Clinical trial NCT00891930
Conditions: Metastatic Colorectal Cancer
Keywords: wild-type KRAS panitumumab biomarker mechanisms of acquired resistance metastatic colorectal cancer
Sponsor: NantBioScience, Inc.
Start date: 2009-05-05; Completion date: 2013-07-22
Enrollment: 74 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to evaluate the mechanism(s) of resistance to the anti-epidermal growth factor receptor (EGFR) antibody panitumumab given in combination with irinotecan in metastatic colorectal carcinoma (mCRC) patients with wild-type Kirsten rat sarcoma-2 virus oncogene (KRAS) tumor status at the time of initial diagnosis.

Detailed description:
In Part 1, all participants will undergo a baseline tumor biopsy and will receive panitumumab with irinotecan. Participants who respond or have stable disease will continue to receive treatment until radiographically-confirmed disease progression. These participants will then undergo a second tumor biopsy and blood sampling and then proceed to Part 2 of the study. Participants with radiographically confirmed disease progression at the time of the first tumor measurement will undergo blood sampling and proceed directly to Part 2.

In Part 2, participants will receive panitumumab with ganitumab. In both parts of the study, panitumumab and irinotecan (Part 1) and panitumumab and ganitumab (Part 2) will be administered every 2 weeks until disease progression, intolerability, withdrawal of consent, death, or unless otherwise indicated by the study team.

Arms: arm 1: Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Interventions: intervention 1: Panitumumab intervention 2: Ganitumab intervention 3: Irinotecan
Intervention descriptions: intervention 1: Panitumumab 6 mg/kg administered via IV infusion over 60 minutes intervention 2: AMG 479 12 mg/kg adminstered by IV infusion over 60 minutes intervention 3: Irinotecan starting dose of 180 mg/m² adminstered via IV infusion

Protocol documents:
Prot_SAP_000.pdf: 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  28 August 2008 
 
Page 1 of 132 
 
 
Title:  A Phase 2 Study of Panitumumab Plus Irinotecan Followed by 
Panitumumab Plus AMG 479 in Subjects With Metastatic Colorectal Carcinoma 
Expressing Wild Type KRAS and Refractory to Oxaliplatin- or Irinotecan- and 
Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired Resistance 
to Panitumumab 
Panitumumab / AMG 479 
 
Amgen Protocol Number 20070820 
 
EudraCT Number: 2008-004752-77 
 
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 (EU): 
Ines Barbosa 
Clinical Research Study Manager 
1, Sanderson Road 
Uxbridge Business Park 
London 
UB8 1DH 
Tel: + 44 1895 525516 
Fax: + 44 1895 525112 
Key Sponsor Contact (US & 
EU): 
Katherine Ruffner 
Clinical Research Medical Director 
1 Amgen Center Dr. 
Mailstop 38-2-A 
Thousand Oaks, CA 91320 
Tel: + 1 805-447-1583 
Fax: +1 805-480-4978 
Date: 
28 August 2008 
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:  + 1 800-772-6436.  For all other study-related 
questions, continue to contact the Key Sponsor Contact. 


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  28 August 2008 
 
Page 2 of 132 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 2 Study of Panitumumab Plus 
Irinotecan Followed by Panitumumab Plus AMG 479 in Subjects With Metastatic 
Colorectal Carcinoma Expressing Wild Type KRAS and Refractory to Oxaliplatin- or 
Irinotecan- and Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired 
Resistance to Panitumumab, dated 28 August 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 9 May 1997 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  
 
Date (DD Month YYYY) 
 


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  28 August 2008 
 
Page 3 of 132 
 
 
Protocol Synopsis 
Title:  A Phase 2 Study of Panitumumab Plus Irinotecan Followed by Panitumumab Plus 
AMG 479 in Subjects With Metastatic Colorectal Carcinoma Expressing Wild Type KRAS and 
Refractory to Oxaliplatin- or Irinotecan- and Oxaliplatin-containing Regimens to Evaluate 
Mechanisms of Acquired Resistance to Panitumumab   
Study Phase:  2  
Indication:  Metastatic colorectal cancer expressing wild type (wt) KRAS and refractory to 
irinotecan- and oxaliplatin-containing regimens, or refractory to oxaliplatin-containing regimens. 
OBJECTIVES  
Primary  
Part 1:   
To determine if acquired resistance to panitumumab therapy in subjects with KRAS wild-type 
mCRC correlates with emergence of mutant KRAS tumors.  (Acquired resistance is defined as 
disease progression on panitumumab and irinotecan that occurs after a period of disease 
response or stable disease on treatment with this regimen is observed and radiographically-
confirmed.)   
Part 2:   
To determine if inhibition of the IGF-1R pathway with AMG 479 can overcome resistance to 
panitumumab therapy, as demonstrated by the objective response rate (ORR) to panitumumab 
and AMG 479 following disease progression on panitumumab and irinotecan.   
Secondary  
Part 1: 
• 
To determine ORR and other measures of efficacy (ie, TTR, DOR, PFS, OS) to panitumumab 
plus irinotecan  
• 
To evaluate the safety of panitumumab and irinotecan 
Part 2: 
• 
To determine measures of efficacy (ie, TTR, DOR, PFS, OS) of panitumumab plus AMG 479 
• 
To evaluate the safety of panitumumab and AMG 479 
Exploratory 
• 
To evaluate whether mutations of any other tumor genes, including but not limited to Raf and 
PI3K, predict disease response to panitumumab and irinotecan (Part 1) or panitumumab and 
AMG 479 (Part 2)   
• 
To evaluate whether any baseline subject characteristics, including but not limited to prior 
treatment history, predict responses to panitumumab and irinotecan (Part 1) or panitumumab 
and AMG 479 (Part 2)   
• 
To determine whether the status of potential tumor biomarkers (eg Raf, PI3K) evolve during 
tumor progression by comparing the status of biomarkers of the archival primary tumor tissue 
with that of the tumors biopsied on study   
Hypotheses:   
The KRAS mutation rate is higher in subjects with acquired resistance to panitumumab therapy 
than other subjects in mCRC with wt KRAS receiving panitumumab and irinotecan   


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  28 August 2008 
 
Page 4 of 132 
 
 
Study Design:   
This is a global, multicenter, open-label phase 2 study designed to evaluate the mechanism(s) of 
resistance to the anti-EGFR antibody panitumumab given in combination with irinotecan in mCRC 
subjects with wild-type KRAS tumor status at the time of initial diagnosis.   
In Part 1, all subjects will undergo a baseline tumor biopsy and will receive panitumumab with 
irinotecan.  Subjects that respond (complete or partial response ± confirmation) or have stable 
disease (based on modified RECIST criteria, Appendix F) will continue to receive treatment until 
radiographically-confirmed disease progression.  These subjects will then undergo a second 
tumor biopsy and blood sampling and then proceed to Part 2 of the study.   
Subjects that experience radiographically-confirmed disease progression at the time of first tumor 
measurement will undergo blood sampling then proceed directly on to Part 2 of the study; tumor 
biopsy will not be required in these subjects.   
In Part 2, all subjects will receive panitumumab with AMG 479.   
In both parts of the study, panitumumab and irinotecan (Part 1) and panitumumab and AMG 479 
(Part 2) will be administered Q2W until disease progression, intolerability, withdrawal of consent, 
death, or unless otherwise indicated by the study team.   
All subjects that permanently discontinue all investigational products will complete a safety follow-
up visit 30 days (+3 day window) after the last dose of investigational product.   
Subjects that end the treatment prior to radiographically-confirmed disease progression will be 
followed for radiographically-confirmed disease progression at the 30 day safety follow-up visit 
and then every 8 weeks (± 1 week window) until radiographically-confirmed disease progression, 
start of new cancer treatment, death, withdrawal of consent or at the end of the study, whichever 
is earlier.   
Subjects who have discontinued study treatment for any reason but have not withdrawn full 
consent to participate in the study, will be contacted by telephone or clinical visit every 3 months 
for overall survival and disease status assessments up to 2 years after the last subject is enrolled 
in Part 1.   
Primary and Secondary Endpoints:   
Primary Endpoints: 
• 
Emergence of Mutant KRAS:  KRAS mutation status changed from wild-type at baseline to 
mutant at the time of the second biopsy following the radiographic evidence of acquired 
resistance to panitumumab plus irinotecan (Part 1).   
• 
Objective Response Rate (ORR):  Confirmed complete or partial response (per modified 
RECIST) to panitumumab and AMG 479 (Part 2)   
Secondary Endpoints: 
• 
Efficacy: ORR (Part 1), Time to Response (TTR), Duration of Response (DOR), Progression-
free Survival (PFS), and Overall Survival (OS) (both Part 1 and Part 2)   
• 
Safety: Incidence and severity of adverse events, significant changes in laboratory values, 
incidence of anti-antibody formation (both Part 1 and Part 2)   
Sample Size:  Approximately 75 subjects   
Summary of Subject Eligibility Criteria:   
Key Inclusion Criteria 
• 
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum    
• 
Subjects with wild-type KRAS tumor status confirmed by central laboratory assessment    


