Clinical trial NCT00791154
Conditions: Lung Cancer Small Cell Lung Cancer Solid Tumors Extensive-stage Small Cell Lung Cancer
Keywords: Extensive disease Extrathoracic metasasis Malignant pericardial effusion Malignant pleural effusion Contralateral hilar adenopathy
Sponsor: NantCell, Inc.
Start date: 2008-12-02; Completion date: 2013-05-01
Enrollment: 213 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is titled "A Phase 1b/2 trial of AMG 479 or AMG 102 with Platinum-Based Chemotherapy as First-Line Treatment for Extensive Stage Small-Cell Lung Cancer (SCLC)."

Part 1, the phase 1b portion of this study, is a multicenter, open-label investigation to identify safe dose levels of either AMG 102 or AMG 479 in combination with etoposide plus cisplatin or carboplatin in subjects with previously untreated extensive stage SCLC.

Part 2, the phase 2 portion of this study, is a multicenter, double-blind, 3-arm investigation to evaluate overall survival of either AMG 102 or AMG 479 in combination with platinum-based chemotherapy.

Detailed description:

Arms: arm 1: Blinded AMG 479 study drug and carboplatin or cisplatin and etoposide arm 2: Blinded AMG 102 study drug and carboplatin or cisplatin and etoposide arm 3: Blinded placebo and carboplatin or cisplatin and etoposide
Interventions: intervention 1: AMG 479 intervention 2: Etoposide intervention 3: Placebo intervention 4: AMG 102 intervention 5: Carboplatin intervention 6: Cisplatin
Intervention descriptions: intervention 1: AMG 479 is administered to subjects intervention 2: Etoposide is administered to subjects intervention 3: Placebo is administered with Carboplatin and Etoposide intervention 4: AMG 102 is administered to subjects intervention 5: Carboplatin is administered to some subjects in combination intervention 6: Cisplatin is administered to some subjects in combination

Protocol documents:
Prot_SAP_000.pdf: 
Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date: June 7, 2008 
 
Page 1 of 153 
 
 
A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based 
Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer 
AMG 479 and AMG 102 
Amgen Protocol Number 20060534 
 
 
Clinical Study Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Phone:  805.447.0000 
Fax:  805.499.9495 
Ada Braun, MD PhD 
Key Sponsor Contacts: 
Clinical Research Medical Director  
Amgen Inc 
Phone:  805.447.4596 
Fax:  805.480.4978 
ada.braun@amgen.com
 
Megan Ingram 
Clinical Research Study Manager - Primary 
Amgen SF LLC 
Phone:  650.244.2867 
Fax:  650.837.9716 
mingram@amgen.com
 
Polly Rawlings 
Clinical Research Study Manager - Europe 
Amgen Limited 
Phone:  +44 1895 525476 
Fax:  +44 1895 525101  
prawling@amgen.com   
Date: 
07 June 2008 
EudraCT Number: 
2008-003292-42 
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: 1-805-447-5000 
 For all other study-related questions, continue to contact the Key Sponsor Contact. 
CONFIDENTIAL 
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Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date: June 7, 2008 
 
Page 2 of 153 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in 
Combination with Platinum-based Chemotherapy as First-Line Treatment for Extensive 
Stage Small Cell Lung Cancer dated 07 June 2008, 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) 
 
CONFIDENTIAL 
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Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date: June 7, 2008 
 
Page 3 of 153 
 
 
Protocol Synopsis 
Title:  A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based 
Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer 
Study Phase:  1b/ 2  
Indication:  Previously Untreated Extensive Stage Small Cell Lung Cancer (SCLC) 
Primary Objective:   
Part 1: To identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin, and of AMG 102 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin that can be administered safely and is tolerated as determined by the 
incidence of dose-limiting toxicity (DLT) 
Part 2: To estimate the relative treatment effect of AMG 479 (at the dose selected in Part 1) in 
combination with chemotherapy (etoposide plus carboplatin and/or etoposide plus cisplatin, as 
determined in part 1), and of AMG 102 (at the dose selected in Part 1) in combination with 
chemotherapy, compared with placebo plus chemotherapy, as measured by the respective 
hazard ratios (HR) for overall survival (OS).   
 
