note: If a subject is receiving 
only one of the two investigational products on a day PK is collected, then a pre-and post-infusion blood sample will be 
collected. 
l. Antibody Samples.  Antibody samples will be collected at weeks 1, 7, 23, 47, and every 6 months thereafter during 
treatment, and at the 30-day and 60-day follow-up visits.  If the last antibody sample taken after the last dose of 
investigational product (ie, the 30-day safety follow-up or 60-day follow-up) is positive for HAPA or positive for 
neutralizing human anti-AMG 102 or anti-AMG 479 antibodies, then additional antibody samples will be collected at 
each 3 month LTFU visit (see Section 7.4).  Note: subjects treated on cohort 3 in part 2 that go onto receive treatment 
in part 3, will be tested for HAPA at the 30-day safety follow-up for part 3. 
m. Investigational Product Administration.  Investigational product must be administered after all other study 
procedures (eg, laboratory sample collection), unless otherwise specified (eg, post-dose PK).  After the first dose of 
investigational product, each subject will be assessed for dose adjustments (see Section 6).  The Q2W schedule of all 
subsequent doses will be planned according to study day 1 or within ± 3 days of the planned dose. 
n. Radiological Assessments.  A CT or MRI of the chest, abdomen, pelvis, and all other sites of disease will be 
performed at weeks 8 (+1 week) and within +/- 1 week at weeks 12, 16, 24, 32, 40, and 48, and every 12 weeks 
thereafter until radiographic disease progression or the subject begins another treatment.  Subjects with symptoms 
suggestive of disease progression will be evaluated for tumor response at the time symptoms occur.  The same 
modality of imaging used at screening should be used throughout the study for direct comparison.  Radiological images 
performed as standard of care ≤ 35 days before enrollment may be used for screening purposes.  All assessments will 
be made by the investigator using modified RECIST (see Appendix F).  Subjects with a complete response or partial 
response will have confirmatory radiological images performed no less than 4 weeks (28 days) after the criteria for 
response are first met.  See footnote p below for LTFU imaging requirements. 
o. Inclusion Criteria for Part 3.  Subjects initially randomized in part 2 that meet the criteria outlined in Section 4.3 may 
be unblinded to determine their treatment assignment in part 2.  Subjects assigned to Cohort 3 may be further 
randomized in part 3.  The first dose of blinded investigational product (ie, AMG 102 or AMG 479) must be administered 
≥ 2 weeks, but ≤ 5 weeks (2 to 5 weeks) after the last dose of panitumumab received in part 2.  The first dose of part 3 
investigational product must be received ≤ 3 days after randomization in part 3.  See Sections 4.3 and 7.2, and 
Appendix B. 
p. LTFU.  After the 30-day safety follow-up visit, subjects will be followed for radiographic disease progression (if not 
documented previously) and survival every 3 months (± 28 day window) beginning after the 30-day safety follow-up and 
continuing for up to 2 years after the last subject is randomized in part 2 or 3, whichever occurs last (see Section 7.4 for 
details).  See footnote l for additional information related to follow-up for positive antibodies to panitumumab, AMG 102, 
or AMG 479. 
q. End of Study.  The end of study will occur after the subject completes the LTFU
q, withdraws consent from the study, or 
death occurs. 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  09 February 2010 
Page 1 of 153 
 
 
CONFIDENTIAL 
A
 ®
 
Title:  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 
Panitumumab / AMG 102 / AMG 479 
 
Amgen Protocol Number 20060447 
 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive  
Thousand Oaks, CA 91320-1799 
United States 
Tel:  +1 805-447-1000 
Fax:  +1 805-480-0614 
Key Sponsor Contact (US): 
Shanna Stout 
Clinical Research Study Manager 
Tel:  +1 805-447-8580 
Fax:  +1 805-480-1291 
Key Sponsor Contact  
(US and Europe): 
Dominic Smethurst 
Medical Director 
1 Sanderson Road  
Uxbridge Business Park 
London 
UB81DH 
Tel:  +44 1895 525364 
Fax:  +44 1895 525112  
Date: 
22 April 2008 
Amendment 1 Date: 
09 February 2010 
EudraCT Number: 
2008-001751-21 
 
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:  +1 800-77-AMGEN (for US sites) or  
+1 800-772-6436 (for all other countries).  For all other study-related questions, continue 
to contact the Key Sponsor Contact. 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  09 February 2010 
Page 2 of 153 
 
 
CONFIDENTIAL 
A
 ®
 
Investigator’s Agreement 
I have read the attached protocol entitled 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, dated 09 February 2010, 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 FDA regulations/guidelines set forth 
21 CFR Parts 11, 50, 54, 56, and 312 and other 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:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  09 February 2010 
Page 3 of 153 
 
 
CONFIDENTIAL 
A
 ®
 
Protocol Synopsis 
Title:  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  
Study Phase:  1b/2 
Indication:  wild-type KRAS metastatic colorectal cancer 
This protocol consists of 3 parts.  Part 1 is the dose finding phase 1b portion of the study.  
Enrollment in part 1 was closed as of 04 May 2009.  Part 2 is the phase 2, randomized, 
3-cohort portion of the study.  Enrollment in part 2 was closed as of 05 February 2010. Part 3 
is an extension of the phase 2 (part 2) in which select subjects from part 2 may continue 
treatment in 1 of 2 cohorts.  Throughout this protocol synopsis, the various portions of the study 
will be referred to as part 1, 2, or 3. 
Primary Objective:   
Part 1:  To identify a tolerable dose of AMG 102 in combination with panitumumab based on the 
incidence of dose-limiting toxicities (DLTs).  [Note: Enrollment in part 1 is now complete and a 
dose of AMG 102 (ie, 10 mg/kg) in combination with panitumumab has been identified for 
use in part 2.  See Section 2.5.3 for additional information on dose selected.  The 
information for part 1 remains throughout this protocol for reference only]. 
Part 2:  To evaluate the efficacy as assessed by the overall objective response rate (ORR) of 
AMG 102 (tolerable dose selected from part 1) in combination with panitumumab and AMG 479 in 
combination with panitumumab versus panitumumab alone 
Secondary Objective(s):  
Part 1: 
 
• 
To evaluate the safety of AMG 102 in combination with panitumumab 
• 
Pharmacokinetics (PK) exposure of AMG 102 and panitumumab when given in 
combination 
Part 2:   
• 
To evaluate the safety and efficacy of AMG 102 (tolerable dose selected from part 1) in 
combination with panitumumab and AMG 479 in combination with panitumumab versus 
panitumumab alone 
• 
PK exposure of AMG 102 and panitumumab when given in combination 
• 
PK exposure of AMG 479 and panitumumab when given in combination 
• 
PK exposure of panitumumab when given alone 
Exploratory Objective(s):   
The exploratory objectives will include, but will not be limited to the following:  
Part 1:   
• 
To evaluate the efficacy of AMG 102 in combination with panitumumab 
Part 3:   
• 
To evaluate the safety and efficacy of AMG 102 and AMG 479 monotherapy following 
treatment with panitumumab (cohort 3) in part 2 
• 
Pharmacodynamic response of AMG 102 as assessed by hepatocyte growth factor/c-Met 
(HGF/c-Met), pathway markers, tumor apoptosis markers, angiogenic cytokines, and 
other biomarkers (Part 1, 2, and 3) 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  09 February 2010 
Page 4 of 153 
 
 
CONFIDENTIAL 
A
 ®
 
• 
Pharmacodynamic response of AMG 479 as assessed by insulin-like growth factor-1 
(IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), and growth hormone 
(Part 2 and 3) 
• 
Correlation between plasma HGF levels or tumor ribonucleic acid (RNA) expression, and 
tumor response (Parts 1, 2, and 3) 
• 
Effects of tumor genetic variation in pathway genes, cancer genes, drug target genes, 
and other biomarker genes on subject response to investigational product  (Parts 1, 2, 
and 3) 
• 
Effect of genetic variation in cancer genes, drug target genes, drug metabolism genes, 
and other biomarker genes on subject response to investigational product on a subset of 
subjects.  Separate pharmacogenetic informed consent required. (Parts 1, 2, and 3) 
Hypotheses:   
Part 1:  Treatment with AMG 102 in combination with panitumumab will be safe and well 
tolerated.  
Part 2:  Treatment with AMG 102 or AMG 479 in combination with panitumumab will exhibit a 
greater ORR with acceptable safety than treatment with panitumumab alone.   
Part 3:  Hypothesis forming exploratory work will be undertaken to evaluate safety and efficacy 
among those subjects in part 2 that go on to receive AMG 102 or AMG 479 monotherapy in 
part 3. 
Study Design:  This is a global, multicenter, open-label phase 1b and randomized, 
double-blinded 2-part phase 2 study designed to evaluate the safety and efficacy of AMG 102 or 
AMG 479 in combination with panitumumab versus panitumumab alone in mCRC subjects with 
wild-type KRAS tumor status.   
Panitumumab will be open-label throughout the study (parts 1 and 2).   
Investigational product will be administered every 2 weeks.   
Part 1: 
In part 1, approximately 6 to 18 subjects (6 to 9 subjects at each dose level of AMG 102 
evaluated in combination with panitumumab) will be enrolled to receive open-label AMG 102 in 
combination with panitumumab with the purpose of identifying a tolerable dose of AMG 102 for 
the part 2 portion of the study.   
AMG 102 10 mg/kg will be the starting dose evaluated in combination with panitumumab 6 mg/kg.  
Dose de-escalation of AMG 102 to 5 mg/kg will take place if determined necessary by the study 
team based on the interim safety analysis and incidence of DLTs.  The dose of AMG 102 that is 
determined tolerable in combination with panitumumab in part 1 will be the selected dose used in 
part 2.   
Subjects enrolled in part 1 will not be eligible for randomization in part 2. 
Part 2: 
Panitumumab will be open-label.  AMG 102, AMG 479, and placebo will be blinded and will be 
referred to as blinded investigational product.  In part 2, approximately 126 subjects will be 
randomized in a ratio of 1:1:1 to 1 of the following 3 double-blinded treatment groups.  The 
randomization will be stratified for prior chemotherapy regimen received in the metastatic setting: 
irinotecan or oxaliplatin vs both.  
Cohort 1:   panitumumab 6 mg/kg and AMG 102 10 mg/kg (the tolerable dose selected from 
part 1 was 10 mg/kg)   
Cohort 2:   panitumumab 6 mg/kg and AMG 479 12 mg/kg   
Cohort 3:   panitumumab 6 mg/kg 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  09 February 2010 
Page 5 of 153 
 
 
CONFIDENTIAL 
A
 ®
 
Subjects randomized to cohort 3 of part 2 may be eligible to receive treatment with blinded 
investigational product in part 3 (see below). 
Part 3: 
Upon radiographic disease progression per modified RECIST v1.0, clinical progression, or 
intolerability to all investigational products, subjects that meet the criteria outlined in protocol 
Section 4.3 may be unblinded via the IVRS by the investigator or designated study staff to 
determine treatment assignment.  Subjects randomized to cohort 3 (ie, panitumumab) of part 2 
may be further randomized in part 3 in a ratio of 1:1 to 1 of the following 2 double-blinded 
treatment groups.  The randomization will be stratified for reason for panitumumab 
discontinuation in part 2: disease progression (radiographic or clinical) versus intolerability. 
Cohort 3a: AMG 102 10 mg/kg  
Cohort 3b: AMG 479 12 mg/kg  
The dose of AMG 102 (ie, 10 mg/kg) in part 3 will not be affected by the outcome of the interim 
safety analysis in part 1. 
Investigational product will be administered every 2 weeks (Q2W) until disease progression, 
intolerability, withdrawal, death, or unless otherwise indicated by the study team (see 
investigational product administration details below). 
All subjects that permanently discontinue all investigational products will complete a safety 
follow-up visit 30 days (+3 day window) and a follow-up visit 60 days (+14 day window) after the 
last dose of investigational product.   
Subjects will be followed for radiographic disease progression (if not documented previously) and 
survival in the long-term follow-up portion of the study every 3 months (± 28 day window) after the 
30 day safety follow up visit for up to 2 years after the last subject is enrolled in part 2. 
 