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  28 August 2008 
 
Page 5 of 132 
 
 
• 
Radiographic evidence of disease progression while on or ≤ 6 months after treatment with 
irinotecan- and oxaliplatin- or oxaliplatin-based chemotherapy for mCRC    
• 
Radiographic measurement of tumor burden done within 28 days prior to Day 1 (start of 
treatment with investigational product)   
• 
At least 1 uni-dimensionally measurable lesion ≥ 20 mm using conventional CT or MRI or 
≥ 10 mm by spiral CT per modified RECIST.  Lesion must not be chosen from a previously 
irradiated field, unless there has been documented disease progression in that field after 
irradiation and prior to enrollment.  All sites of disease must be evaluated   
• 
At least 1 tumor (metastatic lesion or unresected primary tumor) that is amenable to core 
needle biopsy, as determined by the clinician who will perform the biopsy   
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix E)   
• 
Male or female ≥ 18 years of age at the time of informed consent   
• 
Willing to undergo two core biopsy procedures of tumors (metastasis or unresected primary)   
Key Exclusion Criteria 
• 
History of prior or concurrent central nervous system (CNS) metastases   
• 
Prior treatment with anti-EGFR antibodies (eg, panitumumab, cetuximab) or EGFR small 
molecule inhibitors (eg, erlotinib, gefitinib)   
• 
Prior treatment with monoclonal antibodies directed against IGF-1R   
• 
Use of systemic chemotherapy and radiotherapy ≤ 21 days before enrollment   
• 
Use of any antibody therapy (eg, bevacizumab) ≤ 42 days before enrollment   
• 
Use of anti-tumor therapies including prior experimental agents or approved anti-tumor small 
molecules ≤ 30 days before enrollment   
• 
Known UGT1A1 polymorphisms predisposing to increased irinotecan toxicity   
• 
History of irinotecan intolerance that may interfere with planned treatment   
• 
History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of 
interstitial lung disease on baseline chest computerized tomography (CT) scan   
• 
Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, 
acute or chronic active hepatitis B infection   
• 
Any co-morbid disease or condition that could increase the risk of toxicity (eg, significant 
ascites, significant pleural effusion)   
• 
Any uncontrolled concurrent illness (eg, infection, bleeding diathesis) or history of any 
medical condition that may interfere with the interpretation of the study results   
• 
Major surgical procedure ≤ 28 days before enrollment or minor surgical procedure ≤ 14 days 
before enrollment.  Subjects must have recovered from surgery related toxicities.   
Investigational Product Dosage and Administration:   
Panitumumab (6 mg/kg starting dose) and AMG 479 (12 mg/kg starting dose) will be open-label 
throughout the study.  The total dose of panitumumab and AMG 479 may be rounded up or down 
by no greater than 10 mg.   
The first dose of investigational products will be referred to as study day 1 of week 1.  
Investigational products will be administered on the same day Q2W (eg, week 1, 3, 5, 7) until 
progressive disease, intolerability, withdrawal, death, or unless otherwise indicated.  The  
Q2W schedule of all subsequent doses of investigational product will be planned according to 
study day 1 or within ± 3 days of the planned dose.   
In Part 1, the first dose of investigational product (panitumumab) must be administered ≥ 7 days 
after the first biopsy and ≤ 28 days after the last radiographic measurement of disease burden.   


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  28 August 2008 
 
Page 6 of 132 
 
 
In Part 2, for subjects that undergo the second core biopsy, the first dose of investigational 
product (panitumumab and AMG 479) must be administered ≥ 7 days after the second biopsy 
procedure and < 28 days after radiographically-confirmed disease progression.  For subjects who 
do not undergo the second core biopsy procedure, the first dose of investigational product 
(panitumumab and AMG 479) must be administered ≤ 28 days after radiographically-confirmed 
disease progression.  If the investigational product dosing cannot be done within the time 
windows specified above, permission to start treatment must be sought from Amgen.   
In Part 1, the first infusion of panitumumab will be given over 60 ± 15 minutes.  If the first infusion 
of panitumumab is well tolerated (ie without any serious infusion-related reactions) all subsequent 
infusions (including all infusions given in Part 2) may be administered over 30 ± 10 minutes.  In 
the event a subject’s actual weight requires greater than 150 mL volume infusion, panitumumab 
will be administered over 60 to 90 minutes ± 15 minutes, as tolerated.  Doses higher than 
1000 mg should be diluted to 150 ml in 0.9% sodium chloride solution, USP (saline solution) and 
infused over 60 to 90 ± 15 minutes.   
AMG 479 will be administered by an IV infusion over a 60 ± 15 minute period during the initial 
dose administration.  If the dose administration is well tolerated, subsequent administrations may 
be made over 30 ± 10 minutes.  In the event a subject’s actual weight requires greater than 
150 mL volume infusion, AMG 479 will be administered over 60 to 90 minutes ± 15 minutes, as 
tolerated.  Infusion times can be extended to a maximum of 120 min for subjects deemed unable 
to tolerate the 90 min infusion.   
Filtration of diluted AMG 479 is not required.   
All subjects should be observed for any adverse reactions during infusions of panitumumab 
(Part 1) and during panitumumab and AMG 479 infusions and for at least 60 minutes following 
completion of the first administration of AMG 479 (Part 2).  The observation period for subsequent 
infusions may be reduced at the discretion of the investigator.   
Control Group:  N/A 
Procedures:   
Screening for Part 1 will occur within 35 days before enrollment.   
Screening for Part 2 will begin on the date of radiographically confirmed disease progression and 
must be completed within 28 days.   
During initial 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) and other biomarker analysis.  Only 
subjects with confirmed wild-type KRAS tumor status will be eligible for this study.  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.   
Screening and on-study assessments such as physical exam, vital signs, ECOG, ECG (screening 
only), and CT or MRI scans of the chest, abdomen, and pelvis will be performed.   
Screening and on-study local laboratory tests will be performed including hematology, chemistry, 
carcinoembryonic antigen (CEA), glycosylated hemoglobin (HgbA1c) and urine or serum 
pregnancy (for women of child-bearing potential).   
During the study, blood samples will be collected for antibody formation and biomarkers and 
submitted to the central laboratory.  Tumor tissue sampling by core biopsy of a locally advanced 
or metastatic lesion will also be collected prior to the start of study treatment in Part 1 and in 
addition, for subjects who initially respond to panitumumab plus irinotecan or have stable disease 
and subsequently have radiographically-confirmed disease progression, there will be a second 
biopsy collection prior to start of study treatment in Part 2.  These samples will be submitted to 
the central laboratory.   


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  28 August 2008 
 
Page 7 of 132 
 
 
During the study, CT or MRI scans of the chest, abdomen, pelvis and all other sites of disease 
will be performed every 8 weeks (± 1 week window) until radiographically-confirmed disease 
progression.   
Statistical Considerations:   
The primary goal of the statistical analysis is to test whether acquired resistance to panitumumab 
therapy in mCRC with wt KRAS tumors correlates with emergence of mutant KRAS tumors and to 
evaluate the efficacy and safety of both panitumumab plus irinotecan and panitumumab plus 
AMG 479.  Summary statistics including confidence intervals will be generated for all efficacy 
endpoints.  Safety analyses will be descriptive and will be presented in tabular format with the 
appropriate summary statistics.  One interim analysis is planned for this study.  The study is not 
anticipated to stop early unless a major unexpected safety signal is detected.   
Sponsor/Licensee:  Amgen Inc. 
 


