Clinical trial NCT01231347
Conditions: Adenocarcinoma of the Pancreas Advanced Solid Tumors Cancer Cancer of Pancreas Cancer of the Pancreas Metastases Metastatic Cancer Metastatic Pancreatic Cancer Pancreas Cancer Pancreatic Cancer Bone Metastases Endocrine Cancer Oncology Oncology Patients Solid Tumors Advanced Malignancy
Keywords: pancreas gemcitabine metastatic jaundice
Sponsor: NantCell, Inc.
Start date: 2011-04-07; Completion date: 2012-12-12
Enrollment: 800 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
AMG 479 is an investigational fully human monoclonal antibody that targets type 1 insulin-like growth factor receptor (IGF-1R). Signaling through IGF-1R plays an important role in the regulation of cell growth and survival. The primary purpose of the study is to determine if AMG 479 and gemcitabine improves overall survival as compared to placebo and gemcitabine.

Detailed description:

Arms: arm 1: Arm 1: AMG 479-placebo IV days 1 and 15 plus gemcitabine 1000 mg/m2 IV days 1, 8, and 15 of a 28 day cycle arm 2: Arm 2: AMG 479 12 mg/kg IV days 1 and 15 plus gemcitabine 1000 mg/m2 IV days 1, 8, and 15 of a 28 day cycle arm 3: Arm 3: AMG 479 20 mg/kg IV days 1 and 15 plus gemcitabine 1000 mg/m2 IV days 1, 8, and 15 of a 28 day cycle
Interventions: intervention 1: AMG 479 intervention 2: Placebo intervention 3: AMG 479 intervention 4: gemcitabine
Intervention descriptions: intervention 1: AMG 479 12 mg/kg administered intravenously on days 1 and 15 of a 28 day cycle intervention 2: Placebo administered intravenously on days 1 and 15 of a 28 day cycle intervention 3: AMG 479 20mg/kg administered intravenously on days 1 and 15 of a 28 day cycle intervention 4: gemcitabine 1000mg/m2 administered intravenously on days 1, 8 and 15 of a 28 day cycle

Protocol documents:
Prot_SAP_000.pdf: 
Approved 
 
 
Product:  AMG 479 
Protocol Number:  20060540 
Date:  20 September 2010 
Page 1 of 115 
 
Title:  A Phase 3, Multicenter, Randomized, Double-Blind, Placebo Controlled, Trial 
of AMG 479 or Placebo in Combination with Gemcitabine as First-line 
Therapy for Metastatic Adenocarcinoma of the Pancreas 
 
GAMMA 
(Gemcitabine and AMG 479 in Metastatic Adenocarcinoma of the Pancreas) 
 
Amgen Protocol Number (AMG 479) 20060540 
 
EudraCT number 2010-020398-18 
Clinical Study Sponsor: 
Amgen Inc 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: 805-447-1000 
Key Sponsor Contact: 
Jesse McGreivy, MD 
Clinical Research Medical Director 
Amgen Inc 
1120 Veterans Blvd., ASF B3-3 
South San Francisco, CA 94080 
Phone: 650-244-2634 
Fax: 650-837-9716 
Email: jessem@amgen.com 
Kay Smith 
Global Clinical Research Study Manager 
Amgen Ltd  
240 Cambridge Science Park 
Milton Road 
Cambridge, CB4 0WD, UK 
Tel: +44 (0) 1223 436339 
Fax: +44 (0) 1223 420319 
Email: kay@amgen.com  
Mandy Parson 
Clinical Research Study Manager 
Amgen Inc  
One Amgen Center Drive, 38-3-C 
Thousand Oaks, CA 91320-1799 
Phone: 805- 313-4891 
Fax: 805-375-9528 
Email: mparson@amgen.com  
Date: 
20 September 2010 
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:   
US sites: 1-800-77-AMGEN 
For all other countries: 1-805-447-5000 
For all other study-related questions, continue to contact the Key Sponsor Contact. 