Primary and Secondary Endpoints:   
Primary Endpoints:   
Part 1:  Subject incidence of DLTs 
Part 2:  Overall ORR 
Secondary Endpoints:  
Part 2:   
• 
Duration of response 
• 
Time to response 
• 
Disease control 
• 
Progression-free survival  
• 
On-treatment progression-free-survival 
• 
Overall survival 
• 
Incidence of all AEs and clinical laboratory abnormalities 
• 
Incidence of antibody formation to panitumumab, AMG 102, and AMG 479 
• 
Cmin, Cmax, and AUC for panitumumab and AMG 102 (Part 1) 
• 
Cmin and Cmax for panitumumab, AMG 102, and AMG 479 (Part 2) 
 


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Sample Size: 
Part 1:  Approximately 6 to 18 subjects (n = 6 to 9 per dose level of AMG 102 evaluated in 
combination with panitumumab). 
Part 2:  Approximately 126 subjects (n = 42 per cohort) 
Part 3:  Subjects from cohort 3 of part 2 will cross over to part 3 (n = 42) 
Summary of Subject Eligibility Criteria:   
Key Inclusion Criteria (Parts 1 and 2) 
• 
Man or woman ≥ 18 years of age 
• 
A life expectancy estimate of ≥ 3 months 
• 
ECOG 0 or 1 
• 
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or 
rectum  
• 
Wild-type KRAS tumor status of archival tumor tissue confirmed by an Amgen 
approved central laboratory or an experienced laboratory (local laboratory) per 
local regulatory guidelines using a validated test method 
• 
Radiographic evidence of disease progression during or following prior treatment with 
irinotecan and/or oxaliplatin based chemotherapy for mCRC  
• 
At least 1 uni-dimensionally measurable lesion ≥ 20 mm (CT or MRI) or ≥ 10 mm (spiral 
CT) in 1 dimension per modified RECIST v1.0  
• 
Adequate hematology, renal, and hepatic function (see Section 4.1.3) 
• 
Magnesium ≥ lower limit of normal 
• 
Subjects with known diabetes (Type 1 or 2) must have adequate glycemic function, as 
follows: 
- 
Must be controlled with a glycosylated hemoglobin (HgbA1c) of < 8.0% 
- 
Documented fasting blood sugars < 160 mg/dL 
Key Exclusion Criteria (Parts 1 and 2) 
• 
Prior treatment with anti-EGFr inhibitors (eg, panitumumab, cetuximab, erlotinib, 
gefitinib), unless treatment was received in the adjuvant setting ≥ 6 months before 
enrollment 
• 
Prior treatment with c-Met, IGF-IR, or IGF-IIR inhibitors 
• 
Prior treatment with either AMG 102 or AMG 479 
• 
Use of experimental or approved systemic chemotherapy or radiotherapy ≤ 21 days 
before enrollment 
• 
Use of experimental or approved targeted therapies ≤ 30 days before enrollment 
• 
History of prior or concurrent central nervous system (CNS) metastases 
• 
History of other primary cancer, unless: 
- 
Curatively resected non-melanomatous skin cancer 
- 
Curatively treated cervical carcinoma in situ 
- 
Other primary solid tumor treated with curative intent and no known active 
disease present for ≥ 5 years before enrollment 
• 
History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of 
interstitial lung disease on baseline chest computerized tomography (CT) scan 


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• 
Clinically significant cardiovascular disease (including myocardial infarction, unstable 
angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 
≤ 1 year before enrollment 
• 
Active inflammatory bowel disease or other active bowel disease causing chronic 
diarrhea (defined as ≥ grade 2 per CTCAE version 3.0) 
• 
Any co-morbid disease or condition that could increase the risk of toxicity (eg, significant 
ascites, significant pleural effusion) 
• 
Serious or non-healing wound ≤ 35 days before enrollment 
• 
Major surgical procedure ≤ 35 days before enrollment or minor surgical procedure 
≤ 14 days before enrollment.  Subjects must have recovered from surgery related 
toxicities.  Central venous catheter placement, fine needle aspiration, thoracocentesis, or 
paracentesis is not considered a major or minor surgical procedure. 
See protocol Section 4.3 for inclusion criteria for part 3. 
Investigational Product Dosage and Administration:   
Investigational product will be diluted in 0.9% sodium chloride.  Investigational product will be 
administered by IV infusion beginning on week 1 and continuing Q2W until disease progression, 
intolerability, withdrawal, death, or unless otherwise indicated by the study team or DRT (see 
Sections 6.7 and 6.8).  Note:  Subjects in cohort 3 of part 2 may be eligible to receive treatment 
with blinded investigational product in part 3 (see Sections 4.3 and 7.2).   
In part 1 and 2, panitumumab will be administered IV by infusion pump through a peripheral line 
or indwelling catheter using a nonpyrogenic, low protein binding 0.2- or 0.22-micron pore size 
in-line filter (obtained by each center) infusion set up over 60 minutes ± 15 minutes.  The infusion 
time should be extended to 90 minutes ± 15 minutes for doses higher than 1000 mg.  
Administration of panitumumab by methods other than infusion pump must be discussed 
and approved by Amgen prior to administration.  
Following completion of the panitumumab infusion and proper flushing of the infusion line, 
AMG 102 (part 1) or blinded investigational product (part 2) will be administered IV over 
60 minutes ± 15 minutes.  Filtration of diluted AMG 102 (part 1) and blinded investigational 
product (parts 2 and 3) is not required.   
If a dose of panitumumab and AMG 102 (part 1) or blinded investigational product (part 2) is well 
tolerated (ie, without any serious infusion-related reactions), then subsequent IV infusions may be 
administered over 30 minutes ± 10 minutes.   
These infusion times also apply to blinded investigational product (ie, AMG 102 or placebo, and 
AMG 479 or placebo) in part 3. 
AMG 102 (part 1) and blinded investigational product (parts 2 and 3) must be stored frozen 
protected from light at a freezer set point of -30°C or -70°C.  Panitumumab must be stored 
between 2°C to 8°C and protected from direct sunlight.   
Control Group:  In part 2, panitumumab will serve as control group.  There will be no control 
group in part 1 or 3. 
Procedures:   
Screening will occur within 35 days before enrollment/randomization (date informed consent 
form is signed to date of enrollment/randomization). 
Screening and on-study assessments will be performed such as physical exam, vital signs, 
ECOG, ECG (screening only), and CT or MRI scans of the chest, abdomen, and pelvis. 


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Only subjects with confirmed wild-type KRAS tumor status will be eligible for this study 
(see Section 4.1.1): 
• 
KRAS tumor status, for purposes of determining eligibility for this study, may be 
obtained through previously known KRAS tumor status, or local or central KRAS 
testing during study screening (see Section 7.1.1). 
• 
Regardless of how KRAS tumor status is obtained, archived formalin-fixed 
paraffin-embedded tumor tissue (block or unstained tumor slides) from the primary 
or metastatic site must be submitted to the central laboratory along with the 
associated pathology reports for other exploratory biomarker analyses and/or the 
evaluation of KRAS tumor status (if applicable) (see Section 7.2). 
Screening and on-study local laboratory tests will be performed including hematology, chemistry, 
carcinoembryonic antigen (CEA), glycosylated hemoglobin (HgbA1c), thyroid stimulating 
hormone (TSH), prothrombin time (PT)/international normalized ratio (INR), and urine or 
serum pregnancy (for women of child-bearing potential). 
During the study, blood samples will be collected for antibody formation, biomarker, and PK 
analyses and submitted to the central laboratory.  Subjects enrolled in part 1 will undergo more 
frequent blood sample collection for PK during weeks 5 to 6.  This will require 4 extra visits. 
During the study, CT or MRI scans of the chest, abdomen, pelvis and all other sites of disease  
will be performed at week 8 (+ 1 week window) and within ± 1 week at weeks 12, 16, 24, 32, 40, 
and 48, and every 12 weeks thereafter until radiographic disease progression or the subject 
begins another anti-cancer treatment. 
Statistical Considerations: Tolerability of AMG 102 in combination of panitumumab will be 
assessed in part 1 based on the subject incidence of DLTs.  A subject will be considered DLT 
evaluable if the subject has received at least 2 doses of panitumumab and AMG 102 as 
scheduled (ie, Week 1 and 3) and has a minimum 4 week (28 days) follow-up for safety or has 
received at lease 1 dose of panitumumab and AMG 102 and has a DLT within the first 4 weeks 
(28 days) on study.  See Section 2.5.3 for AMG 102 Dose Selected for Part 2. 
Overall safety will be evaluated throughout the study including all enrolled subjects who receive at 
least 1 dose of investigational product (Safety Analysis Set).  Efficacy will be evaluated on 
subjects in the Safety Analysis Set.  The primary analysis for the ORR will include all enrolled 
subjects in part 2 in the Safety Analysis set with measurable disease at baseline.   
The primary analysis for part 2 will occur after a minimum potential follow-up of 24 weeks 
after the last subject is randomized in part 2.  All other available data will be summarized.  
ORR will be analyzed based on Bayesian methodology.  Historical ORRs from 4 previous 
panitumumab trials combined with the response outcome from cohort 3 of the study will provide a 
posterior distribution for the overall panitumumab monotherapy ORR.  A combination regimen 
may be considered promising and possibly warrant further evaluation in a larger subsequent 
study if the posterior probability that the odds ratio (ie, combination versus panitumumab alone) is 
greater than 1 is ≥ 0.90.  Likewise, a combination may not be considered promising if the 
posterior probability that the odds ratio is greater than 1 is ≤ 0.50.   
Final analyses will include data 2 years after the last subject is randomized in part 2.  
Analyses will be separated by parts 1, 2 and 3. 
Sponsor/Licensee:  Amgen Inc. 


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Protocol Number:  20060447 
Date:  09 February 2010 
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Study Design and Treatment Schema 
 
 


 
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15. 
APPENDICES  
Appendix A.  Schedule of Assessments (Part 1 and Part 2) 
 
Screening 
Week 
Study Proceduresar 
-35 
days 
-7 
days 
1 
2
3 
4
5 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Hour (D = day) 
 
 
 
 
 
 
D1 
24 
D2 
48 
D3 
96 
D5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Collection windowk 
 
 
 
 
 
 
 
± 4 hrs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Assessmentsr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent & eligibility review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
Xe 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, height, weight & ECOGb 
Xe 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECGc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of AEs, SAEs, conmedsd 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsfr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Hematology 
 
Xe 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
  Chemistryg 
 
Xeg 
 
 
X 
 
Xg 
 
 
 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
  PT and INR (Part 2) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
  HgbA1c 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
  TSH 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
  CEA 
 
Xe 
 
 
 
 
 
 
 
 
 
 
Xf 
 
 
 
X 
 
 
 
X 
 
 
 
 
  Urine/Serum Pregnancy (-3 days)f 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory Sample Collectionhr 
  Tumor Tissuei 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  PK (Part 1)jf 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  PK (Part 2)kf 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  Biomarker 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product Administrationr 
Review dose adjustment criteriam 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product admin.m 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsnr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI-Chest, Abdomen, & Pelvis 
Xe 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 


 
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Protocol Number:  20060447 
Date:  09 February 2010 
Page 116 of 153 
 
 
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Appendix A.  Schedule of Assessments (continued) 
(Part 1 and Part 2) 
 
Study Proceduresar 
Week 
 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
General Assessmentsr 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, 
& conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsfr 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
   PT and INR (Part 2) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Central Laboratory Sample Collectionhr 
   PK (Part 1)jf  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
   PK (Part 2)kf 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
   Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Investigational Product Administrationr 
Review dose 
adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product 
administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsnr 
CT/MRI - Chest, 
Abdomen, & Pelvis 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Investigator 
Assessment of Tumor 
Response 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 


 
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Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  09 February 2010 
Page 117 of 153 
 
 
CONFIDENTIAL 
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Appendix A.  Schedule of Assessments (continued) 
(Part 1 and Part 2) 
 
Study Proceduresar 
Week 49 until Radiographic Disease Progression 
Visits repeated every 12 weeks 
(unless otherwise indicated) 
30-Day 
Safety 
Follow-
up Visit 
(+3 day 
window) 
60-Day 
Follow-
up Visit 
(+14 
day 
window) 
LTFU 
(± 28 
day 
window) 
End of 
Studyq 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
 
 
General Assessmentsr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Review inclusion criteria for part 3 (see 
Section 4.3 & Appendix B) o 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
 
 
 
Local Laboratory Testsfr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
 
 
   PT and INR (Part 2) 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Central Laboratory Sampleshr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   PK (Part 1)jf  
 
 
 
 
 
 
 
 
 
 
 
Xj 
X 
X 
 
 
   PK (Part 2)kf  
 
 
 
 
 
 
 
 
 
 
 
Xk 
X 
X 
 
 
   Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
   Antibodieslp 
 
 
 
 
 
 
 
 
 
 
 
X 
Xl 
Xl 
Xp 
 
Investigational Product Administrationr 
Review dose adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Investigational product administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Radiological Assessmentsnr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI of Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 


 
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Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  09 February 2010 
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Appendix B.  Schedule of Assessments (Part 3) 
 
Study Proceduresa 
Qualification 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion criteria for part 3 
(see Section 4.3) 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind in IVRS 
Note: only eligible subjects may be randomized 
in part 3 (see Section 7.2) 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
X 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
   PT and INR  
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
   HgbA1c 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA 
X 
 
 
 
 
 
 
 
Xf 
 
 
 
X 
 
 
 
X 
 
 
 
 
Central Laboratory Testsh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Biomarker 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
   Antibodieslp 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review dose adjustment criteriam 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product administrationm 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI - Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Investigator Assessment of Tumor Response 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 


 
Approved 
 
 
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Protocol Number:  20060447 
Date:  09 February 2010 
Page 119 of 153 
 