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  28 August 2008 
 
Page 8 of 132 
 
 
Study Design and Treatment Schema 
 
 
 
 


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  01 October 2009 
 
Page 1 of 139 
 
 
Title:  A Phase 2 Study of Panitumumab Plus Irinotecan Followed by 
Panitumumab Plus AMG 479 in Subjects With Metastatic Colorectal Carcinoma 
Expressing Wild Type KRAS and Refractory to Oxaliplatin- or Irinotecan- and 
Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired Resistance 
to Panitumumab 
Panitumumab / AMG 479 
 
Amgen Protocol Number 20070820 
 
EudraCT Number: 2008-004752-77 
 
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 (EU): 
Ines Barbosa 
Clinical Research Study Manager 
1, Sanderson Road 
Uxbridge Business Park 
London 
UB8 1DH 
Tel: + 44 1895 525516 
Fax: + 44 1895 525112 
Key Sponsor Contact (US & 
EU): 
Roger Sidhu 
Clinical Research Senior Medical Scientist 
1 Amgen Center Dr. 
Mailstop 38-2-B 
Thousand Oaks, CA 91320 
Tel: + 1 805-447-5878 
Fax: +1 805-480-1291 
Date: 
28 August 2008 
Amendment 1 
01 October 2009 
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:  + 1 800-772-6436.  For all other study-related 
questions, continue to contact the Key Sponsor Contact. 


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  01 October 2009 
 
Page 2 of 139 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 2 Study of Panitumumab Plus 
Irinotecan Followed by Panitumumab Plus AMG 479 in Subjects With Metastatic 
Colorectal Carcinoma Expressing Wild Type KRAS and Refractory to Oxaliplatin- or 
Irinotecan- and Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired 
Resistance to Panitumumab, dated 01 October 2009, 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 9 May 1997 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  
 
Date (DD Month YYYY) 
 


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  01 October 2009 
 
Page 3 of 139 
 
 
Protocol Synopsis 
Title:  A Phase 2 Study of Panitumumab Plus Irinotecan Followed by Panitumumab Plus 
AMG 479 in Subjects With Metastatic Colorectal Carcinoma Expressing Wild Type KRAS and 
Refractory to Oxaliplatin- or Irinotecan- and Oxaliplatin-containing Regimens to Evaluate 
Mechanisms of Acquired Resistance to Panitumumab   
Study Phase:  2  
Indication:  Metastatic colorectal cancer expressing wild type (wt) KRAS and refractory to 
irinotecan- and oxaliplatin-containing regimens, or refractory to oxaliplatin-containing regimens. 
OBJECTIVES  
Primary  
Part 1:   
To determine if acquired resistance to panitumumab therapy in subjects with KRAS wild-type 
mCRC correlates with emergence of mutant KRAS tumors.  (Acquired resistance is defined as 
disease progression on panitumumab and irinotecan that occurs after a period of disease 
response or stable disease on treatment with this regimen is observed and radiographically-
confirmed.)   
Part 2:   
To determine if inhibition of the IGF-1R pathway with AMG 479 can overcome resistance to 
panitumumab therapy, as demonstrated by the objective response rate (ORR) to panitumumab 
and AMG 479 following disease progression on panitumumab and irinotecan.   
Secondary  
Part 1: 
• 
To determine ORR and other measures of efficacy (ie, TTR, DOR, PFS, OS) to panitumumab 
plus irinotecan  
• 
To evaluate the safety of panitumumab and irinotecan 
Part 2: 
• 
To determine measures of efficacy (ie, TTR, DOR, PFS, OS) of panitumumab plus AMG 479 
• 
To evaluate the safety of panitumumab and AMG 479 
Exploratory 
• 
To evaluate whether mutations of any other tumor genes, including but not limited to Raf and 
PI3K, predict disease response to panitumumab and irinotecan (Part 1) or panitumumab and 
AMG 479 (Part 2)   
• 
To evaluate whether any baseline subject characteristics, including but not limited to prior 
treatment history, predict responses to panitumumab and irinotecan (Part 1) or panitumumab 
and AMG 479 (Part 2)   
• 
To determine whether the status of potential tumor biomarkers (eg Raf, PI3K) evolve during 
tumor progression by comparing the status of biomarkers of the archival primary tumor tissue 
with that of the tumors biopsied on study   
Hypotheses:   
The KRAS mutation rate is higher in subjects with acquired resistance to panitumumab therapy 
than other subjects in mCRC with wt KRAS receiving panitumumab and irinotecan.   


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  01 October 2009 
 
Page 4 of 139 
 
 
Study Design:   
This is a global, multicenter, open-label phase 2 study designed to evaluate the mechanism(s) of 
resistance to the anti-EGFR antibody panitumumab given in combination with irinotecan in mCRC 
subjects with wild-type KRAS tumor status.   
In Part 1, all subjects will undergo a baseline tumor biopsy and will receive panitumumab with 
irinotecan.  Subjects that respond (complete or partial response ± confirmation) or have stable 
disease (based on modified RECIST v1.0 criteria, Appendix F) will continue to receive treatment 
until radiographically-confirmed disease progression.  These subjects will then undergo a second 
tumor biopsy and blood sampling and then proceed to Part 2 of the study.   
Subjects that experience radiographically-confirmed disease progression at the time of first tumor 
measurement will undergo blood sampling then proceed directly on to Part 2 of the study; tumor 
biopsy will not be required in these subjects.   
In Part 2, all subjects will receive panitumumab with AMG 479.   
In both parts of the study, panitumumab and irinotecan (Part 1) and panitumumab and AMG 479 
(Part 2) will be administered Q2W until disease progression, intolerability, withdrawal of consent, 
death, or unless otherwise indicated by the study team.   
All subjects that permanently discontinue all investigational products will complete a safety 
follow-up visit 30 days (+3 day window) after the last dose of investigational product.   
Subjects that end the treatment prior to radiographically-confirmed disease progression will be 
followed for radiographically-confirmed disease progression at the 30 day safety follow-up visit 
and then every 8 weeks (± 1 week window) until radiographically-confirmed disease progression, 
start of new cancer treatment, death, withdrawal of consent or at the end of the study, whichever 
is earlier.   
Subjects who have discontinued study treatment for any reason but have not withdrawn full 
consent to participate in the study, will be contacted by telephone or clinical visit every 3 months 
for overall survival and disease status assessments up to 2 years after the last subject is enrolled 
in Part 2.   
Primary and Secondary Endpoints:   
Primary Endpoints: 
• 
Emergence of Mutant KRAS:  KRAS mutation status changed from wild-type at baseline to 
mutant at the time of the second biopsy following the radiographic evidence of acquired 
resistance to panitumumab plus irinotecan (Part 1).   
• 
Objective Response Rate (ORR):  Confirmed complete or partial response (per modified 
RECIST v1.0) to panitumumab and AMG 479 (Part 2)   
Secondary Endpoints: 
• 
Efficacy: ORR (Part 1), Time to Response (TTR), Duration of Response (DOR), Progression-
free Survival (PFS), On-treatment PFS, and Overall Survival (OS) (both Part 1 and Part 2)   
• 
Safety: Incidence and severity of adverse events, significant changes in laboratory values, 
incidence of anti-antibody formation (both Part 1 and Part 2)   
Sample Size:  Approximately 75 subjects   


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  01 October 2009 
 
Page 5 of 139 
 
 
Summary of Subject Eligibility Criteria:   
Key Inclusion Criteria 
• 
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum    
• 
Wild-type KRAS tumor status of archival tumor tissue (preferably from the primary 
tumor) 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 while on or ≤ 6 months after treatment with 
irinotecan- and oxaliplatin- or oxaliplatin-based chemotherapy for mCRC    
− 
Subjects in whom relapse is diagnosed within 6 months after completing adjuvant 
chemotherapy (with oxaliplatin containing regimen) will be considered as having 
failed a prior regimen for metastatic disease 
• 
Radiographic measurement of tumor burden done within 28 days prior to Day 1 (start of 
treatment with investigational product)   
• 
At least 1 uni-dimensionally measurable lesion ≥ 20 mm using conventional CT or MRI or 
≥ 10 mm by spiral CT per modified RECIST v1.0.  Lesion must not be chosen from a 
previously irradiated field, unless there has been documented disease progression in that 
field after irradiation and prior to enrollment.  All sites of disease must be evaluated   
• 
At least 1 tumor (metastatic lesion or unresected primary tumor) that is amenable to core 
needle biopsy, as determined by the clinician who will perform the biopsy   
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix E)   
• 
Male or female ≥ 18 years of age at the time of informed consent   
• 
Willing to undergo 2 serial core biopsy procedures of tumors (metastasis or unresected 
primary)  
Key Exclusion Criteria 
• 
History of prior or concurrent central nervous system (CNS) metastases   
• 
Prior treatment with anti-EGFR antibodies (eg, panitumumab, cetuximab) or EGFR small 
molecule inhibitors (eg, erlotinib, gefitinib)   
• 
Prior treatment with monoclonal antibodies directed against IGF-1R or small molecule 
inhibitors directed against IGF-1R  
• 
 Use of systemic chemotherapy and radiotherapy ≤ 21 days before enrollment.  Subject 
must have recovered from acute toxicities related to radiotherapy.   
• 
Use of any antibody therapy (eg, bevacizumab) ≤ 42 days before enrollment   
• 
Use of anti-tumor therapies including prior experimental agents or approved anti-tumor small 
molecules ≤ 30 days before enrollment   
• 
Known UGT1A1 polymorphisms predisposing to increased irinotecan toxicity   
• 
History of irinotecan intolerance that may interfere with planned treatment   
• 
History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of 
interstitial lung disease on baseline chest computerized tomography (CT) scan   
• 
Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, 
acute or chronic active hepatitis B infection   
• 
Any co-morbid disease or condition that could increase the risk of toxicity (eg, significant 
ascites, significant pleural effusion)   


