Clinical trial NCT00626106
Conditions: Breast Cancer Breast Tumors Metastatic Cancer
Keywords: postmenopausal hormone receptor positive locally advanced metastatic
Sponsor: NantCell, Inc.
Start date: 2008-03-27; Completion date: 2011-09-23
Enrollment: 156 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, phase 2 study. Subjects will include postmenopausal women with confirmed HR-positive, locally advanced or metastatic breast cancer, who have disease progression during or within 12 months after completing prior adjuvant endocrine therapy or during the first prior endocrine therapy for metastatic disease.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: AMG 479 intervention 2: Placebo
Intervention descriptions: intervention 1: AMG 479 administered with exemestane or fulvestrant intervention 2: Placebo administered with either exemestane or fulvestrant

Protocol documents:
Prot_SAP_000.pdf: 
Approved 
 
 
Product:  AMG 479 
Protocol Number:  20060362 
Date:  Amendment 2, 01 June 2011 
 
Page 1 of 113 
 
 
 
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An International, Randomized, Double-blind, Placebo-controlled, Phase 2 Study of 
AMG 479 with Exemestane or Fulvestrant in Postmenopausal Women with 
Hormone Receptor Positive Locally Advanced or Metastatic Breast Cancer  
AMG 479 
Amgen Protocol Number 20060362 
 
Clinical Study Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Phone:  805.447.0000 
Fax:  805.499.9495 
Key Sponsor Contacts: 
Jesse McGreivy, MD 
Medical Monitor 
Amgen SF LLC 
Phone:  650.244.2634 
Fax:  650.837.9716 
 
Nancy Kenyon 
Clinical Research Study Manager 
Amgen 
One Amgen Center Drive 
Phone:  805-447-5737 
Fax:  805-480-2891 
Cell:  805-208-4380 
e-mail – nkenyon@amgen.com 
 
Cherry Locke 
Clinical Research Study Manager-Europe 
Amgen United Kingdom - Op Ex 
Tel: +44 (0) 1223 436301 
Fax: +44 (0) 1223 228138 
e-mail - clocke@amgen.com 
 
Date: 
Date: 
Amendment 2, 01 June 2011 
Amendment 1, 03 April 2008 
Date: 
14 November 2007 
EudraCT Number 
2007-006050-25 
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; Canadian sites: 1-866-50-AMGEN; 
Australian and European sites: 805-447-5000.   For all other study-related questions, continue to 
contact the Key Sponsor Contact. 


Approved 
 
 
Product:  AMG 479 
Protocol Number:  20060362 
Date:  Amendment 2, 01 June 2011 
 
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Investigator’s Agreement 
I have read the attached protocol entitled An International, Randomized, Double-blind, 
Placebo-controlled, Phase 2 Study of AMG 479 with Exemestane or Fulvestrant in 
Postmenopausal Women with Hormone Receptor Positive Locally Advanced or 
Metastatic Breast Cancer dated Amendment 2, 01 June 2011 and agree to abide by all 
provisions set forth therein. 
I agree to comply with the International Conference on Harmonization Tripartite 
Guideline on Good Clinical Practice and local ethics 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 sub investigators (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:  20060362 
Date:  Amendment 2, 01 June 2011 
 