 
CONFIDENTIAL 
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Appendix B.  Schedule of Assessments (continued) 
(Part 3) 
 
Study Proceduresa 
Week 
 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
General Assessments 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, 
& conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsf 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
   PT and INR 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Central Laboratory Sample Collectionh 
   Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Investigational Product Administration 
Review dose 
adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product 
administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsn 
CT/MRI - Chest, 
Abdomen, & Pelvis 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Investigator 
Assessment of Tumor 
Response 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 


 
Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  09 February 2010 
Page 120 of 153 
 
 
CONFIDENTIAL 
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Appendix B.  Schedule of Assessments (continued) 
(Part 3) 
 
 
Study Proceduresar 
Week 49 until Radiographic Disease Progression 
Visits repeated every 12 weeks 
(unless otherwise indicated) 
30-Day 
Safety 
Follow-
up Visit 
(+3 day 
window) 
60-Day 
Follow-
up Visit 
(+14 
day 
window) 
LTFU 
(± 28 
day 
window) 
End of 
Studyq 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Local Laboratory Testsf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
   PT and INR 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Central Laboratory Sampleshr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
   Antibodieslp 
 
 
 
 
 
 
 
 
 
 
 
X 
Xl 
Xl 
Xp 
 
Investigational Product Administrationr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review dose adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Investigational product administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Radiological Assessmentsn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI - Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 
Footnotes for Appendices A & B are on the following pages 


 
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Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date: 09 February 2010 
Page 121 of 153 
 
 
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A
 ®
 
Appendix A & B.  Schedule of Assessments Footnotes 
a. Study Procedures.  All treatment procedures must be performed within ± 3 days of the planned visit. 
b. Vital signs, PE, Height, Weight, ECOG.  Vital signs will include BP, resting pulse, respiration rate, and temp.  Height will be collected at screening.  See Appendix 
E for ECOG scale.  For part 3, only ECOG is required at qualification. 
c. ECG.  A 12-lead ECG will be performed at screening and should include HR, QRS, QT, QTc, and PR intervals. 
d. AEs, SAEs, and Concomitant Medications.  AEs, SAEs, and con-meds should be reviewed at each study visit and recorded on the eCRF.  All SAEs should be 
reported to Amgen within 24 hours.  See Section 9 for details. 
e. Standard of Care.  Vitals, PE, ECOG, hematology, chemistry, CEA, pregnancy test, and CT or MRI scans of the chest, abdomen, and pelvis will be considered 
standard of care and may be performed before consent.  However, for screening and baseline purposes, they must be performed within the timeframes specified 
(Section 7.1).   
f. 
Local Laboratory Analytes.  See Section 7, Table 7-1 for a complete list of laboratory analytes.  The screening hematology and chemistry performed ≤ 7 days 
before enrollment will be used as baseline.  Urine or serum pregnancy test must be completed ≤ 3 days before enrollment/randomization.  Blood samples will be 
collected before each dose of investigational product, except for the post-infusion PK.  The blood samples may be collected ≤ 3 days before the dose of 
investigational product.  However, for PK, it is preferred that the pre-infusion blood samples are collected on the day of investigational product 
administration.    
g. Chemistry.  Glucose (non-fasting) is included as part of the chemistry assessment for all subjects.  For subjects in part 2 and 3, a fasting glucose will replace 
the glucose assessment at screening, weeks 5, 9, every 4 weeks thereafter, and at the 30-day safety follow-up visit.   
h. Central Laboratory Assessments.  Refer to the central laboratory manual(s) provided separately for instructions on the collection, processing, and shipment of 
tumor tissue, antibody, PK, and biomarker samples.   
i. 
Tumor Tissue.  During screening, archived formalin-fixed paraffin-embedded colorectal tumor tissue (block or unstained slides) from the primary or 
metastatic site collected prior to the study will be submitted to the central laboratory along with the associated pathology report for evaluation of KRAS tumor 
status, if applicable, EGFr membrane staining and/or other exploratory biomarker analyses (see Section 7.5).  See KRAS testing in Section 7.1.1 for 
additional information on KRAS testing. 
j. 
PK Assessments (Part 1).  Subjects enrolled in part 1 will undergo more intensive PK blood sample collection during weeks 5 through 6.  This will require 4 extra 
visits.  For all subjects enrolled in part 1, PK samples will be collected pre-panitumumab infusionf and post-AMG 102 infusion  
(± 5 min. after end of infusion) at weeks 1, 5, 7, 13, 23, 47, and every 6 months thereafter during treatment.  During week 5, PK samples will be collected at 
week 5, hours 24 (day 2), 48 (day 3), 96 (day 5), and 168 (day 8/week 6) post-end of AMG 102 infusion.  A PK sample will also be collected at the 30-day and  
60-day follow-up visit(s).  Note: If a subject is receiving only one of the two investigational products on a day PK is collected, then a pre-and post-infusion blood 
sample will be collected. 
k. PK Assessments (Part 2).  PK samples will be collected pre-panitumumab infusionf and post-blinded investigational product infusion (± 5 min. after end of 
infusion) at weeks 1, 3, 5, 7, 13, 23, 47, and every 6 months thereafter during treatment.  A PK sample will also be collected at the  
30-day and 60-day follow-up visit(s). Note: If a subject is receiving only one of the two investigational products on a day PK is collected, then a pre-and 
post-infusion blood sample will be collected. 


 
Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date: 09 February 2010 
Page 122 of 153 
 
 
CONFIDENTIAL 
A
 ®
 
l. 
Antibody Samples.  Antibody samples will be collected at weeks 1, 7, 23, 47, and every 6 months thereafter during treatment, and at the 30-day and 60-day 
follow-up visits.  See Section 7.4 for additional antibody assessments in LTFU for subjects with a positive or neutralizing positive antibody result.  Note: 
subjects treated on cohort 3 in part 2 that go onto receive treatment in part 3, will be tested for HAPA at the 30-day safety follow-up for part 3. 
m. Investigational Product Administration.  Investigational product must be administered after all other study procedures (eg, laboratory sample collection), unless 
otherwise specified (eg, post-dose PK).  After the first dose of investigational product, each subject will be assessed for dose adjustments (see Section 6).  The 
Q2W schedule of all subsequent doses will be planned according to study day 1 or within ± 3 days of the planned dose. 
n. Radiological Assessments.  A CT or MRI of the chest, abdomen, pelvis, and all other sites of disease will be performed at weeks 8 (+1 week) and within  
+/- 1 week at weeks 12, 16, 24, 32, 40, and 48, and every 12 weeks thereafter until radiographic disease progression or the subject begins another treatment.  
Subjects with symptoms suggestive of disease progression will be evaluated for tumor response at the time symptoms occur.  The same modality of imaging used 
at screening should be used throughout the study for direct comparison.  Radiological images performed as standard of care ≤ 35 days before enrollment may be 
used for screening purposes.  All assessments will be made by the investigator using modified RECIST v1.0 (see Appendix F).  Subjects with a complete response 
or partial response will have confirmatory radiological images performed no less than 4 weeks (28 days) after the criteria for response are first met.  See footnote p 
below for LTFU imaging requirements. 
o. Inclusion Criteria for Part 3.  Subjects initially randomized in part 2 that meet the criteria outlined in Section 4.3 may be unblinded to determine their treatment 
assignment in part 2.  Subjects assigned to Cohort 3 may be further randomized in part 3.  The first dose of blinded investigational product must be administered  
≥ 2 weeks, but ≤ 6 weeks (2 to 6 weeks) after the last dose of investigational product received in part 2.  Any exceptions to the first dose of blinded 
investigational product should be discussed with and approved by Amgen prior to implementation.  The first dose of part 3 investigational product must be 
received ≤ 3 days after randomization in part 3.  See Sections 4.3 and 7.2, and Appendix B. 
p. LTFU.  After the 30-day safety follow-up visit, subjects will be followed for radiographic disease progression (if not documented previously) and survival every  
3 months (± 28 day window) beginning after the 30-day safety follow-up and continuing for up to 2 years after the last subject is randomized in part 2 (see  
Section 7.4 for details).  See footnote l for additional information related to follow-up for positive antibodies to panitumumab, AMG 102, or  
AMG 479. 
q. End of Study (subject).  The end of study for each subject is defined as the date the subject withdraws consent from study, completes the LTFUp, or death. 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  06 April 2011 
Page 1 of 161 
 
Title:  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 
Panitumumab / AMG 102 / AMG 479 
 
Amgen Protocol Number 20060447 
 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive  
Thousand Oaks, CA 91320-1799 
United States 
Tel:  +1 805-447-1000 
Fax:  +1 805-480-0614 
Key Sponsor Contact (US): 
Dawn Boisvert 
Clinical Research Study Manager 
Tel:  +1 805-313-6416 
Fax:  +1 805-480-1291 
Key Sponsor Contact  
(US and Europe): 
Dominic Smethurst 
Medical Director 
1 Sanderson Road  
Uxbridge Business Park 
London 
UB81DH 
Tel:  +44 1895 525364 
Fax:  +44 1895 525112  
Date: 
22 April 2008 
Amendment 1 Date: 
09 February 2010 
Amendment 2 Date: 
06 April 2011 
EudraCT Number: 
2008-001751-21 
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:  +1 800-77-AMGEN (for US sites) or  
+1 800-772-6436 (for all other countries).  For all other study-related questions, continue 
to contact the Key Sponsor Contact. 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  06 April 2011 
Page 2 of 161 
 
Investigator’s Agreement 
I have read the attached protocol entitled 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, dated 06 April 2011, 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 FDA regulations/guidelines set forth 
21 CFR Parts 11, 50, 54, 56, and 312 and other 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:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  06 April 2011 
Page 3 of 161 
 
Protocol Synopsis 
Title:  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  
Study Phase:  1b/2 
Indication:  wild-type KRAS metastatic colorectal cancer 
This protocol consists of 3 parts.  Part 1 is the dose finding phase 1b portion of the study.  
Enrollment in part 1 was closed as of 04 May 2009.  Part 2 is the phase 2, randomized, 3-cohort 
portion of the study.  Enrollment in part 2 was closed as of 05 February 2010. Part 3 is an 
extension of the phase 2 (part 2) in which select subjects from part 2 may continue treatment in 1 
of 2 cohorts.  Throughout this protocol synopsis, the various portions of the study will be referred 
to as part 1, 2, or 3. 
Primary Objective:   
Part 1:  To identify a tolerable dose of AMG 102 in combination with panitumumab based on the 
incidence of dose-limiting toxicities (DLTs).  [Note: Enrollment in part 1 is now complete and a 
dose of AMG 102 (ie, 10 mg/kg) in combination with panitumumab has been identified for use in 
part 2.  See Section 2.5.3 for additional information on dose selected.  The information for part 1 
remains throughout this protocol for reference only]. 
Part 2:  To evaluate the efficacy as assessed by the overall objective response rate (ORR) of 
AMG 102 (tolerable dose selected from part 1) in combination with panitumumab and AMG 479 in 
combination with panitumumab versus panitumumab alone 
Secondary Objective(s):  
Part 1: 
 
• 
To evaluate the safety of AMG 102 in combination with panitumumab 
• 
Pharmacokinetics (PK) exposure of AMG 102 and panitumumab when given in 
combination 
Part 2:   
• 
To evaluate the safety and efficacy of AMG 102 (tolerable dose selected from part 1) in 
combination with panitumumab and AMG 479 in combination with panitumumab versus 
panitumumab alone 
• 
PK exposure of AMG 102 and panitumumab when given in combination 
• 
PK exposure of AMG 479 and panitumumab when given in combination 
• 
PK exposure of panitumumab when given alone 
Exploratory Objective(s):   
The exploratory objectives will include, but will not be limited to the following:  
Part 1:   
• 
To evaluate the efficacy of AMG 102 in combination with panitumumab 
Part 3:   
• 
To evaluate the safety and efficacy of AMG 102 and AMG 479 monotherapy following 
treatment with panitumumab (cohort 3) in part 2 
• 
Pharmacodynamic response of AMG 102 as assessed by hepatocyte growth factor/c-Met 
(HGF/c-Met), pathway markers, tumor apoptosis markers, angiogenic cytokines, and 
other biomarkers (Part 1, 2, and 3) 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  06 April 2011 
Page 4 of 161 
 