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  01 October 2009 
 
Page 6 of 139 
 
 
• 
Any uncontrolled concurrent illness (eg, infection, bleeding diathesis) or history of any 
medical condition that may interfere with the interpretation of the study results   
• 
Major surgical procedure ≤ 28 days before enrollment or minor surgical procedure ≤ 14 days 
before enrollment.  Subjects must have recovered from surgery related toxicities.  Core 
biopsy, central venous catheter placement, fine needle aspiration, thoracentesis, or 
paracentesis is not considered a major or minor surgical procedure.  
Investigational Product Dosage and Administration:   
Panitumumab (6 mg/kg starting dose) and AMG 479 (12 mg/kg starting dose) will be open-label 
throughout the study.  The total dose of panitumumab and AMG 479 may be rounded up or down 
by no greater than 10 mg.   
The first dose of investigational products will be referred to as study day 1 of week 1.  
Investigational products will be administered on the same day Q2W (eg, week 1, 3, 5, 7) until 
progressive disease, intolerability, withdrawal, death, or unless otherwise indicated.  The  
Q2W schedule of all subsequent doses of investigational product will be planned according to 
study day 1 or within ± 3 days of the planned dose.   
In Part 1 the subjects will receive panitumumab 6 mg/kg Q2W plus irinotecan 180 mg/m2 
Q2W.  The first dose of investigational product (panitumumab) must be administered 
≥ 7 days after the first biopsy and ≤ 28 days after enrollment and the most recent 
radiographic measurement of disease burden.  Upon radiographically-confirmed disease 
progression per modified RECIST v1.0 or clinical progression, subjects will go on to 
receive panitumumab 6 mg/kg Q2W plus AMG 479 12 mg/kg Q2W (Part 2).  Subjects that 
experience disease control (CR, PR, or SD) followed by the development of acquired 
resistance and subsequent disease progression during Part 1 of the study will undergo a 
second core biopsy prior to starting treatment on Part 2.  Subjects with primary resistance 
to panitumumab and irinotecan demonstrating disease progression on the first restaging 
radiographic scans done on study will proceed directly to Part 2 of the study without 
undergoing a second core biopsy.  
In Part 2, for subjects that undergo the second core biopsy, the first dose of investigational 
product (panitumumab 6 mg/kg Q2W and AMG 479 12 mg/kg Q2W) must be administered 
≥ 7 days after the second biopsy procedure and ≤ 28 days after radiographically-confirmed 
disease progression.  For subjects who do not undergo the second core biopsy procedure, the 
first dose of investigational product (panitumumab and AMG 479) must be administered 
≤ 28 days after radiographically-confirmed disease progression.  If the investigational product 
dosing cannot be done within the time windows specified above, permission to start treatment 
must be sought from Amgen.   
In Part 1, 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.  If 
the first infusion of panitumumab is well tolerated (ie without any serious infusion-related 
reactions) all subsequent infusions (including all infusions given in Part 2) may be administered 
over 30 ± 10 minutes.  In the event a subject’s actual weight requires greater than 150 mL volume 
infusion, panitumumab will be administered over 60 to 90 minutes ± 15 minutes, as tolerated.  
Doses higher than 1000 mg should be diluted to 150 mL in 0.9% sodium chloride solution, USP 
(saline solution) and infused over 60 to 90 ± 15 minutes.   
AMG 479 will be administered by an IV infusion over a 60 ± 15 minute period during the initial 
dose administration.  If the dose administration is well tolerated, subsequent administrations may 
be made over 30 ± 10 minutes.  In the event a subject’s actual weight requires greater than 
150 mL volume infusion, AMG 479 will be administered over 60 to 90 minutes ± 15 minutes, as 
tolerated.  Infusion times can be extended to a maximum of 120 min for subjects deemed unable 
to tolerate the 90 min infusion.   


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  01 October 2009 
 
Page 7 of 139 
 
 
Filtration of diluted AMG 479 is not required.   
All subjects should be observed for any adverse reactions during infusions of panitumumab 
(Part 1) and during panitumumab and AMG 479 infusions and for at least 60 minutes following 
completion of the first administration of AMG 479 (Part 2).  The observation period for subsequent 
infusions may be reduced at the discretion of the investigator.   
Control Group:  N/A 
Procedures:   
Screening for Part 1 will occur within 35 days before enrollment (date main informed consent 
form is signed to date of enrollment). 
Screening for Part 2 will begin on the date of radiographically confirmed disease progression and 
must be completed within 28 days.   
• 
If the KRAS status of tumor tissue from the primary tumor or metastasis for a subject 
has not previously been determined by an Amgen approved central laboratory or by an 
experienced laboratory (per local regulatory guidelines) using a validated test method 
during initial screening, archived formalin-fixed paraffin-embedded tumor tissue block or 
unstained tumor slides along with the corresponding pathology report will be submitted to 
the central laboratory or local laboratory for evaluation of KRAS tumor status (wild-type or 
mutant).  
Regardless of how the 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 
report for evaluation of KRAS (if applicable), EGFR membrane staining, and other 
exploratory biomarker analyses (see Section 7.7). 
Only subjects with confirmed wild-type KRAS tumor status will be eligible for this study.  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.   
Screening and on-study assessments such as physical exam, vital signs, ECOG, ECG (screening 
only), and CT or MRI scans of the chest, abdomen, and pelvis will be performed.   
Screening and on-study local laboratory tests will be performed including hematology, chemistry, 
carcinoembryonic antigen (CEA), glycosylated hemoglobin (HgbA1c), 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 and biomarkers and 
submitted to the central laboratory.  Tumor tissue sampling by core biopsy of a locally advanced 
or metastatic lesion will be collected prior to the start of study treatment in Part 1.  In addition, for 
subjects who initially respond to panitumumab plus irinotecan or have stable disease and 
subsequently have radiographically-confirmed disease progression, a second biopsy will be 
collected prior to start of study treatment in Part 2.  These samples will be submitted to the 
central laboratory.   
During the study, CT or MRI scans of the chest, abdomen, pelvis and all other sites of disease 
will be performed every 8 weeks (± 1 week window) until radiographically-confirmed disease 
progression, start of new cancer treatment, death, withdrawal of consent or at the end of 
the study, whichever is earlier.   


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  01 October 2009 
 
Page 8 of 139 
 
 
Statistical Considerations:   
The primary goal of the statistical analysis is to test whether acquired resistance to panitumumab 
therapy in mCRC with wt KRAS tumors correlates with emergence of mutant KRAS tumors and to 
evaluate the efficacy and safety of both panitumumab plus irinotecan and panitumumab plus 
AMG 479.  Summary statistics including confidence intervals will be generated for all efficacy 
endpoints.  Safety analyses will be descriptive and will be presented in tabular format with the 
appropriate summary statistics.  One interim analysis is planned for this study.  The study is not 
anticipated to stop early unless a major unexpected safety signal is detected.   
Sponsor/Licensee:  Amgen Inc. 
 


Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  01 October 2009 
 
Page 9 of 139 
 
 
Study Design and Treatment Schema 
 
 
 
 


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  27 May 2011 
 
Page 1 of 139 
 
 
Title:  A Phase 2 Study of Panitumumab Plus Irinotecan Followed by 
Panitumumab Plus AMG 479 in Subjects With Metastatic Colorectal Carcinoma 
Expressing Wild-type KRAS and Refractory to Oxaliplatin- or Irinotecan- and 
Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired Resistance 
to Panitumumab 
Panitumumab / AMG 479 
 
Amgen Protocol Number 20070820 
 
EudraCT Number: 2008-004752-77 
 
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 (EU): 
Alison Billington 
Clinical Research Study Manager 
1, Sanderson Road 
Uxbridge Business Park 
London 
UB8 1DH 
Tel: + 44 1895 525339 
Fax: + 44 1895 525107 
Key Sponsor Contact (US & 
EU): 
Richard Williams, MD, PhD 
Clinical Research Senior Medical Scientist 
1 Amgen Center Dr. 
Mailstop 27-4-A 
Thousand Oaks, CA 91320 
Tel: + 1 805-447-1633 
Fax: +1 805-447-6244 
Date: 
28 August 2008 
Amendment 1 
01 October 2009 
Amendment 2 
27 May 2011 
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:  + 1 800-772-6436.  For all other study-related 
questions, continue to contact the Key Sponsor Contact. 


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  27 May 2011 
 
Page 2 of 139 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 2 Study of Panitumumab Plus 
Irinotecan Followed by Panitumumab Plus AMG 479 in Subjects With Metastatic 
Colorectal Carcinoma Expressing Wild-type KRAS and Refractory to Oxaliplatin- or 
Irinotecan- and Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired 
Resistance to Panitumumab, dated 27 May 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 9 May 1997 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  
 
Date (DD Month YYYY) 
 


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  27 May 2011 
 
Page 3 of 139 
 
 
Protocol Synopsis 
Title:  A Phase 2 Study of Panitumumab Plus Irinotecan Followed by Panitumumab Plus 
AMG 479 in Subjects With Metastatic Colorectal Carcinoma Expressing Wild-type KRAS and 
Refractory to Oxaliplatin- or Irinotecan- and Oxaliplatin-containing Regimens to Evaluate 
Mechanisms of Acquired Resistance to Panitumumab   
Study Phase:  2  
Indication:  Metastatic colorectal cancer expressing wild type (wt) KRAS and refractory to 
irinotecan- and oxaliplatin-containing regimens, or refractory to oxaliplatin-containing regimens. 
OBJECTIVES  
Primary  
Part 1:   
To determine if acquired resistance to panitumumab therapy in subjects with KRAS wild-type 
mCRC correlates with emergence of mutant KRAS tumors.  (Acquired resistance is defined as 
disease progression on panitumumab and irinotecan that occurs after a period of disease 
response or stable disease on treatment with this regimen is observed and radiographically-
confirmed.)   
Part 2:   
To determine if inhibition of the IGF-1R pathway with AMG 479 can overcome resistance to 
panitumumab therapy, as demonstrated by the objective response rate (ORR) to panitumumab 
and AMG 479 following disease progression on panitumumab and irinotecan.   
Secondary  
Part 1: 
• 
To determine ORR and other measures of efficacy (ie, TTR, DOR, PFS, OS) to panitumumab 
plus irinotecan  
• 
To evaluate the safety of panitumumab and irinotecan 
Part 2: 
• 
To determine measures of efficacy (ie, TTR, DOR, PFS, OS) of panitumumab plus AMG 479 
• 
To evaluate the safety of panitumumab and AMG 479 
Exploratory 
• 
To evaluate whether mutations of any other tumor genes, including but not limited to Raf and 
PI3K, predict disease response to panitumumab and irinotecan (Part 1) or panitumumab and 
AMG 479 (Part 2)   
• 
To evaluate whether any baseline subject characteristics, including but not limited to prior 
treatment history, predict responses to panitumumab and irinotecan (Part 1) or panitumumab 
and AMG 479 (Part 2)   
• 
To determine whether the status of potential tumor biomarkers (eg Raf, PI3K) evolve during 
tumor progression by comparing the status of biomarkers of the archival primary tumor tissue 
with that of the tumors biopsied on study   
Hypotheses:   
The KRAS mutation rate is higher in subjects with acquired resistance to panitumumab therapy 
than other subjects in mCRC with wt KRAS receiving panitumumab and irinotecan.   


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  27 May 2011 
 
Page 4 of 139 
 
 
Study Design:   
This is a global, multicenter, open-label phase 2 study designed to evaluate the mechanism(s) of 
resistance to the anti-EGFR antibody panitumumab given in combination with irinotecan in mCRC 
subjects with wild-type KRAS tumor status.   
In Part 1, all subjects will undergo a baseline tumor biopsy and will receive panitumumab with 
irinotecan.  Subjects that respond (complete or partial response ± confirmation) or have stable 
disease (based on modified RECIST v1.0 criteria, Appendix F) will continue to receive treatment 
until radiographically-confirmed disease progression.  These subjects will then undergo a second 
tumor biopsy and blood sampling and then proceed to Part 2 of the study.   
Subjects that experience radiographically-confirmed disease progression at the time of first tumor 
measurement will undergo blood sampling then proceed directly on to Part 2 of the study; tumor 
biopsy will not be required in these subjects.   
In Part 2, all subjects will receive panitumumab with AMG 479.   
In both parts of the study, panitumumab and irinotecan (Part 1) and panitumumab and AMG 479 
(Part 2) will be administered Q2W until disease progression, intolerability, withdrawal of consent, 
death, or unless otherwise indicated by the study team.   
All subjects that permanently discontinue all investigational products will complete a safety 
follow-up visit 30 days (+3 day window) after the last dose of investigational product.   
Subjects that end the treatment prior to radiographically-confirmed disease progression will be 
followed for radiographically-confirmed disease progression at the 30 day safety follow-up visit 
and then every 8 weeks (± 1 week window) until radiographically-confirmed disease progression, 
start of new cancer treatment, death, withdrawal of consent or at the end of the study, whichever 
is earlier.   
Subjects who have discontinued study treatment for any reason but have not withdrawn full 
consent to participate in the study, will be contacted by telephone or clinical visit every 3 months 
(± 28 days) for overall survival and disease status assessments up to 2 years after the last 
subject is enrolled in Part 2.   
Primary and Secondary Endpoints:   
Primary Endpoints: 
• 
Emergence of Mutant KRAS:  KRAS mutation status changed from wild-type at baseline to 
mutant at the time of the second biopsy following the radiographic evidence of acquired 
resistance to panitumumab plus irinotecan (Part 1).   
• 
Objective Response Rate (ORR):  Confirmed complete or partial response (per modified 
RECIST v1.0) to panitumumab and AMG 479 (Part 2)   
Secondary Endpoints: 
• 
Efficacy: ORR (Part 1), Time to Response (TTR), Duration of Response (DOR), 
Progression-free Survival (PFS), and Overall Survival (OS) (both Part 1 and Part 2)   
• 
Safety: Incidence and severity of adverse events, significant changes in laboratory values, 
incidence of anti-antibody formation (both Part 1 and Part 2)   
Sample Size:  Approximately 75 subjects   


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  27 May 2011 
 
Page 5 of 139 
 
 
Summary of Subject Eligibility Criteria:   
Key Inclusion Criteria 
• 
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum    
• 
Wild-type KRAS tumor status of archival tumor tissue (preferably from the primary tumor) 
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 while on or ≤ 6 months after treatment with 
irinotecan- and oxaliplatin- or oxaliplatin-based chemotherapy for mCRC    
− 
Subjects in whom relapse is diagnosed within 6 months after completing adjuvant 
chemotherapy (with oxaliplatin containing regimen) will be considered as having 
failed a prior regimen for metastatic disease 
• 
Radiographic measurement of tumor burden done within 28 days prior to Day 1 (start of 
treatment with investigational product)   
• 
At least 1 uni-dimensionally measurable lesion ≥ 20 mm using conventional CT or MRI or 
≥ 10 mm by spiral CT per modified RECIST v1.0.  Lesion must not be chosen from a 
previously irradiated field, unless there has been documented disease progression in that 
field after irradiation and prior to enrollment.  All sites of disease must be evaluated   
• 
At least 1 tumor (metastatic lesion or unresected primary tumor) that is amenable to core 
needle biopsy, as determined by the clinician who will perform the biopsy   
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix E)   
• 
Male or female ≥ 18 years of age at the time of informed consent   
• 
Willing to undergo two serial core biopsy procedures of tumors (metastasis or unresected 
primary)  
Key Exclusion Criteria 
• 
History of prior or concurrent central nervous system (CNS) metastases   
• 
Prior treatment with anti-EGFR antibodies (eg, panitumumab, cetuximab) or EGFR small 
molecule inhibitors (eg, erlotinib, gefitinib)   
• 
Prior treatment with monoclonal antibodies directed against IGF-1R or small molecule 
inhibitors directed against IGF-1R  
• 
Use of systemic chemotherapy and radiotherapy ≤ 21 days before enrollment.  Subject must 
have recovered from acute toxicities related to radiotherapy.   
• 
Use of any antibody therapy (eg, bevacizumab) ≤ 42 days before enrollment   
• 
Use of anti-tumor therapies including prior experimental agents or approved anti-tumor small 
molecules ≤ 30 days before enrollment   
• 
Known UGT1A1 polymorphisms predisposing to increased irinotecan toxicity   
• 
History of irinotecan intolerance that may interfere with planned treatment   
• 
History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of 
interstitial lung disease on baseline chest computerized tomography (CT) scan   
• 
Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, 
acute or chronic active hepatitis B infection   
• 
Any co-morbid disease or condition that could increase the risk of toxicity (eg, significant 
ascites, significant pleural effusion)   