Secondary Objectives:  
Part 1: 
 
To evaluate safety as assessed by the incidence of adverse events and laboratory 
abnormalities not defined as DLT 
 
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody 
formation and anti-AMG 102 antibody formation  
 
To evaluate pharmacokinetics (PK) as assessed by the maximum observed serum 
concentration (Cmax) and the minimum observed serum concentration (Cmin) for 
AMG 479 and for AMG 102  
Part 2:  
 
To evaluate clinical benefit as assessed by the objective response rate (ORR) as 
measured by modified Response Evaluation Criteria in Solid Tumors (RECIST), 
duration of response (DOR), time to progression (TTP), progression-free survival 
(PFS), median OS (mOS), and OS rates at 10, 12, 24 and 36 months 
 
To evaluate safety as assessed by the incidence of adverse events and laboratory 
abnormalities 
 
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody 
formation and anti-AMG 102 antibody formation  
 
To evaluate PK as assessed by Cmax and Cmin for AMG 479 and for AMG 102  
 
To estimate the effect of AMG 479 and of AMG 102 on subject’s health related 
quality of life (HRQoL) using the European Organisation for Research and 
Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and its lung cancer 
module (QLQ-LC13) 
 
 
 
 
 
 
 
 
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Protocol Number:  20060534 
Date: June 7, 2008 
 
Page 4 of 153 
 
 
Exploratory Objectives: 
Part 1 and Part 2: 
 
To evaluate PK as assessed by area under the curve (AUC) and Cmax for 
etoposide, cisplatin and carboplatin  
 
To investigate the relationship between AMG 479 and AMG 102 PK and treatment 
outcomes (including clinical and pharmacodynamic endpoints)  
 
To investigate the biomarker profile at baseline, and the pharmacodynamic 
response, as assessed by biomarkers for AMG 479 (eg, serum IGF-1, IGF-BP3, 
GH, and other factors involved in regulating the IGF-1/IGF-1R pathway) and for 
AMG 102 (eg, HGF/SF:c-Met pathway markers, tumor apoptosis markers, 
angiogenic cytokines and other biomarkers), and correlate with treatment outcomes 
 
To investigate other potential biomarker development (eg, biochemical levels and 
abundance of drug targets, tumor somatic mutations in drug target, pathway, and 
cancer genes) by biochemical analysis of blood samples and tumor tissue (if 
available), and correlate with treatment outcomes  
 
To investigate the effect of genetic variations in cancer genes, drug target and 
pathway genes, and other biomarker genes, and correlate with treatment outcomes 
(optional for subjects; requires separate informed consent) 
 
Hypotheses:   
Part 1  will identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin and of AMG 102 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin that is safe and tolerated as determined by the incidence of DLT.   
Part 2  will estimate the relative efficacy of AMG 479 (at the dose selected in Part 1), and of 
AMG 102 (at the dose selected in Part 1), and of placebo plus platinum-based chemotherapy 
(etoposide plus carboplatin and/or etoposide plus cisplatin, as determined in part 1) as measured 
by the respective OS HR.  Given a hypothesized HR of 0.74 for each comparison, the target 
maximum half width of 0.22 for the OS HR 2-sided 80% CI will be achieved after 100 deaths.  
 