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Protocol Synopsis 
Title:  An International, Randomized, Double-blind, Placebo-controlled, Phase 2 Study of 
AMG 479 with Exemestane or Fulvestrant in Postmenopausal Women with Hormone Receptor 
Positive Locally Advanced or Metastatic Breast Cancer  
Study Phase: 2 
Indication:  Postmenopausal women with hormone receptor (HR)-positive, locally advanced or 
metastatic breast cancer who have disease progression during or within 12 months after 
completing prior adjuvant endocrine therapy or during the first prior endocrine therapy for 
metastatic disease 
Primary Objective:  To provide an estimate of the relative efficacy of Arm A (AMG 479 in 
combination with endocrine therapy [exemestane or fulvestrant] versus Arm B (AMG 479 placebo 
in combination with endocrine therapy [exemestane or fulvestrant]) as measured by the 
progression free survival (PFS) hazard ratio. This estimate will be precise enough to provide 
guidance for further development of AMG 479.for use in the planning of a phase 3 study in this 
patient population.  Additionally, this study will provide qualitative estimates of PFS for treatment 
arms A and B. 
Secondary Objectives: To investigate the effect of AMG 479 compared with placebo when 
administered in combination with exemestane or fulvestrant on:  
• 
the safety and tolerability  
• 
the impact to patient reported outcomes (PROs) 
• 
the pharmacokinetics (PK) of AMG 479  
• 
additional efficacy measures including clinical benefit rate, objective response rate, 
duration of response, time to progression (TTP), time-to-response, time-to-treatment 
failure, and survival time  
Exploratory Objectives:  To assess the potential effect of co-administration of AMG 479 and 
endocrine therapy (exemestane or fulvestrant) on the PK of the endocrine therapy (exemestane 
or fulvestrant).  
To investigate the effect of AMG 479 compared with placebo when administered in combination 
with exemestane or fulvestrant on biomarkers using biochemical analysis of blood and tumor 
samples, including the correlation between biomarker measurements at baseline and/or in 
response to treatment outcomes.  
To investigate the effect of genetic variation in drug metabolism genes, breast cancer genes, and 
drug target genes on treatment outcomes (this part of the study is optional for subjects). 
Hypothesis:  This study will provide an estimate of the relative efficacy of AMG 479 in 
combination with endocrine therapy (exemestane or fulvestrant) versus AMG 479 placebo in 
combination with endocrine therapy (exemestane or fulvestrant) as measured by the PFS hazard 
ratio.  Additionally, this study will provide the estimate of PFS for each treatment arm. 
Study Design:  This is a randomized, double-blind, placebo-controlled, phase 2 study.  Subjects 
will include postmenopausal women with confirmed hormone receptor (HR)-positive, locally 
advanced or metastatic breast cancer, who have disease progression during or within 12 months 
after completing prior adjuvant endocrine therapy or during the first prior endocrine therapy for 
metastatic disease. 
Based on investigator discretion, subjects will be prescribed an endocrine therapy of either 
exemestane or fulvestrant to be administered throughout the study.  The study plans to 
randomize 150 subjects in a 2:1 ratio to Arm A: AMG 479 in combination with endocrine therapy 
(exemestane or fulvestrant) or Arm B: placebo in combination with endocrine therapy 
(exemestane or fulvestrant). 


Approved 
 
 
Product:  AMG 479 
Protocol Number:  20060362 
Date:  Amendment 2, 01 June 2011 
 
Page 4 of 113 
 
 
 