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  27 May 2011 
 
Page 6 of 139 
 
 
• 
Any uncontrolled concurrent illness (eg, infection, bleeding diathesis) or history of any 
medical condition that may interfere with the interpretation of the study results   
• 
Major surgical procedure ≤ 28 days before enrollment or minor surgical procedure ≤ 14 days 
before enrollment.  Subjects must have recovered from surgery related toxicities.  Core 
biopsy, central venous catheter placement, fine needle aspiration, thoracentesis, or 
paracentesis is not considered a major or minor surgical procedure.  
Investigational Product Dosage and Administration:   
Panitumumab (6 mg/kg starting dose) and AMG 479 (12 mg/kg starting dose) will be open-label 
throughout the study.  The total dose of panitumumab and AMG 479 may be rounded up or down 
by no greater than 10 mg.   
The first dose of investigational products will be referred to as study day 1 of week 1.  
Investigational products will be administered on the same day Q2W (eg, week 1, 3, 5, 7) until 
progressive disease, intolerability, withdrawal, death, or unless otherwise indicated.  The  
Q2W schedule of all subsequent doses of investigational product will be planned according to 
study day 1 or within ± 3 days of the planned dose.   
In Part 1 the subjects will receive panitumumab 6 mg/kg Q2W plus irinotecan 180 mg/m2 Q2W.  
The first dose of investigational product (panitumumab) must be administered ≥ 7 days after the 
first biopsy and ≤ 28 days after enrollment and the most recent radiographic measurement of 
disease burden.  Upon radiographically-confirmed disease progression per modified RECIST v1.0 
or clinical progression, subjects will go on to receive panitumumab 6 mg/kg Q2W plus AMG 479 
12 mg/kg Q2W (Part 2).  Subjects that experience disease control (CR, PR, or SD) followed by 
the development of acquired resistance and subsequent disease progression during Part 1 of the 
study will undergo a second core biopsy prior to starting treatment on Part 2.  Subjects with 
primary resistance to panitumumab and irinotecan demonstrating disease progression on the first 
restaging radiographic scans done on study will proceed directly to Part 2 of the study without 
undergoing a second core biopsy.  
In Part 2, for subjects that undergo the second core biopsy, the first dose of investigational 
product (panitumumab 6 mg/kg Q2W and AMG 479 12 mg/kg Q2W) must be administered 
≥ 7 days after the second biopsy procedure and ≤ 28 days after radiographically-confirmed 
disease progression.  For subjects who do not undergo the second core biopsy procedure, the 
first dose of investigational product (panitumumab and AMG 479) must be administered 
≤ 28 days after radiographically-confirmed disease progression.  If the investigational product 
dosing cannot be done within the time windows specified above, permission to start treatment 
must be sought from Amgen.   
In Part 1, 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.  If the first infusion 
of panitumumab is well tolerated (ie without any serious infusion-related reactions) all subsequent 
infusions (including all infusions given in Part 2) may be administered over 30 ± 10 minutes.  In 
the event a subject’s actual weight requires greater than 150 mL volume infusion, panitumumab 
will be administered over 60 to 90 minutes ± 15 minutes, as tolerated.  Doses higher than 
1000 mg should be diluted to 150 mL in 0.9% sodium chloride solution, USP (saline solution) and 
infused over 60 to 90 ± 15 minutes.   
AMG 479 will be administered by an IV infusion through a peripheral line or indwelling 
catheter using a nonpyrogenic, low protein binding filter with a 0.2- or 0.22-micron pore 
size in-line filter (obtained by each center) infusion set-up over a 60 ± 15 minute period 
during the initial dose administration.  If the dose administration is well tolerated, subsequent 
administrations may be made over 30 ± 10 minutes.  In the event a subject’s actual weight 
requires greater than 150 mL volume infusion, AMG 479 will be administered over 60 to 
90 minutes ± 15 minutes, as tolerated.  Infusion times can be extended to a maximum of 
120 minutes for subjects deemed unable to tolerate the 90 minutes infusion.  


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  27 May 2011 
 
Page 7 of 139 
 
 
All subjects should be observed for any adverse reactions during infusions of panitumumab 
(Part 1) and during panitumumab and AMG 479 infusions and for at least 60 minutes following 
completion of the first administration of AMG 479 (Part 2).  The observation period for subsequent 
infusions may be reduced at the discretion of the investigator.   
Control Group:  N/A 
Procedures:   
Screening for Part 1 will occur within 35 days before enrollment (date main informed consent form 
is signed to date of enrollment). 
Screening for Part 2 will begin on the date of radiographically confirmed disease progression and 
must be completed within 28 days.   
• 
If the KRAS status of tumor tissue from the primary tumor or metastasis for a subject has not 
previously been determined by an Amgen approved central laboratory or by an experienced 
laboratory (per local regulatory guidelines) using a validated test method during initial 
screening, archived formalin-fixed paraffin-embedded tumor tissue block or unstained tumor 
slides along with the corresponding pathology report will be submitted to the central 
laboratory or local laboratory for evaluation of KRAS tumor status (wild-type or mutant).  
Regardless of how the 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 report for evaluation of 
KRAS (if applicable), EGFR membrane staining, and other exploratory biomarker analyses (see 
Section 7.7). 
Only subjects with confirmed wild-type KRAS tumor status will be eligible for this study.  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.   
Screening and on-study assessments such as physical exam, vital signs, ECOG, ECG (screening 
only), and CT or MRI scans of the chest, abdomen, and pelvis will be performed.   
Screening and on-study local laboratory tests will be performed including hematology, chemistry, 
carcinoembryonic antigen (CEA), glycosylated hemoglobin (HgbA1c), 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 and biomarkers and 
submitted to the central laboratory.  Tumor tissue sampling by core biopsy of a locally advanced 
or metastatic lesion will be collected prior to the start of study treatment in Part 1.  In addition, for 
subjects who initially respond to panitumumab plus irinotecan or have stable disease and 
subsequently have radiographically-confirmed disease progression, a second biopsy will be 
collected prior to start of study treatment in Part 2.  These samples will be submitted to the central 
laboratory.   
During the study, CT or MRI scans of the chest, abdomen, pelvis and all other sites of disease 
will be performed every 8 weeks (± 1 week window) until radiographically-confirmed disease 
progression, start of new cancer treatment, death, withdrawal of consent or at the end of the 
study, whichever is earlier.   


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  27 May 2011 
 
Page 8 of 139 
 
 
Statistical Considerations:   
The primary goal of the statistical analysis is to test whether acquired resistance to panitumumab 
therapy in mCRC with wt KRAS tumors correlates with emergence of mutant KRAS tumors and to 
evaluate the efficacy and safety of both panitumumab plus irinotecan and panitumumab plus 
AMG 479.  Summary statistics including confidence intervals will be generated for all efficacy 
endpoints.  Safety analyses will be descriptive and will be presented in tabular format with the 
appropriate summary statistics.  One interim analysis is planned for this study.  The study is not 
anticipated to stop early unless a major unexpected safety signal is detected.   
Sponsor/Licensee:  Amgen Inc. 
 