Study Design: 
This study has 2 parts.   
Part 1 is a multi-center, open-label dose de-escalation phase 1b segment of AMG 479 in 
combination with etoposide plus cisplatin (Cohort 1) or carboplatin (Cohort 2), and of AMG 102 in 
combination with etoposide plus cisplatin (Cohort 3) or carboplatin (Cohort 4). Once respective 
doses of AMG 479 and of AMG 102 have been identified that are safe and tolerated based on the 
incidence of DLT, Part 2 will open for enrollment.  
Part 2 is a randomized, double-blind, placebo-controlled phase 2 segment of AMG 479 (at the 
dose selected in Part 1), and of AMG 102 (at the dose selected in Part 1), and of placebo plus 
platinum-based chemotherapy (etoposide plus carboplatin and/or etoposide plus cisplatin, as 
determined in part 1) as first-line treatment for subjects with extensive stage SCLC. Subjects (n = 
180) will be randomized in a 1:1:1 ratio to each treatment arm (n = 60 per arm). Randomization 
will be stratified according to gender (female; male) and chemotherapy (etoposide and cisplatin; 
etoposide and carboplatin).  
In both parts of the study, chemotherapy (etoposide plus carboplatin or cisplatin) will be 
administered on day 1 of each 21-day (Q3W) cycle. Etoposide will also be administered on day 2 
and 3 of each Q3W cycle. Premedication (see Section 6.2.2.3), vigorous hydration and diuresis 
(see Section 6.2.2.4) will be required for chemotherapy treatment. Investigational product (IP; 
AMG 479 [Part 1, Cohorts 1 and 2; Part 2, Arm A] or AMG 102 [Part 1, Cohorts 3 and 4; Part 2, 
Arm B] or placebo [Part 2, Arm C]) will be administered after the chemotherapy infusion on day 2 
of the initial cycle, and day 1 of each Q3W cycle thereafter. Four cycles of chemotherapy will be 
given.  Patients with best tumor response (maximum tumor regression, per RECIST) after the 
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Protocol Number:  20060534 
Date: June 7, 2008 
 
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second on-study treatment tumor assessment will receive an additional 2 cycles (a total of 6 
cycles) of chemotherapy.  Subjects who complete 4 to 6 cycles of chemotherapy or who 
discontinue chemotherapy early will continue to receive IP (AMG 479, or AMG 102, or placebo) 
single agent maintenance therapy on day 1 of each Q3W cycle for up to  24 months from the date 
of first study treatment administration (study day 1).  Subjects who have completed 24 months of 
IP may be eligible for continued treatment with IP by extension protocol or as provided for by the 
local country’s regulatory mechanism (see Section 13).  Study treatment will cease if a subject 
experiences progressive disease (PD), death, unacceptable toxicity, withdraws consent, or due to 
an administrative decision (by the investigator or Amgen).   
Radiological imaging to assess PD (per modified RECIST) will be performed every 6 weeks                     
(± 7 days) during the first 6 months of the study, and every 9 weeks (± 7 days) thereafter, until 
subjects develop PD (per modified RECIST) or begin a new cancer treatment.  
A follow-up visit will occur 30 days (+ 7 days) and 60 days (+ 14 days) after the last dose of 
protocol-specified treatment. Subjects will be contacted every 3 months (± 2 weeks) in the long-
term follow-up, for up to 36 months from the date of the last subject randomized, to assess 
survival. Please refer to the Study Schema for an overview of the 2-part study design.  
 
Primary and Secondary Endpoints:  See Section 10 for details 
 
Primary Endpoints 
 
Part 1:    ▪  The incidence of adverse events and clinical laboratory abnormalities defined as DLT 
 
Part 2:    ▪  OS  
 
Secondary Endpoints 
 
 
Part 1: 
 
The incidence of adverse events and laboratory abnormalities not defined as DLT 
 
The incidence of anti-AMG 479 and anti-AMG 102 antibody formation  
 
PK (Cmax and Cmin for AMG 479 and AMG 102)  
 
Part 2: 
 
ORR, DOR, TTP, PFS, mOS, and OS rates at 10,12, 24, and 36 months 
 
The incidence of adverse events and laboratory abnormalities 
 
The incidence of anti-AMG 479 and anti-AMG 102 antibody formation  
 
PK (Cmax and Cmin) for AMG 479 and AMG 102 
 
EORTC QLQ-C30 and EORTC QLQ-LC13 scores 
 
Exploratory Endpoints 
Part 1 and Part 2: 
 
PK (AUC and Cmax) for etoposide, cisplatin and carboplatin  
 
Relationship between AMG 479 and AMG 102 PK and treatment outcomes (including 
clinical and pharmacodynamic endpoints)  
 
Baseline biomarker profile and pharmacodynamic response, as assessed by AMG 479 
and AMG 102 biomarkers, and correlation with treatment outcomes  
 
Biochemical levels and abundance of drug targets and other biomarkers in blood 
samples and tumor tissue (if available), and correlation with treatment outcomes  
 
Genetic variations in cancer genes, drug target and pathway genes, and other biomarker 
genes, and correlation with treatment outcomes   
 