• 
Pharmacodynamic response of AMG 479 as assessed by insulin-like growth factor-1 
(IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), and growth hormone 
(Part 2 and 3) 
• 
Correlation between plasma HGF levels or tumor ribonucleic acid (RNA) expression, and 
tumor response (Parts 1, 2, and 3) 
• 
Effects of tumor genetic variation in pathway genes, cancer genes, drug target genes, 
and other biomarker genes on subject response to investigational product  (Parts 1, 2, 
and 3) 
• 
Effect of genetic variation in cancer genes, drug target genes, drug metabolism genes, 
and other biomarker genes on subject response to investigational product on a subset of 
subjects.  Separate pharmacogenetic informed consent required. (Parts 1, 2, and 3) 
Hypotheses:   
Part 1:  Treatment with AMG 102 in combination with panitumumab will be safe and well 
tolerated.  
Part 2:  Treatment with AMG 102 or AMG 479 in combination with panitumumab will exhibit a 
greater ORR with acceptable safety than treatment with panitumumab alone.   
Part 3:  Hypothesis forming exploratory work will be undertaken to evaluate safety and efficacy 
among those subjects in part 2 that go on to receive AMG 102 or AMG 479 monotherapy in 
part 3. 
Study Design:  This is a global, multicenter, open-label phase 1b and randomized, 
double-blinded 2-part phase 2 study designed to evaluate the safety and efficacy of AMG 102 or 
AMG 479 in combination with panitumumab versus panitumumab alone in mCRC subjects with 
wild-type KRAS tumor status.   
Panitumumab will be open-label throughout the study (parts 1 and 2).   
Investigational product will be administered every 2 weeks.   
Part 1: 
In part 1, approximately 6 to 18 subjects (6 to 9 subjects at each dose level of AMG 102 
evaluated in combination with panitumumab) will be enrolled to receive open-label AMG 102 in 
combination with panitumumab with the purpose of identifying a tolerable dose of AMG 102 for 
the part 2 portion of the study.   
AMG 102 10 mg/kg will be the starting dose evaluated in combination with panitumumab 6 mg/kg.  
Dose de-escalation of AMG 102 to 5 mg/kg will take place if determined necessary by the study 
team based on the interim safety analysis and incidence of DLTs.  The dose of AMG 102 that is 
determined tolerable in combination with panitumumab in part 1 will be the selected dose used in 
part 2.   
Subjects enrolled in part 1 will not be eligible for randomization in part 2. 
Part 2: 
Panitumumab will be open-label.  AMG 102, AMG 479, and placebo will be blinded and will be 
referred to as blinded investigational product.  In part 2, approximately 126 subjects will be 
randomized in a ratio of 1:1:1 to 1 of the following 3 double-blinded treatment groups.  The 
randomization will be stratified for prior chemotherapy regimen received in the metastatic setting: 
irinotecan or oxaliplatin vs both.  
Cohort 1:   panitumumab 6 mg/kg and AMG 102 10 mg/kg (the tolerable dose selected from 
part 1 was 10 mg/kg)   
Cohort 2:   panitumumab 6 mg/kg and AMG 479 12 mg/kg   
Cohort 3:   panitumumab 6 mg/kg 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  06 April 2011 
Page 5 of 161 
 
Subjects randomized to cohort 3 of part 2 may be eligible to receive treatment with blinded 
investigational product in part 3 (see below). 
Part 3: 
Upon radiographic disease progression per modified RECIST v1.0, clinical progression, or 
intolerability to all investigational products, subjects that meet the criteria outlined in protocol 
Section 4.3 may be unblinded via the IVRS by the investigator or designated study staff to 
determine treatment assignment.  Subjects randomized to cohort 3 (ie, panitumumab) of part 2 
may be further randomized in part 3 in a ratio of 1:1 to 1 of the following 2 double-blinded 
treatment groups.  The randomization will be stratified for reason for panitumumab 
discontinuation in part 2: disease progression (radiographic or clinical) versus intolerability. 
Cohort 3a: AMG 102 10 mg/kg  
Cohort 3b: AMG 479 12 mg/kg  
The dose of AMG 102 (ie, 10 mg/kg) in part 3 will not be affected by the outcome of the interim 
safety analysis in part 1. 
Investigational product will be administered every 2 weeks (Q2W) until disease progression, 
intolerability, withdrawal, death, or unless otherwise indicated by the study team (see 
investigational product administration details below). 
All subjects that permanently discontinue all investigational products will complete a safety 
follow-up visit 30 days (+3 day window) and a follow-up visit 60 days (+14 day window) after the 
last dose of investigational product.   
Subjects will be followed for radiographic disease progression (if not documented previously) and 
survival in the long-term follow-up portion of the study every 3 months (± 28 day window) after the 
30 day safety follow up visit for up to 2 years after the last subject is enrolled in part 2. 
 
Primary and Secondary Endpoints:   
Primary Endpoints:   
Part 1:  Subject incidence of DLTs 
Part 2:  Overall ORR 
Secondary Endpoints:  
Part 2:   
• 
Duration of response 
• 
Time to response 
• 
Disease control 
• 
Progression-free survival  
• 
On-treatment progression-free-survival 
• 
Overall survival 
• 
Incidence of all AEs and clinical laboratory abnormalities 
• 
Incidence of antibody formation to panitumumab, AMG 102, and AMG 479 
• 
Cmin, Cmax, and AUC for panitumumab and AMG 102 (Part 1) 
• 
Cmin and Cmax for panitumumab, AMG 102, and AMG 479 (Part 2) 
 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  06 April 2011 
Page 6 of 161 
 
Sample Size: 
Part 1:  Approximately 6 to 18 subjects (n = 6 to 9 per dose level of AMG 102 evaluated in 
combination with panitumumab). 
Part 2:  Approximately 126 subjects (n = 42 per cohort) 
Part 3:  Subjects from cohort 3 of part 2 will cross over to part 3 (n = 42) 
Summary of Subject Eligibility Criteria:   
Key Inclusion Criteria (Parts 1 and 2) 
• 
Man or woman ≥ 18 years of age 
• 
A life expectancy estimate of ≥ 3 months 
• 
ECOG 0 or 1 
• 
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or 
rectum  
• 
Wild-type KRAS tumor status of archival tumor tissue confirmed by an Amgen approved 
central laboratory or an experienced laboratory (local laboratory) per local regulatory 
guidelines using a validated test method 
• 
Radiographic evidence of disease progression during or following prior treatment with 
irinotecan and/or oxaliplatin based chemotherapy for mCRC  
• 
At least 1 uni-dimensionally measurable lesion ≥ 20 mm (CT or MRI) or ≥ 10 mm (spiral 
CT) in 1 dimension per modified RECIST v1.0  
• 
Adequate hematology, renal, and hepatic function (see Section 4.1.3) 
• 
Magnesium ≥ lower limit of normal 
• 
Subjects with known diabetes (Type 1 or 2) must have adequate glycemic function, as 
follows: 
- 
Must be controlled with a glycosylated hemoglobin (HgbA1c) of < 8.0% 
- 
Documented fasting blood sugars < 160 mg/dL 
Key Exclusion Criteria (Parts 1 and 2) 
• 
Prior treatment with anti-EGFr inhibitors (eg, panitumumab, cetuximab, erlotinib, 
gefitinib), unless treatment was received in the adjuvant setting ≥ 6 months before 
enrollment 
• 
Prior treatment with c-Met, IGF-IR, or IGF-IIR inhibitors 
• 
Prior treatment with either AMG 102 or AMG 479 
• 
Use of experimental or approved systemic chemotherapy or radiotherapy ≤ 21 days 
before enrollment 
• 
Use of experimental or approved targeted therapies ≤ 30 days before enrollment 
• 
History of prior or concurrent central nervous system (CNS) metastases 
• 
History of other primary cancer, unless: 
- 
Curatively resected non-melanomatous skin cancer 
- 
Curatively treated cervical carcinoma in situ 
- 
Other primary solid tumor treated with curative intent and no known active 
disease present for ≥ 5 years before enrollment 
• 
History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of 
interstitial lung disease on baseline chest computerized tomography (CT) scan 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  06 April 2011 
Page 7 of 161 
 
• 
Clinically significant cardiovascular disease (including myocardial infarction, unstable 
angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 
≤ 1 year before enrollment 
• 
Active inflammatory bowel disease or other active bowel disease causing chronic 
diarrhea (defined as ≥ grade 2 per CTCAE version 3.0) 
• 
Any co-morbid disease or condition that could increase the risk of toxicity (eg, significant 
ascites, significant pleural effusion) 
• 
Serious or non-healing wound ≤ 35 days before enrollment 
• 
Major surgical procedure ≤ 35 days before enrollment or minor surgical procedure 
≤ 14 days before enrollment.  Subjects must have recovered from surgery related 
toxicities.  Central venous catheter placement, fine needle aspiration, thoracocentesis, or 
paracentesis is not considered a major or minor surgical procedure. 
See protocol Section 4.3 for inclusion criteria for part 3. 
Investigational Product Dosage and Administration:   
Investigational product will be diluted in 0.9% sodium chloride.  Investigational product will be 
administered by IV infusion beginning on week 1 and continuing Q2W until disease progression, 
intolerability, withdrawal, death, or unless otherwise indicated by the study team or DRT (see 
Sections 6.7 and 6.8).  Note:  Subjects in cohort 3 of part 2 may be eligible to receive treatment 
with blinded investigational product in part 3 (see Sections 4.3 and 7.2).   
In parts 1 and 2, panitumumab will be administered IV by infusion pump through a peripheral line 
or indwelling catheter using a nonpyrogenic, low protein binding 0.2- or 0.22-micron pore size 
in-line filter (obtained by each center) infusion set up over 60 minutes ± 15 minutes.  The infusion 
time should be extended to 90 minutes ± 15 minutes for doses higher than 1000 mg.  
Administration of panitumumab by methods other than infusion pump must be discussed and 
approved by Amgen prior to administration.  
In parts 2 and 3, the blinded investigational product (AMG 102, AMG 479, and placebo) will 
be administered IV 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 (obtained by each 
center) infusion set-up. 
Following completion of the panitumumab infusion and proper flushing of the infusion line, 
AMG 102 (part 1) or blinded investigational product (part 2) will be administered IV over 
60 minutes ± 15 minutes.     
If a dose of panitumumab and AMG 102 (part 1) or blinded investigational product (part 2) is well 
tolerated (ie, without any serious infusion-related reactions), then subsequent IV infusions may be 
administered over 30 minutes ± 10 minutes.   
These infusion times also apply to blinded investigational product (ie, AMG 102 or placebo, and 
AMG 479 or placebo) in part 3. 
AMG 102 (part 1) and blinded investigational product (parts 2 and 3) must be stored frozen 
protected from light at a freezer set point of -30°C or -70°C.  Panitumumab must be stored 
between 2°C to 8°C and protected from direct sunlight.   
Control Group:  In part 2, panitumumab will serve as control group.  There will be no control 
group in part 1 or 3. 
Procedures:   
Screening will occur within 35 days before enrollment/randomization (date informed consent form 
is signed to date of enrollment/randomization). 
Screening and on-study assessments will be performed such as physical exam, vital signs, 
ECOG, ECG (screening only), and CT or MRI scans of the chest, abdomen, and pelvis. 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  06 April 2011 
Page 8 of 161 
 
Only subjects with confirmed wild-type KRAS tumor status will be eligible for this study (see 
Section 4.1.1): 
• 
KRAS tumor status, for purposes of determining eligibility for this study, may be obtained 
through previously known KRAS tumor status, or local or central KRAS testing during 
study screening (see Section 7.1.1). 
• 
Regardless of how KRAS tumor status is obtained, archived formalin-fixed paraffin-
embedded tumor tissue (block or unstained tumor slides) from the primary or metastatic 
site must be submitted to the central laboratory along with the associated pathology 
reports for other exploratory biomarker analyses and/or the evaluation of KRAS tumor 
status (if applicable) (see Section 7.2). 
Screening and on-study local laboratory tests will be performed including hematology, chemistry, 
carcinoembryonic antigen (CEA), glycosylated hemoglobin (HgbA1c), thyroid stimulating 
hormone (TSH), prothrombin time (PT)/international normalized ratio (INR), and urine or serum 
pregnancy (for women of child-bearing potential). 
During the study, blood samples will be collected for antibody formation, biomarker, and PK 
analyses and submitted to the central laboratory.  Subjects enrolled in part 1 will undergo more 
frequent blood sample collection for PK during weeks 5 to 6.  This will require 4 extra visits. 
During the study, CT or MRI scans of the chest, abdomen, pelvis and all other sites of disease  
will be performed at week 8 (+ 1 week window) and within ± 1 week at weeks 12, 16, 24, 32, 40, 
and 48, and every 12 weeks thereafter until radiographic disease progression or the subject 
begins another anti-cancer treatment. 
Statistical Considerations: Tolerability of AMG 102 in combination of panitumumab will be 
assessed in part 1 based on the subject incidence of DLTs.  A subject will be considered DLT 
evaluable if the subject has received at least 2 doses of panitumumab and AMG 102 as 
scheduled (ie, Week 1 and 3) and has a minimum 4 week (28 days) follow-up for safety or has 
received at lease 1 dose of panitumumab and AMG 102 and has a DLT within the first 4 weeks 
(28 days) on study.  See Section 2.5.3 for AMG 102 Dose Selected for Part 2. 
Overall safety will be evaluated throughout the study including all enrolled subjects who receive at 
least 1 dose of investigational product (Safety Analysis Set).  Efficacy will be evaluated on 
subjects in the Safety Analysis Set.  The primary analysis for the ORR will include all enrolled 
subjects in part 2 in the Safety Analysis set with measurable disease at baseline.   
The primary analysis for part 2 will occur after a minimum potential follow-up of 24 weeks after 
the last subject is randomized in part 2.  All other available data will be summarized.  ORR will be 
analyzed based on Bayesian methodology.  Historical ORRs from 4 previous panitumumab trials 
combined with the response outcome from cohort 3 of the study will provide a posterior 
distribution for the overall panitumumab monotherapy ORR.  A combination regimen may be 
considered promising and possibly warrant further evaluation in a larger subsequent study if the 
posterior probability that the odds ratio (ie, combination versus panitumumab alone) is greater 
than 1 is ≥ 0.90.  Likewise, a combination may not be considered promising if the posterior 
probability that the odds ratio is greater than 1 is ≤ 0.50.   
Final analyses will include data 2 years after the last subject is randomized in part 2.  
Analyses will be separated by parts 1, 2 and 3. 
Sponsor/Licensee:  Amgen Inc. 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479
Protocol Number:  20060447
Date:  06 April 2011
Page 9 of 161
Study Design and Treatment Schema
 