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  27 May 2011 
 
Page 9 of 139 
 
 
Study Design and Treatment Schema 
 
 
 
 


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  14 November 2012 
 
Page 1 of 141 
 
 
Title:  A Phase 2 Study of Panitumumab Plus Irinotecan Followed by 
Panitumumab Plus AMG 479 in Subjects With Metastatic Colorectal Carcinoma 
Expressing Wild-type KRAS and Refractory to Oxaliplatin- or Irinotecan- and 
Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired Resistance 
to Panitumumab 
Panitumumab / AMG 479 
 
Amgen Protocol Number 20070820 
 
EudraCT Number: 2008-004752-77 
 
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 (EU): 
Lis Mable 
Clinical Research Study Manager 
240 Cambridge Science Park 
Milton Road 
Cambridge, CB4 0WD 
United Kingdom 
Tel: + 44 1223 436719 
Fax: + 44 1223 420319 
Key Sponsor Contact (US & 
EU): 
Roger Sidhu, MD, FRCPC 
Clinical Research Medical Director 
1 Amgen Center Dr. 
Mailstop 38-2-A 
Thousand Oaks, CA 91320 
Tel: + 1 805-447-5857 
Fax: +1 805-480-4978 
Date: 
28 August 2008 
Amendment 1 
01 October 2009 
Amendment 2 
27 May 2011 
Amendment 3 
14 November 2012 
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 
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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 
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If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  + 1 800-772-6436.  For all other study-related 
questions, continue to contact the Key Sponsor Contact. 


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  14 November 2012 
 
Page 2 of 141 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 2 Study of Panitumumab Plus 
Irinotecan Followed by Panitumumab Plus AMG 479 in Subjects With Metastatic 
Colorectal Carcinoma Expressing Wild-type KRAS and Refractory to Oxaliplatin- or 
Irinotecan- and Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired 
Resistance to Panitumumab, dated 14 November 2012, 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 9 May 1997 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  
 
Date (DD Month YYYY) 
 


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  14 November 2012 
 
Page 3 of 141 
 
 
Protocol Synopsis 
Title:  A Phase 2 Study of Panitumumab Plus Irinotecan Followed by Panitumumab Plus 
AMG 479 in Subjects With Metastatic Colorectal Carcinoma Expressing Wild-type KRAS and 
Refractory to Oxaliplatin- or Irinotecan- and Oxaliplatin-containing Regimens to Evaluate 
Mechanisms of Acquired Resistance to Panitumumab   
Study Phase:  2  
Indication:  Metastatic colorectal cancer expressing wild type (wt) KRAS and refractory to 
irinotecan- and oxaliplatin-containing regimens, or refractory to oxaliplatin-containing regimens. 
OBJECTIVES  
Primary  
Part 1:   
To determine if acquired resistance to panitumumab therapy in subjects with KRAS wild-type 
mCRC correlates with emergence of mutant KRAS tumors.  (Acquired resistance is defined as 
disease progression on panitumumab and irinotecan that occurs after a period of disease 
response or stable disease on treatment with this regimen is observed and radiographically-
confirmed.)   
Part 2:   
To determine if inhibition of the IGF-1R pathway with AMG 479 can overcome resistance to 
panitumumab therapy, as demonstrated by the objective response rate (ORR) to panitumumab 
and AMG 479 following disease progression on panitumumab and irinotecan.   
Secondary  
Part 1: 
• 
To determine ORR and other measures of efficacy (ie, TTR, DOR, PFS, OS) to panitumumab 
plus irinotecan  
• 
To evaluate the safety of panitumumab and irinotecan 
Part 2: 
• 
To determine measures of efficacy (ie, TTR, DOR, PFS, OS) of panitumumab plus AMG 479 
• 
To evaluate the safety of panitumumab and AMG 479 
Exploratory 
• 
To evaluate whether mutations of any other tumor genes, including but not limited to Raf and 
PI3K, predict disease response to panitumumab and irinotecan (Part 1) or panitumumab and 
AMG 479 (Part 2)   
• 
To evaluate whether any baseline subject characteristics, including but not limited to prior 
treatment history, predict responses to panitumumab and irinotecan (Part 1) or panitumumab 
and AMG 479 (Part 2)   
• 
To determine whether the status of potential tumor biomarkers (eg Raf, PI3K) evolve during 
tumor progression by comparing the status of biomarkers of the archival primary tumor tissue 
with that of the tumors biopsied on study   
Hypotheses:   
The KRAS mutation rate is higher in subjects with acquired resistance to panitumumab therapy 
than other subjects in mCRC with wt KRAS receiving panitumumab and irinotecan.   


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  14 November 2012 
 
Page 4 of 141 
 
 
Study Design:   
This is a global, multicenter, open-label phase 2 study designed to evaluate the mechanism(s) of 
resistance to the anti-EGFR antibody panitumumab given in combination with irinotecan in mCRC 
subjects with wild-type KRAS tumor status.   
In Part 1, all subjects will undergo a baseline tumor biopsy and will receive panitumumab with 
irinotecan.  Subjects that respond (complete or partial response ± confirmation) or have stable 
disease (based on modified RECIST v1.0 criteria, Appendix F) will continue to receive treatment 
until radiographically-confirmed disease progression.  These subjects will then undergo a second 
tumor biopsy and blood sampling and then proceed to Part 2 of the study.   
Subjects that experience radiographically-confirmed disease progression at the time of first tumor 
measurement will undergo blood sampling then proceed directly on to Part 2 of the study; tumor 
biopsy will not be required in these subjects.   
In Part 2, all subjects will receive panitumumab with AMG 479.   
In both parts of the study, panitumumab and irinotecan (Part 1) and panitumumab and AMG 479 
(Part 2) will be administered Q2W until disease progression, intolerability, withdrawal of consent, 
death, or unless otherwise indicated by the study team.   
All subjects that permanently discontinue all investigational products will complete a safety 
follow-up visit 30 days (+3 day window) after the last dose of investigational product.   
Subjects that end the treatment prior to radiographically-confirmed disease progression will be 
followed for radiographically-confirmed disease progression at the 30 day safety follow-up visit 
and then every 8 weeks (± 1 week window) until radiographically-confirmed disease progression, 
start of new cancer treatment, death, withdrawal of consent or at the end of the study, whichever 
is earlier.   
Subjects who have discontinued study treatment for any reason but have not withdrawn full 
consent to participate in the study, will be contacted by telephone or clinical visit every 3 months 
(± 28 days) for overall survival and disease status assessments up to 2 years (± 2 months) after 
the last subject is enrolled in Part 1.   
Primary and Secondary Endpoints:   
Primary Endpoints: 
• 
Emergence of Mutant KRAS:  KRAS mutation status changed from wild-type at baseline to 
mutant at the time of the second biopsy following the radiographic evidence of acquired 
resistance to panitumumab plus irinotecan (Part 1).   
• 
Objective Response Rate (ORR):  Confirmed complete or partial response (per modified 
RECIST v1.0) to panitumumab and AMG 479 (Part 2)   
Secondary Endpoints: 
• 
Efficacy: ORR (Part 1), Time to Response (TTR), Duration of Response (DOR), 
Progression-free Survival (PFS), and Overall Survival (OS) (both Part 1 and Part 2)   
• 
Safety: Incidence and severity of adverse events, significant changes in laboratory values, 
incidence of anti-antibody formation (both Part 1 and Part 2)   
Sample Size:  Approximately 75 subjects   


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  14 November 2012 
 
Page 5 of 141 
 
 
Summary of Subject Eligibility Criteria:   
Key Inclusion Criteria 
• 
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum    
• 
Wild-type KRAS tumor status of archival tumor tissue (preferably from the primary tumor) 
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 while on or ≤ 6 months after treatment with 
irinotecan- and oxaliplatin- or oxaliplatin-based chemotherapy for mCRC    
− 
Subjects in whom relapse is diagnosed within 6 months after completing adjuvant 
chemotherapy (with oxaliplatin containing regimen) will be considered as having 
failed a prior regimen for metastatic disease 
• 
Radiographic measurement of tumor burden done within 28 days prior to Day 1 (start of 
treatment with investigational product)   
• 
At least 1 uni-dimensionally measurable lesion ≥ 20 mm using conventional CT or MRI or 
≥ 10 mm by spiral CT per modified RECIST v1.0.  Lesion must not be chosen from a 
previously irradiated field, unless there has been documented disease progression in that 
field after irradiation and prior to enrollment.  All sites of disease must be evaluated   
• 
At least 1 tumor (metastatic lesion or unresected primary tumor) that is amenable to core 
needle biopsy, as determined by the clinician who will perform the biopsy   
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix E)   
• 
Male or female ≥ 18 years of age at the time of informed consent   
• 
Willing to undergo two serial core biopsy procedures of tumors (metastasis or unresected 
primary)  
Key Exclusion Criteria 
• 
History of prior or concurrent central nervous system (CNS) metastases   
• 
Prior treatment with anti-EGFR antibodies (eg, panitumumab, cetuximab) or EGFR small 
molecule inhibitors (eg, erlotinib, gefitinib)   
• 
Prior treatment with monoclonal antibodies directed against IGF-1R or small molecule 
inhibitors directed against IGF-1R  
• 
Use of systemic chemotherapy and radiotherapy ≤ 21 days before enrollment.  Subject must 
have recovered from acute toxicities related to radiotherapy.   
• 
Use of any antibody therapy (eg, bevacizumab) ≤ 42 days before enrollment   
• 
Use of anti-tumor therapies including prior experimental agents or approved anti-tumor small 
molecules ≤ 30 days before enrollment   
• 
Known UGT1A1 polymorphisms predisposing to increased irinotecan toxicity   
• 
History of irinotecan intolerance that may interfere with planned treatment   
• 
History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of 
interstitial lung disease on baseline chest computerized tomography (CT) scan   
• 
Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, 
acute or chronic active hepatitis B infection   
• 
Any co-morbid disease or condition that could increase the risk of toxicity (eg, significant 
ascites, significant pleural effusion)   