Sample Size:  Part 1: 24 to 108 subjects; Part 2: 180 subjects 
 
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Protocol Number:  20060534 
Date: June 7, 2008 
 
Page 6 of 153 
 
 
Summary of Subject Eligibility Criteria:  See Section 4 for details 
 
Key Inclusion Criteria 
 
Histologically or cytologically confirmed SCLC 
 
Extensive disease, defined by at least one of the following criteria: 
 
No limited disease (ie, no disease confined to the ipsilateral hemithorax,                           
which can be safely encompassed within a tolerable radiation field) 
 
Extrathoracic metastases  
 
Malignant pericardial or pleural effusion 
 
Contralateral hilar adenopathy 
 
Measurable or non-measurable disease, as defined by modified RECIST 
 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
 
≥ 18 years old 
 
Life expectancy (with therapy) ≥ 3 months 
 
Adequate hematologic, hepatic, coagulation, renal, and metabolic function  
 
Diabetes, if present, must be controlled, with glycosylated hemoglobin (HgbA1c) ≤ 8% 
and fasting blood glucose level ≤ 160 mg/dL 
Key Exclusion Criteria 
 
Prior chemotherapy, chemo-radiation, or investigational agent for SCLC 
 
Prior radiotherapy to > 25% of the bone marrow 
 
Symptomatic or untreated central nervous system (CNS) metastasis (with exceptions) 
 
Currently or previously treated with biological, immunological or other therapies for SCLC 
 
Current serious or non-healing wound or ulcer           
 
History of prior or concurrent other malignancy (with exceptions) 
 
Any clinically significant medical condition other than cancer (eg, cardiovascular disease 
or chronic obstructive pulmonary disease), which could interfere with the safe delivery of 
study treatment or increase risk of toxicity 
 
Study Drug Dosage and Administration:  See Section 6 for details. 
Investigational Product: 
Part 1:   Cohorts 1a and 2a:   
 
AMG 479 18 mg/kg intravenous (IV) on day 2 of the initial cycle, and day 1 of each Q3W 
 
cycle thereafter  
 
AMG 479 18 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment  
 
              Cohort 3a and 4a:   
 
AMG 102 15 mg/kg IV on day 2 of the initial cycle, and day 1 of each Q3W cycle 
 
thereafter 
 
AMG 102 15 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment  
 
Lower doses of AMG 479 and/or AMG 102 may be explored based on safety and PK data, 
to determine the maximum tolerated dose. Refer to Section 6.1.1.1 for details. 
 
Part 2:  AMG 479 (Arm A), AMG 102 (Arm B), at the respective doses selected in Part 1,                            
 
or matching placebo (Arm C), IV Q3W:  
 
 
day 2 of the initial cycle, and day 1 of each Q3W cycle thereafter 
 
IP dose will be calculated based on the subject’s actual body weight at baseline, and the dose is 
not required to be recalculated unless the actual body weight changes by > 10%.  IP will be 
diluted in 0.9% normal saline.   
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Protocol Number:  20060534 
Date: June 7, 2008 
 
Page 7 of 153 
 
 
IP will be administered Q3W, after completion of the chemotherapy infusion (if administered).               
IP will be administered over 60 minutes (min) (± 15 min).  If a dose of IP is well tolerated (ie, 
without serious infusion-related reactions), then subsequent IV infusions may be given over 30 
min (± 10 min).  Infusion time can be extended up to 120 min for subjects deemed unable to 
tolerate the 60 min infusion. 
Chemotherapy (Part 1 and Part 2):    
Etoposide 100 mg/m2 will be administered IV over 90 min (± 15 min) on days 1, 2, and 3 of each 
Q3W cycle, per institutional guidelines.  
Carboplatin (AUC = 5 mg/mL • min) will be administered IV over 30 min (+ 10 min) on day 1 of 
each Q3W cycle after the etoposide infusion is complete, per institutional guidelines. Infusion time 
can be extended up to 60 min for subjects deemed unable to tolerate the 30 min infusion. 
Cisplatin 75 mg/m2 will be administered IV over 60 min (± 15 min) on day 1 of each Q3W cycle 
after the etoposide infusion is complete, per institutional guidelines. Infusion time can be 
extended up to 120 min for subjects deemed unable to tolerate the 60 min infusion.  
Subjects must receive adequate premedication (see Section 6.2.2.3), vigorous hydration and 
diuresis, and monitoring of fluid status (see Section 6.2.2.4).  
 