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At least 45 of the 150 subjects randomized will be required to be prescribed to each endocrine 
therapy (exemestane and fulvestrant). 
Study treatment with AMG 479 or placebo and endocrine therapy (exemestane or fulvestrant) will 
continue until disease progression, unacceptable toxicity, consent withdrawal, investigator 
discretion, initiation of a new anticancer treatment, or death.   
Subjects randomized to placebo in combination with endocrine therapy (Arm B) may have the 
opportunity to continue receiving study treatment as open-label AMG 479 in combination with the 
endocrine therapy originally prescribed (‘roll over treatment’) upon disease progression. 
In order to safeguard the interest of the study subjects and maintain the study integrity, Amgen 
will form an unblinded data review team (DRT) that is external to the study team involved in the 
daily conduct of the study, but internal to Amgen to review safety data and efficacy analysis 
results.   
Endpoints:   
Primary: Progression free survival (PFS), as measured by Response Evaluation Criteria in Solid 
Tumors criteria (modified RECIST) per local review 
Secondary:  
• 
Clinical benefit (complete response, or partial response, or stable disease for ≥ 24 weeks 
as measured by modified RECIST per local review), objective response rate (complete 
and partial response as measured by modified RECIST per local review), duration of 
response, TTP, time-to-response, time-to-treatment failure, and survival   
• 
Incidence of adverse events, abnormal laboratory values, and anti-AMG 479 antibody 
formation 
• 
PK parameters of AMG 479   
• 
Breast cancer related symptoms, health related quality of life, and skin toxicity burden 
Exploratory: Objective response by tumor mutation status, biochemical concentrations and 
abundance of drug targets in tumor tissue and blood samples, genetic variations in drug 
metabolism genes and target genes (optional, separate informed consent required).   
Sample Size:  The study plans to randomize 150 subjects in a 2:1 ratio to Arm A: AMG 479 in 
combination with endocrine therapy (exemestane or fulvestrant) or Arm B: placebo in combination 
with endocrine therapy (exemestane or fulvestrant). 
Key Subject Eligibility Criteria:  
Inclusion 
• 
Histologically or cytologically confirmed carcinoma of the breast with locally advanced or 
metastatic disease not amenable to surgery or radiation with curative intent (based on 
medical history review) 
• 
Confirmation of HR (estrogen and/or progesterone receptor) positive disease using 
institutional standards for analysis of the primary tumor tissue or tissue obtained 
thereafter (based on medical history review)  
• 
Amenable to receive endocrine therapy as per investigator discretion  
• 
Disease progression while receiving prior endocrine therapy for locally advanced or 
metastatic breast cancer or recurrence while receiving prior endocrine therapy as 
adjuvant treatment or within 12 months of treatment discontinuation.   
• 
Measurable or non-measurable disease, as defined by the modified RECIST criteria 
• 
Eastern Cooperative Oncology Group performance status of 0 or 1 
• 
Postmenopausal woman (as defined by the protocol) ≥ 18 years old  


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Product:  AMG 479 
Protocol Number:  20060362 
Date:  Amendment 2, 01 June 2011 
 
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• 
Adequate renal and hepatic function 
• 
Adequate glycemic function, for subjects with known diabetes (Type 1 or 2) 
Exclusion 
• 
HR-unknown, or -negative disease (based on medical history review) 
• 
Not amenable to receive endocrine therapy, including but not limited to, inflammatory 
breast cancer, rapidly progressing disease, or symptomatic visceral disease 
• 
Central nervous system metastases, unless previously treated by either radiation therapy 
and/or surgical resection, who are clinically stable off corticosteroids before 
randomization 
• 
More than 1 prior endocrine regimen for metastatic breast cancer, or locally advanced 
breast cancer.  There are no restrictions for their administration in the neoadjuvant or 
adjuvant settings, except subjects should not have previously been treated with the 
endocrine therapy planned for use in this study  
• 
More than 1 prior regimen including immunotherapy (eg, vaccines), antibody therapy (eg, 
trastuzumab, bevacizumab), small-molecule therapy (eg, lapatinib) for metastatic breast 
cancer, or locally advanced breast cancer, although there are no restrictions for their 
administration in the neoadjuvant or adjuvant settings 
• 
More than 1 prior regimen including chemotherapy for metastatic breast cancer, or locally 
advanced breast cancer, although there are no restrictions for their administration in the 
neoadjuvant or adjuvant settings 
• 
Administration of prior endocrine anticancer therapies within 1 week of randomization 
• 
Administration of other prior anticancer therapies within 2 weeks of randomization 
Key Subject Inclusion Criteria for Roll Over Treatment:  
• 
Plan to continue study treatment as roll over treatment with open-label AMG 479 and the 
endocrine therapy prescribed at screening, if deemed to have been randomized to Arm B 
(placebo in combination with endocrine therapy [either exemestane or fulvestrant]) 
• 
Disease progression (according to local review using modified RECIST criteria) while 
receiving blinded study treatment  
• 
Able to receive first dose of open-label AMG 479 within 4 weeks of disease progression  
• 
Amenable to continue receiving endocrine therapy prescribed at screening, as per 
investigator discretion  
• 
ECOG performance status of 0 or 1 
• 
Adequate renal and hepatic function 
• 
Adequate glycemic function, for subjects with known diabetes (Type 1 or 2) 
Study Treatment Dosage and Administration:  The AMG 479 dose to be used in the study is 
12 mg/kg IV every 2 weeks.  Based on investigator discretion, subjects will be prescribed an 
endocrine therapy of either exemestane (25 mg tablets once a day [QD] by mouth [PO]) or 
fulvestrant (loading dose [500 mg intramuscular (IM) on study day 1, then 250 mg IM on study 
day 15] then 250 mg IM on study day 29 and every 28 days thereafter) to be administered 
throughout the study.  AMG 479 or placebo will be administered by IV infusion through a 
peripheral line or indwelling catheter using a nonpyrogenic, low protein binding filter with 
a 0.2- or 0.22-micron pore size in-line filter infusion set-up.   