Approved 
 
 
Product:  AMG 479 
Protocol Number:  20060540 
Date:  20 September 2010 
Page 2 of 115 
 
Investigator’s Agreement 
I have read the attached protocol entitled “A Phase 3, Multicenter, Randomized, 
Double-Blind, Placebo Controlled, Trial of AMG 479 or Placebo in Combination with 
Gemcitabine as First-line Therapy for Metastatic Adenocarcinoma of the Pancreas” 
dated 20 September 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 local Ethic Committee and/or Institutional 
Review Board regulations and 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 <<or Coordinating>> 
Investigator 
 
Date (DD Month YYYY) 


Approved 
 
 
Product:  AMG 479 
Protocol Number:  20060540 
Date:  20 September 2010 
Page 3 of 115 
 
Protocol Synopsis 
Title:  A Phase 3, Multicenter, Randomized, Double-Blind, Placebo Controlled Trial of AMG 479 
or Placebo in Combination with Gemcitabine as First-line Therapy for Metastatic Adenocarcinoma 
of the Pancreas 
Study Phase:  3 
Indication:  Metastatic adenocarcinoma of the pancreas 
Primary Objective:  To determine if the treatment of AMG 479 at 12 mg/kg and/or 20 mg/kg in 
combination with gemcitabine improves overall survival as compared with placebo in combination 
with gemcitabine in subjects with metastatic adenocarcinoma of the pancreas 
Secondary Objective(s):   
• 
To evaluate progression-free survival (PFS) per Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 
• 
To evaluate the survival rate at 12-months, and at the timepoints of  3, 6, 9, 18, and 24 
months 
• 
To evaluate objective response rate, time to disease progression, duration of response, and 
disease control rate (partial response [PR} + complete response [CR] + stable disease [SD]) 
as per RECIST version 1.1 
• 
To evaluate subject incidence of adverse events, significant laboratory abnormalities, and 
immunogenicity 
• 
To evaluate AMG 479 dose exposure, dose intensity, and pharmacokinetic (PK) parameters 
and to evaluate relationships between AMG 479 exposure measures and selected safety and 
efficacy measures  
• 
To evaluate gemcitabine dose exposure, dose intensity in all subjects, and gemcitabine PK 
parameters in a subset of subjects 
• 
To evaluate patient reported hepatobiliary symptoms measured by the Functional 
Assessment of Cancer Therapy – Hepatobiliary subscale questionnaire (FACT-Hep-HS) 
• 
To evaluate the efficacy of AMG 479 versus (vs) placebo in combination with gemcitabine 
within an enriched sub-population defined by a single or composite biomarker (eg, high 
insulin growth factor binding protein-3 [IGFBP-3] and/or low IGFBP-2) with respect to OS 
Hypotheses:   
AMG 479 at 12 mg/kg and/or 20 mg/kg in combination with gemcitabine will improve OS 
compared with placebo in combination with gemcitabine in subjects with metastatic 
adenocarcinoma of the pancreas. 
H0: The OS hazard ratio of AMG 479 + gemcitabine relative to gemcitabine alone = 1.00  
H1: The OS hazard ratio of AMG 479 + gemcitabine relative to gemcitabine alone < 1.00 
Study Design:   
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled study.  Subjects 
(n=825) will be randomized in a 2:2:1 ratio to first-line therapy in 1 of 3 arms: 
• 
Arm 1: AMG 479-placebo plus gemcitabine  
• 
Arm 2: AMG 479 at 12 mg/kg plus gemcitabine 
• 
Arm 3: AMG 479 at 20 mg/kg plus gemcitabine 


Approved 
 
 
Product:  AMG 479 
Protocol Number:  20060540 
Date:  20 September 2010 
Page 4 of 115 
 