Control Group:   
Part 1: there is no control group 
 
Part 2: Arm C: Placebo in combination with etoposide plus carboplatin or cisplatin Q3W  
 
Key Study Procedures:  See Section 7.1 and Schedule of Assessments (Appendix A) for details.  
 
Screening Procedures  
 • Review of inclusion and exclusion criteria  
 • Medication and medical history, concomitant medications/treatment(s), adverse events  
 • Vital signs: resting pulse, respiration, blood pressure, and temperature  
 • Physical examination, including height and weight  
 • ECOG performance status assessment  
 • Laboratory tests; including hematology, chemistry, coagulation, urinalysis, pregnancy test  
 • If available, submission of paraffin-embedded tumor tissue (paraffin tumor block, or slides) and     
all available pathology reports 
 • 12-lead electrocardiogram (ECG)  
 • Radiological imaging to assess disease extent (CT scan or MRI of the brain, chest, abdomen, 
and all other sites of disease; within 28 days prior to enrollment)  
 
Treatment and Follow-Up Procedures 
 • Recording of adverse events and concomitant medications  
 • Patient completion of EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires (Part 2)  
 • Vital signs: resting pulse, respiration, blood pressure, and temperature  
 • Physical examination, including weight, and ECOG performance status assessment  
 • Laboratory tests; including hematology, chemistry, pregnancy test  
 • Samples for biomarkers and anti-AMG 479 or anti-AMG 102 antibodies  
 • Samples for AMG 479, AMG 102, carboplatin, cisplatin and etoposide PK (Part 1) 
 • ECG  
 • Radiological imaging to assess disease extent  (CT scan or MRI [same modality throughout 
the study] of the chest, abdomen, and all other sites of disease [except: brain imaging only as 
clinically indicated] every 6 weeks [± 7 days] during the first 6 months of the study, and every 9 
weeks [± 7 days] thereafter)  
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d AMG 102 
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Page 8 of 153 
 
 
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Statistical Considerations: See Section 10 for details.  
Analyses will be presented separately for Part 1 and Part 2 of the study.  The HR for OS will be 
estimated using a Cox regression model stratified by randomization stratification factors and 
controlled for the LDH level as an important covariate.  A Wald chi-square test will provide a 
descriptive p-value for the HR.  Overall survival between the respective pair of treatment arms 
(Arm A/Arm C and Arm B/Arm C) will use a stratified log-rank test for a descriptive comparison. 
 
DRT Safety Reviews and Interim Analysis 
For the protection of subjects, in Part 1 of the study, Safety Review Team (SRT) meetings will be 
held to review safety, laboratory, dosing information and PK data (when available) from each 
AMG 479 and AMG 102 dose cohort, to make recommendations regarding dose selection for 
Part 2, dose de-escalation, or dose stopping.   
In Part 2, an Amgen Data Review Team (DRT) independent of the study team will perform two 
unblinded reviews of the safety data after at least 30 and 60 subjects have been randomized and 
had the opportunity to complete the first cycle of study treatment (safety interim analyses).  
One interim efficacy analysis is planned to review both OS and PFS data 10 months after the last 
subject is randomized.  Approximately 100 OS events are estimated (69 OS events per 
comparison: Arm A/Arm C and Arm B/Arm C) for the interim analysis assuming approximately 
half of the planned enrollment will occur at 15 months. Review of safety data will also occur 
during the interim efficacy analysis. The interim efficacy analysis will provide a preliminary 
assessment of the overall risk/benefit profile. Unless safety concerns arise, the study will not be 
discontinued or modified due to the results of the interim efficacy analysis.  
The primary analysis of Part 2 will be event-driven and will occur after a total of approximately 
130 deaths (89 deaths per planned comparison: Arm A/Arm C and Arm B/Arm C), which is 
anticipated to occur 18 months after end of enrollment.  A final analysis is planned after a 
minimum expected follow-up of 36 months, at which time approximately 163 deaths are expected 
overall (110 per planned comparison).  
Sponsor/Licensee:  Amgen Inc


d AMG 102 
mber:  20060534 
e 7, 2008 
 
         
 