Approved 
 
 
Product:  AMG 479 
Protocol Number:  20060362 
Date:  Amendment 2, 01 June 2011 
 
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Procedures:  Informed consent, radiological assessments including bone scan and CT or MRI 
scans, clinical evaluations, hematology, coagulation factors, chemistry, HgbA1c, urine analysis, 
AMG 479, PK, biomarker and tumor tissue collection, concomitant medication collection, adverse 
event collection, and completion of PRO questionnaires.  
Statistical Considerations:  The sample size of 150 subjects randomized in a 2:1 ratio for test 
versus control (Test: AMG 479 + fulvestrant or exemestane; Control: placebo + fulvestrant or 
exemestane) is intended to generate treatment effect estimates that may aid in the design of a 
potential phase 3 program for AMG 479.  The desired increase in the median PFS, for subjects 
that received AMG 479 in combination with endocrine therapy that is believed to be clinically 
meaningful is 2 months (with a minimum increase of 1.5 months).  Using a median PFS of 
4 months for the treatment of placebo in combination with endocrine therapy (exemestane or 
fulvestrant), a 2 month absolute increase (50% relative increase) in the median PFS translates 
into a hazard ratio of 0.667 [test(n = 100)/control(n = 50)] and a 1.5 month absolute increase 
(37.5% relative increase) in the median PFS translates into a hazard ratio of 0.727. 
Interim analyses of safety data will occur at the time 12 and 30 subjects have completed 
treatment administration for 2 months to assess safety and tolerability of the combination of 
AMG 479 or placebo with endocrine therapy (exemestane or fulvestrant).  The DRT, will review 
cumulative safety data and make recommendations regarding study conduct.  An interim analysis 
of efficacy and safety data is planned at the time 75 PFS events have occurred.  This is estimated 
to occur approximately one month after the last subject is randomized.  Summary statistics and 
Kaplan-Meier (K-M) plots of PFS by treatment arm, 80% confidence intervals for the estimated 
hazard ratio and the K-M estimated proportion of subjects without a PFS event at 6 months 
post-randomization will be generated.  The stratified Cox model will be used to estimate the 
hazard ratio with respect to PFS (using the stratification factors) and to produce an 80% 
confidence interval for the hazard ratio. 
All primary and secondary efficacy analyses will be conducted on the full analysis set.  Subjects 
will be included in the analysis according to their randomized treatment assignment.  The primary 
efficacy analysis will be performed when approximately 120 PFS events have been observed, 
where progression is based on local review.  This is estimated to occur approximately 23 months 
after the first subject is randomized.  At the time of the primary efficacy analysis, summaries will 
be provided for each safety, efficacy and PRO endpoint.  The primary analysis of PFS will use the 
same methods utilized for the interim analysis of PFS. 
Sponsor/Licensee:  Amgen Inc. 
 