S
C
R
E
E
N
E
N
R
O
L
L
Panitumumab 6 mg/kg
+
AMG 102 10 mg/kg (start)
n = 6 to 9
Panitumumab 6 mg/kg
+
AMG 102 5 mg/kg
n = 6 to 9
PART 1 (OPEN-LABEL DOSE FINDING)
n = 6 to 18
PART 2 (PARTIALLY BLINDED*)
n = 126
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
1:1:1
COHORT 1 (n=42)
Panitumumab 6 mg/kg
+
AMG 102 10 mg/kg (dose selected from part 1)
COHORT 2 (n=42)
Panitumumab 6 mg/kg
+
AMG 479 12 mg/kg
COHORT 3 (n=42)
Panitumumab 6 mg/kg
P
R
O
G
R
E
S
S
I
V
E
D
I
S
E
A
S
E
(PD)
PART 3 (DOUBLE-BLINDED)
n = 42 (from cohort 3 of part 2)
Q
U
A
L
I
F
Y
R
A
N
D
O
M
I
Z
E
1:1
COHORT 3a (n=21)
AMG 102 10 mg/kg
COHORT 3b (n=21)
AMG 479 12 mg/kg
P
D
30-
Day
and
60-
Day
F
O
L
L
O
W
U
P
V
I
S
I
T
S
L
O
N
G
T
E
R
M
F
O
L
L
O
W
U
P
*In part 2, panitumumab will be open-label and AMG 102, AMG 479, and placebo will be double-blinded.
Tolerable AMG 102 dose selected from part 1 
was 10 mg/kg


 
Approved 
 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  06 April 2011 
Page 116 of 161 
 
15. 
APPENDICES  
Appendix A.  Schedule of Assessments (Part 1 and Part 2) 
 
Screening 
Week 
Study Proceduresar 
-35 
days 
-7 
days 
1 
2 
3 
4 
5 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Hour (D = day) 
 
 
 
 
 
 
D1 
24 
D2 
48 
D3 
96 
D5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Collection windowk 
 
 
 
 
 
 
 
± 4 hrs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Assessmentsr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent & eligibility review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
Xe 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, height, weight & ECOGb 
Xe 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECGc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of AEs, SAEs, conmedsd 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsfr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Hematology 
 
Xe 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
  Chemistryg 
 
Xeg 
 
 
X 
 
Xg 
 
 
 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
  PT and INR (Part 2) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
  HgbA1c 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
  TSH 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
  CEA 
 
Xe 
 
 
 
 
 
 
 
 
 
 
Xf 
 
 
 
X 
 
 
 
X 
 
 
 
 
  Urine/Serum Pregnancy (-3 days)f 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory Sample Collectionhr 
  Tumor Tissuei 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  PK (Part 1)jf 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  PK (Part 2)kf 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  Biomarker 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product Administrationr 
Review dose adjustment criteriam 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product admin.m 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsnr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI-Chest, Abdomen, & Pelvis 
Xe 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 


 
Approved 
 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date: 06 April 2011 
Page 117 of 161 
 
Appendix A.  Schedule of Assessments (continued) 
(Part 1 and Part 2) 
Study Proceduresar 
Week 
 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
General Assessmentsr 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, 
& conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsfr 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
   PT and INR (Part 2) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Central Laboratory Sample Collectionhr 
   PK (Part 1)jf  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
   PK (Part 2)kf 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
   Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Investigational Product Administrationr 
Review dose 
adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product 
administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsnr 
CT/MRI - Chest, 
Abdomen, & Pelvis 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Investigator 
Assessment of Tumor 
Response 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 


 
Approved 
 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date: 06 April 2011 
Page 118 of 161 
 
Appendix A.  Schedule of Assessments (continued) 
(Part 1 and Part 2) 
Study Proceduresar 
Week 49 until Radiographic Disease Progression 
Visits repeated every 12 weeks 
(unless otherwise indicated) 
30-Day 
Safety 
Follow-
up Visit 
(+3 day 
window) 
60-Day 
Follow-
up Visit 
(+14 
day 
window) 
LTFU 
(± 28 
day 
window) 
End of 
Studyq 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
 
 
General Assessmentsr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Review inclusion criteria for part 3 (see 
Section 4.3 & Appendix B) o 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
 
 
 
Local Laboratory Testsfr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
 
 
   PT and INR (Part 2) 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Central Laboratory Sampleshr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   PK (Part 1)jf  
 
 
 
 
 
 
 
 
 
 
 
Xj 
X 
X 
 
 
   PK (Part 2)kf  
 
 
 
 
 
 
 
 
 
 
 
Xk 
X 
X 
 
 
   Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
   Antibodieslp 
 
 
 
 
 
 
 
 
 
 
 
X 
Xl 
Xl 
Xp 
 
Investigational Product Administrationr 
Review dose adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Investigational product administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Radiological Assessmentsnr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI of Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 


 
Approved 
 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date: 06 April 2011 
Page 119 of 161 
 
Appendix B.  Schedule of Assessments (Part 3) 
 
Study Proceduresa 
Qualification 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion criteria for part 3 
(see Section 4.3) 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind in IVRS 
Note: only eligible subjects may be randomized 
in part 3 (see Section 7.2) 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
X 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
   PT and INR  
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
   HgbA1c 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA 
X 
 
 
 
 
 
 
 
Xf 
 
 
 
X 
 
 
 
X 
 
 
 
 
Central Laboratory Testsh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Biomarker 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
   Antibodieslp 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review dose adjustment criteriam 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product administrationm 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI - Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Investigator Assessment of Tumor Response 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 


 
Approved 
 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date: 06 April 2011 
Page 120 of 161 
 
Appendix B.  Schedule of Assessments (continued) 
(Part 3) 
Study Proceduresa 
Week 
 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
General Assessments 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, 
& conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsf 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
   PT and INR 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Central Laboratory Sample Collectionh 
   Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Investigational Product Administration 
Review dose 
adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Investigational product 
administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsn 
CT/MRI - Chest, 
Abdomen, & Pelvis 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Investigator 
Assessment of Tumor 
Response 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 


 
Approved 
 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date: 06 April 2011 
Page 121 of 161 
 
Appendix B.  Schedule of Assessments (continued) 
(Part 3) 
Study Proceduresar 
Week 49 until Radiographic Disease Progression 
Visits repeated every 12 weeks 
(unless otherwise indicated) 
30-Day 
Safety 
Follow-
up Visit 
(+3 day 
window) 
60-Day 
Follow-
up Visit 
(+14 
day 
window) 
LTFU 
(± 28 
day 
window) 
End of 
Studyq 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Local Laboratory Testsf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
   PT and INR 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Central Laboratory Sampleshr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
   Antibodieslp 
 
 
 
 
 
 
 
 
 
 
 
X 
Xl 
Xl 
Xp 
 
Investigational Product Administrationr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review dose adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Investigational product administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Radiological Assessmentsn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI - Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 
Footnotes for Appendices A & B are on the following pages 


 
Approved 
 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date: 06 April 2011 
Page 122 of 161 
 
Appendix A & B.  Schedule of Assessments Footnotes 
a. Study Procedures.  All treatment procedures must be performed within ± 3 days of the planned visit. 
b. Vital signs, PE, Height, Weight, ECOG.  Vital signs will include BP, resting pulse, respiration rate, and temp.  Height will be collected at screening.  See Appendix 
E for ECOG scale.  For part 3, only ECOG is required at qualification. 
c. ECG.  A 12-lead ECG will be performed at screening and should include HR, QRS, QT, QTc, and PR intervals. 
d. AEs, SAEs, and Concomitant Medications.  AEs, SAEs, and con-meds should be reviewed at each study visit and recorded on the eCRF.  All SAEs should be 
reported to Amgen within 24 hours.  See Section 9 for details. 
e. Standard of Care.  Vitals, PE, ECOG, hematology, chemistry, CEA, pregnancy test, and CT or MRI scans of the chest, abdomen, and pelvis will be considered 
standard of care and may be performed before consent.  However, for screening and baseline purposes, they must be performed within the timeframes specified 
(Section 7.1).   
f. 
Local Laboratory Analytes.  See Section 7, Table 7-1 for a complete list of laboratory analytes.  The screening hematology and chemistry performed ≤ 7 days 
before enrollment will be used as baseline.  Urine or serum pregnancy test must be completed ≤ 3 days before enrollment/randomization.  Blood samples will be 
collected before each dose of investigational product, except for the post-infusion PK.  The blood samples may be collected ≤ 3 days before the dose of 
investigational product.  However, for PK, it is preferred that the pre-infusion blood samples are collected on the day of investigational product administration.    
g. Chemistry.  Glucose (non-fasting) is included as part of the chemistry assessment for all subjects.  For subjects in part 2 and 3, a fasting glucose will replace the 
glucose assessment at screening, weeks 5, 9, every 4 weeks thereafter, and at the 30-day safety follow-up visit.   
h. Central Laboratory Assessments.  Refer to the central laboratory manual(s) provided separately for instructions on the collection, processing, and shipment of 
tumor tissue, antibody, PK, and biomarker samples.   
i. 
Tumor Tissue.  During screening, archived formalin-fixed paraffin-embedded colorectal tumor tissue (block or unstained slides) from the primary or metastatic site 
collected prior to the study will be submitted to the central laboratory along with the associated pathology report for evaluation of KRAS tumor status, if applicable, 
EGFr membrane staining and/or other exploratory biomarker analyses (see Section 7.5).  See KRAS testing in Section 7.1.1 for additional information on KRAS 
testing. 
j. 
PK Assessments (Part 1).  Subjects enrolled in part 1 will undergo more intensive PK blood sample collection during weeks 5 through 6.  This will require 4 extra 
visits.  For all subjects enrolled in part 1, PK samples will be collected pre-panitumumab infusionf and post-AMG 102 infusion  
(± 5 min. after end of infusion) at weeks 1, 5, 7, 13, 23, 47, and every 6 months thereafter during treatment.  During week 5, PK samples will be collected at 
week 5, hours 24 (day 2), 48 (day 3), 96 (day 5), and 168 (day 8/week 6) post-end of AMG 102 infusion.  A PK sample will also be collected at the 30-day and  
60-day follow-up visit(s).  Note: If a subject is receiving only one of the two investigational products on a day PK is collected, then a pre-and post-infusion blood 
sample will be collected. 
k. PK Assessments (Part 2).  PK samples will be collected pre-panitumumab infusionf and post-blinded investigational product infusion (± 5 min. after end of 
infusion) at weeks 1, 3, 5, 7, 13, 23, 47, and every 6 months thereafter during treatment.  A PK sample will also be collected at the  
30-day and 60-day follow-up visit(s). Note: If a subject is receiving only one of the two investigational products on a day PK is collected, then a pre-and 
post-infusion blood sample will be collected. 