 
 
Page 9 of 153 
 
 
PART 1 ENROLLMENT 
Safety Follow-Up 
Long-Term Follow-Up
(Every 3 months for up to 36 months from last subject randomized)
PART 1
PHASE 1B DOSE SELECTION SEGM ENT
PART 2
PHASE 2 SEGMENT
PART 2  RANDOMIZATION 1:1:1
END OF TREATMENT
Platin/Etoposide
PLACEBO
BLINDED
Platin/Etoposide
AMG 102
BLINDED
Platin/Etoposide
ARM A (n=60)
Cisplatin/Etoposide
AM G 479 18 m g/kg
Cohort 1a (n=6 to 9)
Cisplatin/Etoposide
AM G 102 15 m g/kg
Carboplatin/Etoposide
AM G 102 15 m g/kg
SAFETY REVIEW  TEAM REVIEW S DOSE COHORTS, RECOMMENDS PART 2 REGIMEN(S) 
AMG 479 AND AM G 102 AT DOSES IDENTIFIED IN PART 1 
STUDY TREATMENT (3 W eek Cycles)  
Chem otherapy: Etoposide (100 m g/m 2 Days 1, 2, 3) and Carboplatin (AUC  =  5 m g/m L•m in Day 1) or Cisplatin (75 m g/m 2 Day 1)
    -  Chem otherapy for 4 Cycles (6 Cycles, if best tum or response [m axim um  tum or regression, per RECIST] after 2 nd tum or assessm ent) 
  
Investigational Product: AM G 479 or AM G 102 or Placebo (Part 2 only)
    -  Day 2 of initial Cycle 
                             -  Day 1 of Cycle = 2,  up to 24 m onths from  Study Day 1
Prophylactic Cranial Irradiation (for responding subjects , if not previously adm inistered ) prior to IP m aintenance treatm ent
ARM B (n=60)
ARM C (n=60)
Cohort 3a (n=6 to 9)
Cohort 2a (n=6 to 9)
Cohort 4a (n=6 to 9)
AM G 479 
BLINDED
Carboplatin/Etoposide
AM G 479 18 m g/kg
 Dose Cohort  
 Review :
 Determ ine 
 AM G  479 M TD
Pre-Phase 2 Review
                        Physician’s Choice: Carboplatin or Cisplatin
                        Sequential Assignment: AMG 479 or AMG 102
           Physician’s Choice: Carboplatin or Cisplatin
           Stratification: Gender; Platinum Agent (Carboplatin; Cisplatin)
 Dose Cohort  
 Review :
 Determ ine 
 AM G 479 M TD
 Dose Cohort  
 Review :
 Determ ine 
 AM G 102 M TD
 Dose Cohort  
 Review:
 Determ ine 
 AM G 102 MTD
  
CONFIDENTIAL 
 
 
 
 
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Study Design and Treatment Schema 
Products:  AMG 479 an
Protocol Nu
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Protocol Number:  20060534 
Date:  01 April 2009 
Page 1 of 190 
 
A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based 
Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer 
AMG 479 and AMG 102 
Amgen Protocol Number 20060534 
 
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 
Clinical Research Medical Director  
Amgen Inc 
Phone:  650.244.2634 
Fax:  650.837.9716  
jessem@amgen.com 
 
Megan Ingram 
Clinical Research Study Manager - Primary 
Amgen SF LLC 
Phone:  650.244.2867 
Fax:  650.837.9602 
mingram@amgen.com 
 
Jennifer Sampson 
Clinical Research Study Manager - Europe 
Amgen Limited 
Phone:  +44 1895 525313 
Fax:  +44 1895 525101  
Jennifer.Sampson@amgen.com   
Amendment 1 Date: 
01 April 2009 
Date: 
07 June 2008 
EudraCT Number: 
2008-003292-42 
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: 1-805-447-5000 
 For all other study-related questions, continue to contact the Key Sponsor Contact. 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 April 2009 
Page 2 of 190 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in 
Combination with Platinum-based Chemotherapy as First-Line Treatment for Extensive 
Stage Small Cell Lung Cancer dated Amendment 1 01 April 2009, 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) 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 April 2009 
Page 3 of 190 
 