 
Approved 
 
 
 
Product:  AMG 479 
Protocol Number:  20060362 
Date: Amendment 2, 01 June 2011 
 
Page 7 of 113 
 
 
 
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Study Design and Treatment Schema 
ICF SIGNED
ELIGIBLE
SCREENING
Randomization 
End of Study
Treatment
Progressive 
Disease 
or
Unacceptable
Toxicity
or
Consent 
Withdrawal 
or
Investigator 
Discretion
or
Initiation of 
New 
Anti-cancer 
Treatment
or
Death
Safety Follow-Up Visit
Long Term Follow-Up
(Every 3 months for up to 48 months from last subject enrolled)
Screening Period up to 
28 days.
Study
Day 1
Study Treatment continues in 28 day cycles.  Study treatment 
should commence within 3 days from randomization. 
Safety Follow-
up Visit 
30 days after 
last dose of all 
study treatment
Long Term 
Follow-Up
Subjects will be 
followed for 
survival and 
disease status 
information
Randomization will occur 
2:1 (AMG 479 + Endocrine 
Therapy: AMG 479 
placebo + Endocrine 
Therapy).  Endocrine 
Therapy will be either 
exemestane or fulvestrant 
based on Investigator 
discretion. 
AMG 479 Blinded
(12 mg/kg) IV Q2W
Exemestane or Fulvestrant 
Roll Over 
Treatment
Placebo Blinded
IV Q2W
Exemestane or Fulvestrant 
AMG 479 Unblinded
(12 mg/kg) IV Q2W
Exemestane or Fulvestrant 
 


 
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Product:  AMG 479 
Protocol Number:  20060362 
Date:  Amendment 2, 01 June 2011 
 
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Appendix A.  Schedule of Assessments 
Screen
Safety FUo
Long-term FUp
Cycle
Assess for 
Roll Overn
Cycle Days
-28
1
2
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
Study Week
-4
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
Exemestane
X
Fulvestrant
X
X
X
X
X
X
X
X
Q4W
X
AMG 479 or Placebo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
GENERAL AND SAFETY ASSESSMENTS
Informed Consent
X
Review of Eligibility 
X
X
Medical History/Clinical Evaluationb
X
X
X
X
X
X
X
X
Q4W
X
X
Weight and Heightc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
X
X
Vitalsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
X
X
12-Lead ECG
X
Prior and Current Medication Collection
X
X
Adverse Events Collection
X
X
Blood Chemistrye
X
Xg
X
X
X
X
X
X
X
X
X
X
Q4W
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
X
X
Creatinine/Calculated Creatinine Clearancef
X
X
Coagulation
X
Xg
X
X
X
Q8W
X
X
TSH
X
Xg
X
X
X
Q8W
X
X
HgbA1C
Xg
X
X
X
Q8W
X
X
Endocrine Biomarker Collection
X
X
X
X
X
Q8W
X
X
Other Biomarker Collection
X
X
X
X
Q8W
X
X
Pharmacokineticsh
X
X
X
X
X
Q8W
X
X
Anti-AMG 479 Antibody Assay
X
Q24W
X
X
Radiological Assessementi
X
X
X
Q8W
X
Bone Scanj
X
 
X
 
Q12W
X
Tumor Marker CA 15-3 or CA 27-29k
X
X
X
Q8W
Tumor Samplel
X
PRO Assessmentsm
X
X
X
X
Q12W
X
X
Survival Status
X
8
2
3
5
4
6
7
INVESTIGATIONAL PRODUCT ADMINISTRATION
ENDOCRINE TREATMENT ADMINISTRATIONa
CONTINUE ASSESSMENTS UNTIL PD, UNACCEPTABLE TOXICTY, CONSENT WITHDRAWL, PI DISCRETION OR DEATH
Study Treatment
CONTINUE ASSESSMENTS UNTIL SUBSEQUENT PD, UNACCEPTABLE TOXICTY, CONSENT WITHDRAWL, PI DISCRETION OR DEATH
TUMOR RELATED ASSESSMENTS
1
1
LABORATORY ASSESSMENTS 
 