 
Approved 
 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date: 06 April 2011 
Page 123 of 161 
 
l. 
Antibody Samples.  Antibody samples will be collected at weeks 1, 7, 23, 47, and every 6 months thereafter during treatment, and at the 30-day and 60-day 
follow-up visits.  See Section 7.4 for additional antibody assessments in LTFU for subjects with a positive or neutralizing positive antibody result.  Note: subjects 
treated on cohort 3 in part 2 that go onto receive treatment in part 3, will be tested for HAPA at the 30-day safety follow-up for part 3. 
m. Investigational Product Administration.  Investigational product must be administered after all other study procedures (eg, laboratory sample collection), unless 
otherwise specified (eg, post-dose PK).  After the first dose of investigational product, each subject will be assessed for dose adjustments (see Section 6).  The 
Q2W schedule of all subsequent doses will be planned according to study day 1 or within ± 3 days of the planned dose. 
n. Radiological Assessments.  A CT or MRI of the chest, abdomen, pelvis, and all other sites of disease will be performed at weeks 8 (+1 week) and within  
+/- 1 week at weeks 12, 16, 24, 32, 40, and 48, and every 12 weeks thereafter until radiographic disease progression or the subject begins another treatment.  
Subjects with symptoms suggestive of disease progression will be evaluated for tumor response at the time symptoms occur.  The same modality of imaging used 
at screening should be used throughout the study for direct comparison.  Radiological images performed as standard of care ≤ 35 days before enrollment may be 
used for screening purposes.  All assessments will be made by the investigator using modified RECIST v1.0 (see Appendix F).  Subjects with a complete response 
or partial response will have confirmatory radiological images performed no less than 4 weeks (28 days) after the criteria for response are first met.  See footnote p 
below for LTFU imaging requirements. 
o. Inclusion Criteria for Part 3.  Subjects initially randomized in part 2 that meet the criteria outlined in Section 4.3 may be unblinded to determine their treatment 
assignment in part 2.  Subjects assigned to Cohort 3 may be further randomized in part 3.  The first dose of blinded investigational product must be administered  
≥ 2 weeks, but ≤ 6 weeks (2 to 6 weeks) after the last dose of investigational product received in part 2.  Any exceptions to the first dose of blinded investigational 
product should be discussed with and approved by Amgen prior to implementation.  The first dose of part 3 investigational product must be received ≤ 3 days after 
randomization in part 3.  See Sections 4.3 and 7.2, and Appendix B. 
p. LTFU.  After the 30-day safety follow-up visit, subjects will be followed for radiographic disease progression (if not documented previously) and survival every  
3 months (± 28 day window) beginning after the 30-day safety follow-up and continuing for up to 2 years after the last subject is randomized in part 2 (see  
Section 7.4 for details).  See footnote l for additional information related to follow-up for positive antibodies to panitumumab, AMG 102, or  
AMG 479. 
q. End of Study (subject).  The end of study for each subject is defined as the date the subject withdraws consent from study, completes the LTFUp, or death. 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 1 of 159 
 
Title:  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 
Panitumumab / AMG 102 / AMG 479 
Amgen Protocol Number 20060447 
 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive  
Thousand Oaks, CA 91320-1799 
United States 
Tel:  +1 805-447-1000 
Fax:  +1 805-480-0614 
Key Sponsor Contact (US and 
Europe): 
Gosia Orywal-Sykes 
Clinical Research Senior Manager 
Tel:  +44 1895 525472 
Fax: +44 1895 525101 
Key Sponsor Contact  
(US and Europe): 
Stephan Braun, MD, PhD 
Medical Director 
Dammstrasse 23, Opus 105 
6301 Zug 
Switzerland 
Tel:  +41 41 2692 549 
Fax:  +41 41 3690 405  
Date: 
22 April 2008 
Amendment 1 Date: 
09 February 2010 
Amendment 2 Date: 
06 April 2011 
Superseding Amendment 2 Date: 
12 December 2012 
Amendment 3 Date: 
17 June 2013 
EudraCT Number: 
2008-001751-21 
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:  +1 800-77-AMGEN (for US sites) or  
+1 800-772-6436 (for all other countries).  For all other study-related questions, continue 
to contact the Key Sponsor Contact. 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 2 of 159 
 
Investigator’s Agreement 
I have read the attached protocol entitled 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, dated 17 June 2013, 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 FDA regulations/guidelines set forth 
21 CFR Parts 11, 50, 54, 56, and 312 and other 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:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 3 of 159 
 
Protocol Synopsis 
Title:  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  
Study Phase:  1b/2 
Indication:  wild-type KRAS metastatic colorectal cancer 
This protocol consists of 3 parts.  Part 1 is the dose finding phase 1b portion of the study.  
Enrollment in part 1 was closed as of 04 May 2009.  Part 2 is the phase 2, randomized, 3-cohort 
portion of the study.  Enrollment in part 2 was closed as of 05 February 2010. Part 3 is an 
extension of the phase 2 (part 2) in which select subjects from part 2 may continue treatment in 
1 of 2 cohorts.  Throughout this protocol synopsis, the various portions of the study will be 
referred to as part 1, 2, or 3. 
Primary Objective:   
Part 1:  To identify a tolerable dose of AMG 102 in combination with panitumumab based on the 
incidence of dose-limiting toxicities (DLTs).  [Note: Enrollment in part 1 is now complete and a 
dose of AMG 102 (ie, 10 mg/kg) in combination with panitumumab has been identified for use in 
part 2.  See Section 2.5.3 for additional information on dose selected.  The information for part 1 
remains throughout this protocol for reference only]. 
Part 2:  To evaluate the efficacy as assessed by the overall objective response rate (ORR) of 
AMG 102 (tolerable dose selected from part 1) in combination with panitumumab and AMG 479 in 
combination with panitumumab versus panitumumab alone 
Secondary Objective(s):  
Part 1: 
 
• 
To evaluate the safety of AMG 102 in combination with panitumumab 
• 
Pharmacokinetics (PK) exposure of AMG 102 and panitumumab when given in combination 
Part 2:   
• 
To evaluate the safety and efficacy of AMG 102 (tolerable dose selected from part 1) in 
combination with panitumumab and AMG 479 in combination with panitumumab versus 
panitumumab alone 
• 
PK exposure of AMG 102 and panitumumab when given in combination 
• 
PK exposure of AMG 479 and panitumumab when given in combination 
• 
PK exposure of panitumumab when given alone 
Exploratory Objective(s):   
The exploratory objectives will include, but will not be limited to the following:  
Part 1:   
• 
To evaluate the efficacy of AMG 102 in combination with panitumumab 
Part 3:   
• 
To evaluate the safety and efficacy of AMG 102 and AMG 479 monotherapy following 
treatment with panitumumab (cohort 3) in part 2 
• 
Pharmacodynamic response of AMG 102 as assessed by hepatocyte growth factor/c-Met 
(HGF/c-Met), pathway markers, tumor apoptosis markers, angiogenic cytokines, and other 
biomarkers (Part 1, 2, and 3) 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 4 of 159 
 
• 
Pharmacodynamic response of AMG 479 as assessed by insulin-like growth factor-1 (IGF-1), 
insulin-like growth factor binding protein-3 (IGFBP-3), and growth hormone (Part 2 and 3) 
• 
Correlation between plasma HGF levels or tumor ribonucleic acid (RNA) expression, and 
tumor response (Parts 1, 2, and 3) 
• 
Effects of tumor genetic variation in pathway genes, cancer genes, drug target genes, and 
other biomarker genes on subject response to investigational product  (Parts 1, 2, and 3) 
• 
Effect of genetic variation in cancer genes, drug target genes, drug metabolism genes, and 
other biomarker genes on subject response to investigational product on a subset of subjects.  
Separate pharmacogenetic informed consent required. (Parts 1, 2, and 3) 
Hypotheses:   
Part 1:  Treatment with AMG 102 in combination with panitumumab will be safe and well 
tolerated.  
Part 2:  Treatment with AMG 102 or AMG 479 in combination with panitumumab will exhibit a 
greater ORR with acceptable safety than treatment with panitumumab alone.   
Part 3:  Hypothesis forming exploratory work will be undertaken to evaluate safety and efficacy 
among those subjects in part 2 that go on to receive AMG 102 or AMG 479 monotherapy in 
part 3. 
Study Design:  This is a global, multicenter, open-label phase 1b and randomized, 
double-blinded 2-part phase 2 study designed to evaluate the safety and efficacy of AMG 102 or 
AMG 479 in combination with panitumumab versus panitumumab alone in mCRC subjects with 
wild-type KRAS tumor status.   
Panitumumab will be open-label throughout the study (parts 1 and 2).   
Investigational product will be administered every 2 weeks.   
Part 1: 
In part 1, approximately 6 to 18 subjects (6 to 9 subjects at each dose level of AMG 102 
evaluated in combination with panitumumab) will be enrolled to receive open-label AMG 102 in 
combination with panitumumab with the purpose of identifying a tolerable dose of AMG 102 for 
the part 2 portion of the study.   
AMG 102 10 mg/kg will be the starting dose evaluated in combination with panitumumab 6 mg/kg.  
Dose de-escalation of AMG 102 to 5 mg/kg will take place if determined necessary by the study 
team based on the interim safety analysis and incidence of DLTs.  The dose of AMG 102 that is 
determined tolerable in combination with panitumumab in part 1 will be the selected dose used in 
part 2.   
Subjects enrolled in part 1 will not be eligible for randomization in part 2. 
Part 2: 
Panitumumab will be open-label.  AMG 102, AMG 479, and placebo will be blinded and will be 
referred to as blinded investigational product.  In part 2, approximately 126 subjects will be 
randomized in a ratio of 1:1:1 to 1 of the following 3 double-blinded treatment groups.  The 
randomization will be stratified for prior chemotherapy regimen received in the metastatic setting: 
irinotecan or oxaliplatin vs both.  
Cohort 1:   panitumumab 6 mg/kg and AMG 102 10 mg/kg (the tolerable dose selected from 
part 1 was 10 mg/kg)   
Cohort 2:   panitumumab 6 mg/kg and AMG 479 12 mg/kg   
Cohort 3:   panitumumab 6 mg/kg 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 5 of 159 
 
Subjects randomized to cohort 3 of part 2 may be eligible to receive treatment with blinded 
investigational product in part 3 (see below). 
Part 3: 
Upon radiographic disease progression per modified RECIST v1.0, clinical progression, or 
intolerability to all investigational products, subjects that meet the criteria outlined in protocol 
Section 4.3 may be unblinded via the IVRS by the investigator or designated study staff to 
determine treatment assignment.  Subjects randomized to cohort 3 (ie, panitumumab) of part 2 
may be further randomized in part 3 in a ratio of 1:1 to 1 of the following 2 double-blinded 
treatment groups.  The randomization will be stratified for reason for panitumumab 
discontinuation in part 2: disease progression (radiographic or clinical) versus intolerability. 
Cohort 3a: AMG 102 10 mg/kg  
Cohort 3b: AMG 479 12 mg/kg  
The dose of AMG 102 (ie, 10 mg/kg) in part 3 will not be affected by the outcome of the interim 
safety analysis in part 1. 
Investigational product will be administered every 2 weeks (Q2W) until disease progression, 
intolerability, withdrawal, death, or unless otherwise indicated by the study team 
(see investigational product administration details below). 
All subjects that permanently discontinue all investigational products will complete a safety 
follow-up visit 30 days (+3 day window) and a follow-up visit 60 days (+14 day window) after the 
last dose of investigational product.   
Subjects will be followed for radiographic disease progression (if not documented previously) and 
survival in the long-term follow-up portion of the study every 3 months (± 28 day window) after the 
30 day safety follow up visit for up to 2 years after the last subject is enrolled in part 2. 
The subject treatment assignments in parts 2 and 3 will be unblinded after the planned 
data snapshot of the final analysis has been completed.  Subjects receiving placebo will 
discontinue placebo administration and, in the absence of disease progression or 
unacceptable toxicities, may continue to receive investigational product (panitumumab 
AMG 102, or AMG 479, if applicable), Q2W at the investigator’s discretion until disease 
progression, withdrawal of consent, death, or unless otherwise indicated by the study 
team.  Data collection during this period will be limited to investigational product 
administration and serious adverse event reporting (see Section 9.3).  Other 
protocol-specified procedures and observations outlined in the Sections 7.1 through 7.6 
and Schedule of Assessments (Appendices A and B), including blood samples and 
radiographic tumor imaging, will not be collected.  However, the investigator, at his or her 
discretion, may continue to perform the procedures and observations outlined in the 
Section 7 and Schedule of Assessments per local institution standard of care. 
Primary and Secondary Endpoints:   
Primary Endpoints:   
Part 1:  Subject incidence of DLTs 
Part 2:  Overall ORR 
Secondary Endpoints:  
Part 2:   
• 
Duration of response 
• 
Time to response 
• 
Disease control 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 6 of 159 
 