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  14 November 2012 
 
Page 6 of 141 
 
 
• 
Any uncontrolled concurrent illness (eg, infection, bleeding diathesis) or history of any 
medical condition that may interfere with the interpretation of the study results   
• 
Major surgical procedure ≤ 28 days before enrollment or minor surgical procedure ≤ 14 days 
before enrollment.  Subjects must have recovered from surgery related toxicities.  Core 
biopsy, central venous catheter placement, fine needle aspiration, thoracentesis, or 
paracentesis is not considered a major or minor surgical procedure.  
Investigational Product Dosage and Administration:   
Panitumumab (6 mg/kg starting dose) and AMG 479 (12 mg/kg starting dose) will be open-label 
throughout the study.  The total dose of panitumumab and AMG 479 may be rounded up or down 
by no greater than 10 mg.   
The first dose of investigational products will be referred to as study day 1 of week 1.  
Investigational products will be administered on the same day Q2W (eg, week 1, 3, 5, 7) until 
progressive disease, intolerability, withdrawal, death, or unless otherwise indicated.  The  
Q2W schedule of all subsequent doses of investigational product will be planned according to 
study day 1 or within ± 3 days of the planned dose.   
In Part 1 the subjects will receive panitumumab 6 mg/kg Q2W plus irinotecan 180 mg/m2 Q2W.  
The first dose of investigational product (panitumumab) must be administered ≥ 7 days after the 
first biopsy and ≤ 28 days after enrollment and the most recent radiographic measurement of 
disease burden.  Upon radiographically-confirmed disease progression per modified RECIST v1.0 
or clinical progression, subjects will go on to receive panitumumab 6 mg/kg Q2W plus AMG 479 
12 mg/kg Q2W (Part 2).  Subjects that experience disease control (CR, PR, or SD) followed by 
the development of acquired resistance and subsequent disease progression during Part 1 of the 
study will undergo a second core biopsy prior to starting treatment on Part 2.  Subjects with 
primary resistance to panitumumab and irinotecan demonstrating disease progression on the first 
restaging radiographic scans done on study will proceed directly to Part 2 of the study without 
undergoing a second core biopsy.  
In Part 2, for subjects that undergo the second core biopsy, the first dose of investigational 
product (panitumumab 6 mg/kg Q2W and AMG 479 12 mg/kg Q2W) must be administered 
≥ 7 days after the second biopsy procedure and ≤ 28 days after radiographically-confirmed 
disease progression.  For subjects who do not undergo the second core biopsy procedure, the 
first dose of investigational product (panitumumab and AMG 479) must be administered 
≤ 28 days after radiographically-confirmed disease progression.  If the investigational product 
dosing cannot be done within the time windows specified above, permission to start treatment 
must be sought from Amgen.   
In Part 1, 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.  If the first infusion 
of panitumumab is well tolerated (ie without any serious infusion-related reactions) all subsequent 
infusions (including all infusions given in Part 2) may be administered over 30 ± 10 minutes.  In 
the event a subject’s actual weight requires greater than 150 mL volume infusion, panitumumab 
will be administered over 60 to 90 minutes ± 15 minutes, as tolerated.  Doses higher than 
1000 mg should be diluted to 150 mL in 0.9% sodium chloride solution, USP (saline solution) and 
infused over 60 to 90 ± 15 minutes.   
AMG 479 will be administered by an IV infusion through a peripheral line or indwelling catheter 
using a nonpyrogenic, low protein binding filter with a 0.2- or 0.22-micron pore size in-line filter 
(obtained by each center) infusion set-up over a 60 ± 15 minute period during the initial dose 
administration.  If the dose administration is well tolerated, subsequent administrations may be 
made over 30 ± 10 minutes.  In the event a subject’s actual weight requires greater than 150 mL 
volume infusion, AMG 479 will be administered over 60 to 90 minutes ± 15 minutes, as tolerated.  
Infusion times can be extended to a maximum of 120 minutes for subjects deemed unable to 
tolerate the 90 minutes infusion.  


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  14 November 2012 
 
Page 7 of 141 
 
 
All subjects should be observed for any adverse reactions during infusions of panitumumab 
(Part 1) and during panitumumab and AMG 479 infusions and for at least 60 minutes following 
completion of the first administration of AMG 479 (Part 2).  The observation period for subsequent 
infusions may be reduced at the discretion of the investigator.   
Control Group:  N/A 
Procedures:   
Screening for Part 1 will occur within 35 days before enrollment (date main informed consent form 
is signed to date of enrollment). 
Screening for Part 2 will begin on the date of radiographically confirmed disease progression and 
must be completed within 28 days.   
• 
If the KRAS status of tumor tissue from the primary tumor or metastasis for a subject has not 
previously been determined by an Amgen approved central laboratory or by an experienced 
laboratory (per local regulatory guidelines) using a validated test method during initial 
screening, archived formalin-fixed paraffin-embedded tumor tissue block or unstained tumor 
slides along with the corresponding pathology report will be submitted to the central 
laboratory or local laboratory for evaluation of KRAS tumor status (wild-type or mutant).  
Regardless of how the 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 report for evaluation of 
KRAS (if applicable), EGFR membrane staining, and other exploratory biomarker analyses (see 
Section 7.7). 
Only subjects with confirmed wild-type KRAS tumor status will be eligible for this study.  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.   
Screening and on-study assessments such as physical exam, vital signs, ECOG, ECG (screening 
only), and CT or MRI scans of the chest, abdomen, and pelvis will be performed.   
Screening and on-study local laboratory tests will be performed including hematology, chemistry, 
carcinoembryonic antigen (CEA), glycosylated hemoglobin (HgbA1c), 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 and biomarkers and 
submitted to the central laboratory.  Tumor tissue sampling by core biopsy of a locally advanced 
or metastatic lesion will be collected prior to the start of study treatment in Part 1.  In addition, for 
subjects who initially respond to panitumumab plus irinotecan or have stable disease and 
subsequently have radiographically-confirmed disease progression, a second biopsy will be 
collected prior to start of study treatment in Part 2.  These samples will be submitted to the central 
laboratory.   
During the study, CT or MRI scans of the chest, abdomen, pelvis and all other sites of disease 
will be performed every 8 weeks (± 1 week window) until radiographically-confirmed disease 
progression, start of new cancer treatment, death, withdrawal of consent or at the end of the 
study, whichever is earlier.   
Refer to Sections 7.4 and 7.5 for study procedures during the 30-day safety follow-up visit 
and the long-term follow-up visit, respectively. Refer to Section 7.8 for study procedures 
following the completion of all planned study analyses. 


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  14 November 2012 
 
Page 8 of 141 
 
 
Statistical Considerations:   
The primary goal of the statistical analysis is to test whether acquired resistance to panitumumab 
therapy in mCRC with wt KRAS tumors correlates with emergence of mutant KRAS tumors and to 
evaluate the efficacy and safety of both panitumumab plus irinotecan and panitumumab plus 
AMG 479.  Summary statistics including confidence intervals will be generated for all efficacy 
endpoints.  Safety analyses will be descriptive and will be presented in tabular format with the 
appropriate summary statistics.  One interim analysis is planned for this study.  The study is not 
anticipated to stop early unless a major unexpected safety signal is detected.   
Sponsor/Licensee:  Amgen Inc. 
 


Approved 
 
 
Product:  Panitumumab, AMG 479 
Protocol Number:  20070820 
Date:  14 November 2012 
 
Page 9 of 141 
 
 
Study Design and Treatment Schema