Randomization will be stratified according to Eastern Cooperative Oncology Group (ECOG) 
performance status (0 vs 1), the presence of liver metastases (Yes vs No), and by geographical 
region (Western Europe, United States, Canada, Australia vs rest of world). 
AMG 479 at 12 mg/kg, AMG 479 at 20 mg/kg, and placebo will be double-blind; gemcitabine will 
be open label.  Cycles of gemcitabine plus AMG 479 or gemcitabine plus placebo are planned to 
be administered every 28 days (± 3 days) by intravenous (IV) infusion.  Gemcitabine at 
1000 mg/m2 will be administered on days 1, 8, and 15 of each 28 day cycle followed by the 
AMG 479 at 12 mg/kg, AMG 479 at 20 mg/kg, or placebo on days 1 and 15.  Subjects will 
continue to receive protocol specified therapy until disease progression as per RECIST version 
1.1, unacceptable toxicities, withdrawal of consent, or start of a new systemic anti-cancer therapy. 
Subjects who discontinue gemcitabine for toxicities or intolerance that are presumed related to 
gemcitabine can continue AMG 479 or placebo. Tumor response assessment will be performed 
by the investigator as per RECIST guidelines version 1.1.  Subjects will be evaluated for tumor 
response every 8 weeks (± 7 days) independent of the treatment cycle until disease progression, 
withdrawal of consent, or initiation of new systemic anti-cancer therapy.  Subjects with symptoms 
suggestive of disease progression will be evaluated radiologically for tumor progression at the 
time the symptoms occur.  
All subjects will be assessed for non-intensive AMG 479 PK.  Approximately thirteen evaluable 
subjects per arm will be assessed for intensive AMG 479 PK and gemcitabine PK and its 
metabolite (see Section 7.3 for additional details). 
Subjects who discontinue all protocol specified therapy (ie, AMG 479 or AMG 479-placebo and 
gemcitabine) will be followed for safety, immunogenicity and PK at the 30 (+3) day follow-up visit, 
and for post-protocol therapy and survival every 12 weeks (± 14 days) until death, withdrawal of 
consent or the end of the study.  The end of the study will be when a minimum of 90% of 
randomized subjects who have not withdrawn from the study have died. 
 
Primary and Secondary Endpoints:   
Primary Endpoint:  Overall survival  
Secondary Endpoints: Progression-free survival, survival rate at the timepoints of 3, 6, 9, 12, 18, 
and 24 months, objective response rate, time to disease progression, duration of response, 
disease control rate (PR+CR+SD); incidence of subject adverse events, laboratory abnormalities 
and immunogenicity; AMG 479 dose exposure, dose intensity and PK parameters; gemcitabine 
dose exposure, dose intensity and PK parameters; the change in hepatobiliary symptoms using 
the FACT-Hep HS. 
 
Sample Size:  825 subjects 
Summary of Subject Eligibility Criteria:  
Key Inclusion criteria: Subjects must have histologically or cytologically confirmed metastatic 
adenocarcinoma of the pancreas (American Joint Committee on Cancer Stage IV); ECOG score 
of 0 or 1; Men or women ≥ 18 years of age. 
Key Exclusion Criteria: Islet cell, acinar cell carcinoma, non-adenocarcinoma, (eg, lymphoma, 
sarcoma, etc), adenocarcinoma originated from biliary tree or cystadenocarcinoma; currently 
treated or previously treated with biologic, small molecule, immunotherapy, chemotherapy (eg, 
gemcitabine), radiotherapy, chemoradiotherapy or other agents for pancreatic cancer. 


Approved 
 
 
Product:  AMG 479 
Protocol Number:  20060540 
Date:  20 September 2010 
Page 5 of 115 
 