• 
Progression-free survival  
• 
On-treatment progression-free-survival 
• 
Overall survival 
• 
Incidence of all AEs and clinical laboratory abnormalities 
• 
Incidence of antibody formation to panitumumab, AMG 102, and AMG 479 
• 
Cmin, Cmax, and AUC for panitumumab and AMG 102 (Part 1) 
• 
Cmin and Cmax for panitumumab, AMG 102, and AMG 479 (Part 2) 
Sample Size: 
Part 1:  Approximately 6 to 18 subjects (n = 6 to 9 per dose level of AMG 102 evaluated in 
combination with panitumumab). 
Part 2:  Approximately 126 subjects (n = 42 per cohort) 
Part 3:  Subjects from cohort 3 of part 2 will cross over to part 3 (n = 42) 
Summary of Subject Eligibility Criteria:   
Key Inclusion Criteria (Parts 1 and 2) 
• 
Man or woman ≥ 18 years of age 
• 
A life expectancy estimate of ≥ 3 months 
• 
ECOG 0 or 1 
• 
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum  
• 
Wild-type KRAS tumor status of archival tumor tissue confirmed by an Amgen approved 
central laboratory or an experienced laboratory (local laboratory) per local regulatory 
guidelines using a validated test method 
• 
Radiographic evidence of disease progression during or following prior treatment with 
irinotecan and/or oxaliplatin based chemotherapy for mCRC  
• 
At least 1 uni-dimensionally measurable lesion ≥ 20 mm (CT or MRI) or ≥ 10 mm (spiral CT) 
in 1 dimension per modified RECIST v1.0  
• 
Adequate hematology, renal, and hepatic function (see Section 4.1.3) 
• 
Magnesium ≥ lower limit of normal 
• 
Subjects with known diabetes (Type 1 or 2) must have adequate glycemic function, as 
follows: 
- 
Must be controlled with a glycosylated hemoglobin (HgbA1c) of < 8.0% 
- 
Documented fasting blood sugars < 160 mg/dL 
Key Exclusion Criteria (Parts 1 and 2) 
• 
Prior treatment with anti-EGFr inhibitors (eg, panitumumab, cetuximab, erlotinib, gefitinib), 
unless treatment was received in the adjuvant setting ≥ 6 months before enrollment 
• 
Prior treatment with c-Met, IGF-IR, or IGF-IIR inhibitors 
• 
Prior treatment with either AMG 102 or AMG 479 
• 
Use of experimental or approved systemic chemotherapy or radiotherapy ≤ 21 days before 
enrollment 
• 
Use of experimental or approved targeted therapies ≤ 30 days before enrollment 
• 
History of prior or concurrent central nervous system (CNS) metastases 
• 
History of other primary cancer, unless: 
- 
Curatively resected non-melanomatous skin cancer 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 7 of 159 
 
- 
Curatively treated cervical carcinoma in situ 
- 
Other primary solid tumor treated with curative intent and no known active 
disease present for ≥ 5 years before enrollment 
• 
History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of 
interstitial lung disease on baseline chest computerized tomography (CT) scan 
• 
Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, 
symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year 
before enrollment 
• 
Active inflammatory bowel disease or other active bowel disease causing chronic diarrhea 
(defined as ≥ grade 2 per CTCAE version 3.0) 
• 
Any co-morbid disease or condition that could increase the risk of toxicity (eg, significant 
ascites, significant pleural effusion) 
• 
Serious or non-healing wound ≤ 35 days before enrollment 
• 
Major surgical procedure ≤ 35 days before enrollment or minor surgical procedure ≤ 14 days 
before enrollment.  Subjects must have recovered from surgery related toxicities.  Central 
venous catheter placement, fine needle aspiration, thoracocentesis, or paracentesis is not 
considered a major or minor surgical procedure. 
See protocol Section 4.3 for inclusion criteria for part 3. 
Investigational Product Dosage and Administration:   
Investigational product will be diluted in 0.9% sodium chloride.  Investigational product will be 
administered by IV infusion beginning on week 1 and continuing Q2W until disease progression, 
intolerability, withdrawal, death, or unless otherwise indicated by the study team or DRT 
(see Sections 6.7 and 6.8).  Note:  Subjects in cohort 3 of part 2 may be eligible to receive 
treatment with blinded investigational product in part 3 (see Sections 4.3 and 7.2).   
In parts 1 and 2, panitumumab will be administered IV by infusion pump through a peripheral line 
or indwelling catheter using a nonpyrogenic, low protein binding 0.2- or 0.22-micron pore size 
in-line filter (obtained by each center) infusion set up over 60 minutes ± 15 minutes.  The infusion 
time should be extended to 90 minutes ± 15 minutes for doses higher than 1000 mg.  
Administration of panitumumab by methods other than infusion pump must be discussed and 
approved by Amgen prior to administration.  
In parts 2 and 3, the blinded investigational product (AMG 102, AMG 479, and placebo) will be 
administered IV 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 (obtained by each center) infusion 
set-up. 
Following completion of the panitumumab infusion and proper flushing of the infusion line, 
AMG 102 (part 1) or blinded investigational product (part 2) will be administered IV over 
60 minutes ± 15 minutes.     
If a dose of panitumumab and AMG 102 (part 1) or blinded investigational product (part 2) is well 
tolerated (ie, without any serious infusion-related reactions), then subsequent IV infusions may be 
administered over 30 minutes ± 10 minutes.   
These infusion times also apply to blinded investigational product (ie, AMG 102 or placebo, and 
AMG 479 or placebo) in part 3. 
AMG 102 (part 1) and blinded investigational product (parts 2 and 3) must be stored frozen 
protected from light at a freezer set point of -30°C or -70°C.  Panitumumab must be stored 
between 2°C to 8°C and protected from direct sunlight.   
Control Group:  In part 2, panitumumab will serve as control group.  There will be no control 
group in part 1 or 3. 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 8 of 159 
 
Procedures:   
Screening will occur within 35 days before enrollment/randomization (date informed consent form 
is signed to date of enrollment/randomization). 
Screening and on-study assessments will be performed such as physical exam, vital signs, 
ECOG, ECG (screening only), and CT or MRI scans of the chest, abdomen, and pelvis. 
Only subjects with confirmed wild-type KRAS tumor status will be eligible for this study 
(see Section 4.1.1): 
• 
KRAS tumor status, for purposes of determining eligibility for this study, may be obtained 
through previously known KRAS tumor status, or local or central KRAS testing during study 
screening (see Section 7.1.1). 
• 
Regardless of how KRAS tumor status is obtained, archived formalin-fixed 
paraffin-embedded tumor tissue (block or unstained tumor slides) from the primary or 
metastatic site must be submitted to the central laboratory along with the associated 
pathology reports for other exploratory biomarker analyses and/or the evaluation of KRAS 
tumor status (if applicable) (see Section 7.2). 
Screening and on-study local laboratory tests will be performed including hematology, chemistry, 
carcinoembryonic antigen (CEA), glycosylated hemoglobin (HgbA1c), thyroid stimulating 
hormone (TSH), prothrombin time (PT)/international normalized ratio (INR), and urine or serum 
pregnancy (for women of child-bearing potential). 
During the study, blood samples will be collected for antibody formation, biomarker, and PK 
analyses and submitted to the central laboratory.  Subjects enrolled in part 1 will undergo more 
frequent blood sample collection for PK during weeks 5 to 6.  This will require 4 extra visits. 
During the study, CT or MRI scans of the chest, abdomen, pelvis and all other sites of disease  
will be performed at week 8 (+ 1 week window) and within ± 1 week at weeks 12, 16, 24, 32, 40, 
and 48, and every 12 weeks thereafter until radiographic disease progression or the subject 
begins another anti-cancer treatment. 
Data collection for subjects who remain on study treatment after the planned data 
snapshot of the final analysis has been completed will be limited to investigational 
product administration and serious adverse event reporting (see Section 7.7 and 
Section 9.3). 
Statistical Considerations: Tolerability of AMG 102 in combination of panitumumab will be 
assessed in part 1 based on the subject incidence of DLTs.  A subject will be considered DLT 
evaluable if the subject has received at least 2 doses of panitumumab and AMG 102 as 
scheduled (ie, Week 1 and 3) and has a minimum 4 week (28 days) follow-up for safety or has 
received at least 1 dose of panitumumab and AMG 102 and has a DLT within the first 4 weeks 
(28 days) on study.  See Section 2.5.3 for AMG 102 Dose Selected for Part 2. 
Overall safety will be evaluated throughout the study including all enrolled subjects who receive at 
least 1 dose of investigational product (Safety Analysis Set).  Efficacy will be evaluated on 
subjects in the Safety Analysis Set.  The primary analysis for the ORR will include all enrolled 
subjects in part 2 in the Safety Analysis set with measurable disease at baseline.   
The primary analysis for part 2 will occur after a minimum potential follow-up of 24 weeks after 
the last subject is randomized in part 2.  All other available data will be summarized.  ORR will be 
analyzed based on Bayesian methodology.  Historical ORRs from 4 previous panitumumab trials 
combined with the response outcome from cohort 3 of the study will provide a posterior 
distribution for the overall panitumumab monotherapy ORR.  A combination regimen may be 
considered promising and possibly warrant further evaluation in a larger subsequent study if the 
posterior probability that the odds ratio (ie, combination versus panitumumab alone) is greater 
than 1 is ≥ 0.90.  Likewise, a combination may not be considered promising if the posterior 
probability that the odds ratio is greater than 1 is ≤ 0.50.   


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 9 of 159 
 
Final analyses will include data 2 years after the last subject is randomized in part 2.  
Analyses will be separated by parts 1, 2 and 3. 
Sponsor/Licensee:  Amgen Inc. 


Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479
Protocol Number:  20060447
Date:  17 June 2013
Page 10 of 159
Study Design and Treatment Schema
S
C
R
E
E
N
E
N
R
O
L
L
Panitumumab 6 mg/kg
+
AMG 102 10 mg/kg (start)
n = 6 to 9
Panitumumab 6 mg/kg
+
AMG 102 5 mg/kg
n = 6 to 9
PART 1 (OPEN-LABEL DOSE FINDING)
n = 6 to 18
PART 2 (PARTIALLY BLINDED*)
n = 126
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
1:1:1
COHORT 1 (n=42)
Panitumumab 6 mg/kg
+
AMG 102 10 mg/kg (dose selected from part 1)
COHORT 2 (n=42)
Panitumumab 6 mg/kg
+
AMG 479 12 mg/kg
COHORT 3 (n=42)
Panitumumab 6 mg/kg
P
R
O
G
R
E
S
S
I
V
E
D
I
S
E
A
S
E
(PD)
PART 3 (DOUBLE-BLINDED)
n = 42 (from cohort 3 of part 2)
Q
U
A
L
I
F
Y
R
A
N
D
O
M
I
Z
E
1:1
COHORT 3a (n=21)
AMG 102 10 mg/kg
COHORT 3b (n=21)
AMG 479 12 mg/kg
P
D
30-
Day
and
60-
Day
F
O
L
L
O
W
U
P
V
I
S
I
T
S
L
O
N
G
T
E
R
M
F
O
L
L
O
W
U
P
*In part 2, panitumumab will be open-label and AMG 102, AMG 479, and placebo will be double-blinded.
Tolerable AMG 102 dose selected from part 1
was 10 mg/kg


 
Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 119 of 159 
 
Appendix A.  Schedule of Assessments (Part 1 and Part 2) 
 
Screening 
Week
Study Proceduresa,r 
-35 
days 
-7 
days 
1 
2
3 
4
5 
5 
6 
7 
8 
9 
1
0 
1
1 
1
2 
1
3 
1
4 
1
5 
1
6 
1
7 
1
8 
1
9 
2
0 
Hour (D = day) 
 
 
 
 
 
 
D1 
24 
D2 
48 
D3 
96 
D5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Collection windowk 
 
 
 
 
 
 
 
± 4 hrs
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Assessmentsr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent & eligibility review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
Xe 
 
X 
 
X 
 
X 
 
  
 
X 
 
X 
 
X 
 
X 
 
X  X 
 
X 
 
PE, height, weight & ECOGb 
Xe 
 
X 
 
 
 
X 
 
  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECGc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of AEs, SAEs, conmedsd 
X 
 
X 
 
X 
 
X 
 
  
 
X 
 
X 
 
X 
 
X 
 
X  X 
 
X 
 
Local Laboratory Testsf,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Hematology 
 
Xe 
 
 
X 
 
X 
 
  
 
X 
 
X 
 
X 
 
X 
 
X  X 
 
X 
 
  Chemistryg 
 
Xeg 
 
 
X 
 
Xg 
 
 
 
 
X 
 
Xg 
 
X 
 
X
g 
 
X  
X
g 
 
X 
 
  PT and INR (Part 2) 
 
 
 
 
 
 
X 
 
  
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
  HgbA1c 
 
X 
 
 
 
 
X 
 
  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
  TSH 
 
X 
 
 
 
 
X 
 
  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
  CEA 
 
Xe 
 
 
 
 
 
 
 
 
 
 
X
f 
 
 
 
X 
 
 
 
X  
 
 
 
  Urine/Serum Pregnancy (-3 
days)f 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory Sample Collectionh,r 
  Tumor Tissuei 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  PK (Part 1)jf 
 
 
X 
 
 
 
X 
X X X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  PK (Part 2)kf 
 
 
X 
 
X 
 
X 
 
  
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  Biomarker 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product Administrationr 
Review dose adjustment criteriam 
 
 
 
 
X 
 
X 
 
  
 
X 
 
X 
 
X 
 
X 
 
X  X 
 
X 
 
Investigational product admin.m 
 
 
X 
 
X 
 
X 
 
  
 
X 
 
X 
 
X 
 
X 
 
X  X 
 
X 
 
Radiological Assessmentsn,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI-Chest, Abdomen, & 
Pelvis 
Xe 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 


 
Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 120 of 159 
 
Appendix A.  Schedule of Assessments (continued) 
(Part 1 and Part 2) 
Study Proceduresa,r 
Week 
 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
General Assessmentsr 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, 
SAEs, & conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsf,r 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
X
g 
 