 
Approved 
 
 
 
Product:  AMG 479 
Protocol Number:  20060362 
Date:  Amendment 2, 01 June 2011 
 
 
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a 
Endocrine therapy (exemestane or fulvestrant) will be prescribed based on investigator discretion.  Patients prescribed exemestane will have 
compliance reviewed and discussed with subject if needed at every clinic visit.  
b 
Clinical evaluation, including physical exam performed, and ECOG status  
c 
Height will only be collected at screening.  Weight will be required pre-infusion to access the IVRS to obtain box assignment, quantity of vials 
and the volume of AMG 479 or placebo for infusion. 
d 
Vitals, include blood pressure and respiration rate, pulse, and temperature. 
e  
Blood chemistry will be analyzed at the local laboratory and will include: sodium, potassium, chloride, creatinine, CO2, BUN, AST, ALT, 
alkaline phosphatase, and total bilirubin.  Additionally fasting/non-fasting glucose will be assessed (fasting: screening, day 1 of cycles 1-4 then 
every second cycle, roll over treatment assessment [if applicable], and safety follow-up; non-fasting: day 15 of cycles 1-4, and day 1 cycle 5, 
then every second cycle) 
f 
Either serum creatinine or calculated creatinine clearance (by Crockcroft-Gault formula) 
g 
These laboratory assessments do not need to be performed on cycle 1 day 1 if they were performed during screening within 7 days of 
initiation of treatment 
h 
Blood collections for PK analysis will occur for AMG 479 (pre- and post-AMG 479 infusion thru cycle 3), for exemestane (only for subjects 
prescribed exemestane; pre- and post-exemestane administration thru cycle 3), and for fulvestrant (only for subjects prescribed fulvestrant; 
pre-fulvestrant IM injection only thru cycle 3).  No PK sample collection is needed for post-fulvestrant IM injection.  Thereafter, blood collection 
for PK analysis of AMG 479, exemestane, and fulvestrant will only occur pre-dose every  
2 cycles, starting cycle 5. 
i 
Radiological assessments of the chest, abdomen and pelvis may occur by CT or MRI.  The same technique used in screening must be used 
throughout the study.  CT or MRI radiological assessments should occur on day 1 of cycle 3, then every 7 to 8 weeks thereafter.   
j 
Subjects with a positive bone scan at screening will continue to have bone scans performed every 11 to 12 weeks thereafter while on study 
treatment.  Subjects with a negative bone Scans will not be required to continue this procedure.  Confirmatory bone images at baseline (CT 
with bone windows or MRI) at baseline and on during study treatment are required for positive areas on baseline bone scan as specified in 
Section 7.1.1. 
k 
Subjects with a tumor marker CA 15-3 or CA 27-29 out of normal ranges at screening will continue to have this analyte analyzed while on 
study.  The tumor marker selected at screening should remain the same throughout the study.  Subjects with a tumor marker CA 15-3 or 
CA 27-29 within normal ranges at screening will not be required to continue this procedure. 
l 
Tumor Sample (archived block, slides or fresh tissue collected for clinical care purposes) are to be obtained.  A paraffin tumor block or fresh 
tissue from the most recent tumor tissue is preferred. 
m 
PRO questionnaires should be completed before any other study procedures and before the patient is informed of their disease status 
n 
Subjects will have a roll over visit, before initiating open-label AMG 479.  This visit will allow assessment of roll over eligibility and will serve as 
the new baseline from which all changes will be compared.  All subsequent visits and assessments will be performed according to the regular 
schedule of assessments continuing with the next per protocol visit after the last completed visit that occurred during blinded treatment. 
o 
Safety FU- Safety follow-up visit is to be completed 30 to 37 days after last administration of protocol treatment  
p 
All subjects who are alive at the time of discontinuation of protocol therapy will be followed approximately every 3 months for up to 48 months 
from the date of the last subject enrolled into the study to evaluate overall survival and disease status.