Amgen Investigational Product Dosage and Administration:   
Arm 1:  AMG 479-placebo IV days 1 and 15 of a 28 day cycle 
Arm 2:  AMG 479 at 12 mg/kg IV days 1 and 15 of a 28 day cycle 
Arm 3:  AMG 479 at 20 mg/kg IV days 1 and 15 of a 28 day cycle 
Refer to Section 6.1.1 for detailed dosage and administration guidance 
Non Amgen Non-Investigational Product Dosage and Administration 
Gemcitabine at 1000 mg/m2 IV over 30 (±10) minutes on days 1, 8, and 15 of each 28 day cycle 
in Arms 1, 2 and 3 
Procedures:  A complete schedule of assessments is provided in Appendix A. 
Statistical Considerations:  The primary goal of the statistical analysis is to determine if OS in 
Arm 2 and/or Arm 3 is statistically significantly improved compared to Arm 1.  Eight hundred and 
twenty-five subjects will be randomized in a 2:2:1 ratio (330 in Arm 1 and 2, 165 in Arm 3) to 
attain a total of approximately 642 OS events.  Randomization will be stratified by ECOG 
performance score (0 vs 1), and the presence of liver metastases (Yes vs No), and by 
geographical region (Western Europe, United States, Canada, Australia vs rest of world).  A 
log-rank test stratified by the randomization factors will be used to compare OS and Hochberg’s 
procedure will be used to achieve an overall one-sided 2.5% significance level for declaring 
superiority of Arm 2 vs 1 and/or Arm 3 vs 1.  An independent Data Monitoring Committee (DMC) 
external to Amgen will be established to conduct two planned safety and one interim efficacy 
reviews.  The two safety reviews will occur after 50 subjects (approximately 20, 20 and 10 per 
arm) and 150 subjects (approximately 60, 60 and 30 per arm) have been enrolled and had the 
opportunity to complete 1 cycle of protocol specified therapy.  Thereafter the DMC safety reviews 
will occur approximately every 6 months until the primary analysis has been completed.  This will 
occur without a hold in enrollment.  The interim analysis of OS for lack of benefit for Arm 2 and/or 
Arm 3 vs Arm 1 will be performed at approximately 30% (188 events) of the primary analysis total 
event goal. 
 
 
Sponsor/Licensee:  Amgen Inc. 
 


Approved 
 
 
Product:  AMG 479 
Protocol Number:  20060540 
Date:  20 September 2010 
Page 6 of 115 
 
Study Design and Treatment Schema 
 
 
 
 
 
a Subjects with evidence of disease progression (per RECIST v1.1) or unacceptable toxicities will discontinue protocol 
specified therapy and will be followed for survival every 12 weeks (± 14 days)  
 
b Subjects in long term follow up who discontinue protocol specified therapy but have not progressed will continue to be 
evaluated by routine radiographic imaging every 8 weeks (± 7 days) until disease progression (per RECIST v1.1), 
withdrawal of consent or initiation of new systemic anti-cancer therapy 
 
c The end of the study is defined per Section 3.4.2 
 S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N
 Within 7 
days of  
day 1 
 S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N
 Within 7 
days of  
Study day 
1 
 S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N
 Within 7 
days of  
day 1 
 S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N
 Within 7 
days of  
day 1 
 S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N
 Within 7 
days of  
day 1 
 S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N
 Within 7 
days of  
day 1 
 S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N
 Within 7 
days of  
day 1 
 S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N
 Within 7 
days of  
Study day 
1 
 S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N
 Within 7 
days of  
day 1 
 
 
 
E 
N 
D 
 
O
F 
 
S 
T 
U 
D 
Y 
L 
O 
N 
G 
 
T 
E 
R 
M 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
 S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
Treatment Arm 1 
AMG 479-Placebo 
days 1 and 15 + 
Gemcitabine 1000 
mg/m2 days 1, 8, 
and 15 of each 
cycle 
(330 subjects) 
Treatment Arm 2  
AMG 479 12 mg/kg 
days 1 and 15 +  
Gemcitabine 1000 
mg/m2 days 1, 8, 
and 15 of each cycle 
(330 subjects) 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N
 Within 7 
days of  
study day 1 
30 (+3) days 
after last 
protocol 
specified 
therapy 
Cycles repeated every  
28 days (± 3 days) a 
Within  
28 days of 
randomization 
Treatment Arm 3 
AMG 479 20 mg/kg 
days 1 and 15 +  
Gemcitabine 1000 
mg/m2 days 1, 8, 
and 15 of each cycle 
(165 subjects) 
Every  
12 weeks 
(±14 days)b  
 
See 
footnote c, 
below