X 
 
Xg 
 
X 
 
Xg 
 
X  
Xg 
 
X 
 
Xg 
 
X  
Xg 
 
X 
 
Xg 
 
X 
 
   PT and INR (Part 2) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Central Laboratory Sample Collectionh,r 
   PK (Part 1)jf  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
   PK (Part 2)kf 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
   Antibodieslp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Investigational Product Administrationr 
Review dose 
adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
Investigational 
product 
administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsn,r 
CT/MRI - Chest, 
Abdomen, & Pelvis 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Investigator 
Assessment of Tumor 
Response 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 


 
Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 121 of 159 
 
Appendix A.  Schedule of Assessments (continued) 
(Part 1 and Part 2) 
Study Proceduresa,r 
Week 49 until Radiographic Disease Progression 
Visits repeated every 12 weeks 
(unless otherwise indicated) 
30-Day 
Safety 
Follow-up 
Visit 
(+3 day 
window) 
60-Day 
Follow-
up Visit 
(+14 day 
window) 
LTFU 
(± 28 day 
window) 
End of 
Studyq 
 
1
2
3
4
5
6
7
8
9
10 
11 
12
General Assessmentsr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Review inclusion criteria for part 3 (see 
Section 4.3 & Appendix B) o 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
 
 
 
Local Laboratory Testsf,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
 
 
   PT and INR (Part 2) 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Central Laboratory Samplesh,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   PK (Part 1)jf  
 
 
 
 
 
 
 
 
 
 
 
Xj 
X 
X 
 
 
   PK (Part 2)kf  
 
 
 
 
 
 
 
 
 
 
 
Xk 
X 
X 
 
 
   Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
   Antibodieslp 
 
 
 
 
 
 
 
 
 
 
 
X 
Xl 
Xl 
Xp 
 
Investigational Product Administrationr 
Review dose adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Investigational product administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Radiological Assessmentsn,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI of Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 
Investigator Assessment of Tumor 
Response 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
 


 
Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 122 of 159 
 
Appendix B.  Schedule of Assessments (Part 3) 
 
Study Proceduresa,r 
Qualification
Week
 
 
 
 
1
2
3
4
5
6
7
8 
9 
10
11
12
13
14
15
16
17
18
19
20
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion criteria for part 3 
(see Section 4.3) 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind in IVRS 
Note: only eligible subjects may be 
randomized in part 3 (see Section 7.2) 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
PE, weight & ECOGb 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, & conmedsd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
Local Laboratory Testsf,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
   Chemistryg 
X 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X  
Xg 
 
X 
 
Xg 
 
X 
 
   PT and INR  
 
X 
 
 
 
X 
 
 
 
 
 
X  
 
 
 
 
X 
 
 
   HgbA1c 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA 
X 
 
 
 
 
 
 
 
Xf 
 
 
 
X 
 
 
 
X 
 
 
 
 
Central Laboratory Testsh,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Biomarker 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
   Antibodieslp 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product Administrationr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review dose adjustment criteriam 
 
 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
Investigational product administrationm 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
Radiological Assessmentsn,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI - Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Investigator Assessment of Tumor Response 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 


 
Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 123 of 159 
 
Appendix B.  Schedule of Assessments (continued) 
(Part 3) 
Study Proceduresa,r 
Week 
 
21 
2
2 
2
3 
2
4 
25 
2
6 
2
7 
2
8 
29 
3
0 
3
1 
3
2 
33 
3
4 
3
5 
3
6 
37 
3
8 
3
9 
4
0 
41 
4
2 
4
3 
4
4 
45 
4
6 
4
7 
4
8 
General Assessmentsr 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Review of AEs, SAEs, 
& conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
Local Laboratory Testsf,r 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X  
   PT and INR 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X  
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
   CEA  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Central Laboratory Sample Collectionh,r 
   Antibodiesl,p 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Investigational Product Administrationr 
Review dose 
adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
Investigational product 
administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
Radiological Assessmentsn,r 
CT/MRI - Chest, 
Abdomen, & Pelvis 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Investigator 
Assessment of Tumor 
Response 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 


 
Approved 
 
 
Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 124 of 159 
 
Appendix B.  Schedule of Assessments (continued) 
(Part 3) 
Study Proceduresa,r 
Week 49 until Radiographic Disease Progression 
Visits repeated every 12 weeks 
(unless otherwise indicated) 
30-Day 
Safety 
Follow-up 
Visit 
(+3 day 
window) 
60-Day 
Follow-
up Visit 
(+14 day 
window) 
LTFU 
(± 28 day 
window) 
End of 
Studyq 
 
1
2
3
4
5
6
7
8
9
10 
11 
12
General Assessmentsr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
PE, weight & ECOGb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Review of AEs, SAEs, & conmedsd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Local Laboratory Testsf,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
   PT and INR 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
   Chemistryg 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
X 
 
Xg 
 
 
 
   HgbA1c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
   TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
   CEA  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Central Laboratory Samplesh,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
   Antibodiesl,p 
 
 
 
 
 
 
 
 
 
 
 
X 
Xl 
Xl 
Xp 
Investigational Product Administrationr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review dose adjustment criteriam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Investigational product administrationm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Radiological Assessmentsn,r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI - Chest, Abdomen, & Pelvis 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
Investigator Assessment of Tumor Response 
 
 
 
 
 
 
 
 
 
 
 
X 
Xnp 
 
Xnp 
Footnotes for Appendices A & B are on the following pages 


 
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Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 125 of 159 
 
Appendix A & B.  Schedule of Assessments Footnotes 
a. Study Procedures.  All treatment procedures must be performed within ± 3 days of the planned visit. 
b. Vital signs, PE, Height, Weight, ECOG.  Vital signs will include BP, resting pulse, respiration rate, and temp.  Height will be collected at screening.  See 
Appendix E for ECOG scale.  For part 3, only ECOG is required at qualification. 
c. ECG.  A 12-lead ECG will be performed at screening and should include HR, QRS, QT, QTc, and PR intervals. 
d. AEs, SAEs, and Concomitant Medications.  AEs, SAEs, and con-meds should be reviewed at each study visit and recorded on the eCRF.  All SAEs should be 
reported to Amgen within 24 hours.  See Section 9 for details. 
e. Standard of Care.  Vitals, PE, ECOG, hematology, chemistry, CEA, pregnancy test, and CT or MRI scans of the chest, abdomen, and pelvis will be considered 
standard of care and may be performed before consent.  However, for screening and baseline purposes, they must be performed within the timeframes specified 
(Section 7.1).   
f. 
Local Laboratory Analytes.  See Section 7, Table 6 for a complete list of laboratory analytes.  The screening hematology and chemistry performed ≤ 7 days 
before enrollment will be used as baseline.  Urine or serum pregnancy test must be completed ≤ 3 days before enrollment/randomization.  Blood samples will be 
collected before each dose of investigational product, except for the post-infusion PK.  The blood samples may be collected ≤ 3 days before the dose of 
investigational product.  However, for PK, it is preferred that the pre-infusion blood samples are collected on the day of investigational product administration.    
g. Chemistry.  Glucose (non-fasting) is included as part of the chemistry assessment for all subjects.  For subjects in part 2 and 3, a fasting glucose will replace the 
glucose assessment at screening, weeks 5, 9, every 4 weeks thereafter, and at the 30-day safety follow-up visit.   
h. Central Laboratory Assessments.  Refer to the central laboratory manual(s) provided separately for instructions on the collection, processing, and shipment of 
tumor tissue, antibody, PK, and biomarker samples.   
i. 
Tumor Tissue.  During screening, archived formalin-fixed paraffin-embedded colorectal tumor tissue (block or unstained slides) from the primary or metastatic site 
collected prior to the study will be submitted to the central laboratory along with the associated pathology report for evaluation of KRAS tumor status, if applicable, 
EGFr membrane staining and/or other exploratory biomarker analyses (see Section 7.5).  See KRAS testing in Section 7.1.1 for additional information on KRAS 
testing. 
j. 
PK Assessments (Part 1).  Subjects enrolled in part 1 will undergo more intensive PK blood sample collection during weeks 5 through 6.  This will require 4 extra 
visits.  For all subjects enrolled in part 1, PK samples will be collected pre-panitumumab infusionf and post-AMG 102 infusion  
(± 5 min. after end of infusion) at weeks 1, 5, 7, 13, 23, 47, and every 6 months thereafter during treatment.  During week 5, PK samples will be collected at 
week 5, hours 24 (day 2), 48 (day 3), 96 (day 5), and 168 (day 8/week 6) post-end of AMG 102 infusion.  A PK sample will also be collected at the 30-day and 
60-day follow-up visit(s).  Note: If a subject is receiving only one of the two investigational products on a day PK is collected, then a pre-and post-infusion blood 
sample will be collected. 
k. PK Assessments (Part 2).  PK samples will be collected pre-panitumumab infusionf and post-blinded investigational product infusion (± 5 min. after end of 
infusion) at weeks 1, 3, 5, 7, 13, 23, 47, and every 6 months thereafter during treatment.  A PK sample will also be collected at the  
30-day and 60-day follow-up visit(s). Note: If a subject is receiving only one of the two investigational products on a day PK is collected, then a pre-and 
post-infusion blood sample will be collected. 


 
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Product:  Panitumumab/AMG 102/AMG 479 
Protocol Number:  20060447 
Date:  17 June 2013 
Page 126 of 159 
 
l. 
Antibody Samples.  Antibody samples will be collected at weeks 1, 7, 23, 47, and every 6 months thereafter during treatment, and at the 30-day and 60-day 
follow-up visits.  See Section 7.4 for additional antibody assessments in LTFU for subjects with a positive or neutralizing positive antibody result.  Note: subjects 
treated on cohort 3 in part 2 that go onto receive treatment in part 3, will be tested for HAPA at the 30-day safety follow-up for part 3. 
m. Investigational Product Administration.  Investigational product must be administered after all other study procedures (eg, laboratory sample collection), unless 
otherwise specified (eg, post-dose PK).  After the first dose of investigational product, each subject will be assessed for dose adjustments (see Section 6).  The 
Q2W schedule of all subsequent doses will be planned according to study day 1 or within ± 3 days of the planned dose. 
n. Radiological Assessments.  A CT or MRI of the chest, abdomen, pelvis, and all other sites of disease will be performed at weeks 8 (+1 week) and within  
+/- 1 week at weeks 12, 16, 24, 32, 40, and 48, and every 12 weeks thereafter until radiographic disease progression or the subject begins another treatment.  
Subjects with symptoms suggestive of disease progression will be evaluated for tumor response at the time symptoms occur.  The same modality of imaging used 
at screening should be used throughout the study for direct comparison.  Radiological images performed as standard of care ≤ 35 days before enrollment may be 
used for screening purposes.  All assessments will be made by the investigator using modified RECIST v1.0 (see Appendix F).  Subjects with a complete response 
or partial response will have confirmatory radiological images performed no less than 4 weeks (28 days) after the criteria for response are first met.  See footnote p 
below for LTFU imaging requirements. 
o. Inclusion Criteria for Part 3.  Subjects initially randomized in part 2 that meet the criteria outlined in Section 4.3 may be unblinded to determine their treatment 
assignment in part 2.  Subjects assigned to Cohort 3 may be further randomized in part 3.  The first dose of blinded investigational product must be administered 
≥ 2 weeks, but ≤ 6 weeks (2 to 6 weeks) after the last dose of investigational product received in part 2.  Any exceptions to the first dose of blinded investigational 
product should be discussed with and approved by Amgen prior to implementation.  The first dose of part 3 investigational product must be received ≤ 3 days after 
randomization in part 3.  See Sections 4.3 and 7.2, and Appendix B. 
p. LTFU.  After the 30-day safety follow-up visit, subjects will be followed for radiographic disease progression (if not documented previously) and survival every 
3 months (± 28 day window) beginning after the 30-day safety follow-up and continuing for up to 2 years after the last subject is randomized in part 2 (see 
Section 7.4 for details).  See footnote l for additional information related to follow-up for positive antibodies to panitumumab, AMG 102, or  
AMG 479. 
q. End of Study (subject).  The end of study for each subject is defined as the date the subject withdraws consent from study, completes the LTFUp, or death. The 
end of study for each subject who remains on study after the planned data snapshot of the final analysis is defined as date the subject withdrew 
consent from the study, completes the 30-day safety follow-up visit, or death. 
r. 
Study Procedures Following Completion of Data Snapshot of Final Analysis:  Data collection for subjects who remain on study treatment after the 
planned data snapshot of the final analysis has been completed will be limited to investigational product administration and serious adverse event 
reporting (see Section 7.7 and Section 9.3). Other protocol-specified procedures and observations outlined in the Schedule of Assessments and in 
Sections 7.1 through 7.6 of the protocol, including blood samples and radiographic imaging, will not be collected.  However, the investigator, at his or 
her discretion, may continue to perform the procedures and observations outlined in Section 7 and Schedule of Assessments per local institution 
standard of care.