Protocol Synopsis 
Title:  A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based 
Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer 
Study Phase:  1b/ 2  
Indication:  Previously Untreated Extensive Stage Small Cell Lung Cancer (SCLC) 
Primary Objective:   
Part 1: To identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin, and of AMG 102 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin that can be administered safely and is tolerated as determined by the 
incidence of dose-limiting toxicity (DLT) 
Part 2: To estimate the relative treatment effect of AMG 479 (at the dose selected in Part 1) in 
combination with chemotherapy (etoposide plus carboplatin and/or etoposide plus cisplatin, as 
determined in part 1), and of AMG 102 (at the dose selected in Part 1) in combination with 
chemotherapy, compared with placebo plus chemotherapy, as measured by the respective 
hazard ratios (HR) for overall survival (OS).   
 
Secondary Objectives:  
Part 1: 
 
To evaluate safety as assessed by the incidence of adverse events and laboratory 
abnormalities not defined as DLT 
 
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody 
formation and anti-AMG 102 antibody formation  
 
To evaluate pharmacokinetics (PK) as assessed by the maximum observed serum 
concentration (Cmax) and the minimum observed serum concentration (Cmin) for 
AMG 479 and for AMG 102  
Part 2:  
 
To evaluate clinical benefit as assessed by the objective response rate (ORR) as 
measured by modified Response Evaluation Criteria in Solid Tumors (RECIST), 
duration of response (DOR), time to progression (TTP), progression-free survival 
(PFS), median OS (mOS), and OS rates at 10, 12, 24 and 36 months 
 
To evaluate safety as assessed by the incidence of adverse events and laboratory 
abnormalities 
 
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody 
formation and anti-AMG 102 antibody formation  
 
To evaluate PK as assessed by Cmax and Cmin for AMG 479 and for AMG 102  
 
To estimate the effect of AMG 479 and of AMG 102 on subject’s health related 
quality of life (HRQoL) using the European Organisation for Research and 
Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and its lung cancer 
module (QLQ-LC13) 
Exploratory Objectives: 
Part 1 and Part 2: 
 
To evaluate PK as assessed by area under the curve (AUC) and Cmax for 
etoposide, cisplatin and carboplatin  
 
To investigate the relationship between AMG 479 and AMG 102 PK and treatment 
outcomes (including clinical and pharmacodynamic endpoints)  


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 April 2009 
Page 4 of 190 
 
 
To investigate the biomarker profile at baseline, and the pharmacodynamic 
response, as assessed by biomarkers for AMG 479 (eg, serum IGF-1, IGF-BP3, 
GH, and other factors involved in regulating the IGF-1/IGF-1R pathway) and for 
AMG 102 (eg, HGF/SF:c-Met pathway markers, tumor apoptosis markers, 
angiogenic cytokines and other biomarkers), and correlate with treatment outcomes 
 
To investigate other potential biomarker development (eg, biochemical levels and 
abundance of drug targets, tumor somatic mutations in drug target, pathway, and 
cancer genes) by biochemical analysis of blood samples and tumor tissue (if 
available), and correlate with treatment outcomes  
 
To investigate the effect of genetic variations in cancer genes, drug target and 
pathway genes, and other biomarker genes, and correlate with treatment outcomes 
(optional for subjects; requires separate informed consent) 
Hypotheses:   
Part 1 will identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin and of AMG 102 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin that is safe and tolerated as determined by the incidence of DLT.   
Part 2 will estimate the relative efficacy of AMG 479 (at the dose selected in Part 1), and of 
AMG 102 (at the dose selected in Part 1), and of placebo plus platinum-based chemotherapy 
(etoposide plus carboplatin and/or etoposide plus cisplatin, as determined in part 1) as measured 
by the respective OS HR.  Given a hypothesized HR of 0.74 for each comparison, the target 
maximum half width of 0.22 for the OS HR 2-sided 80% CI will be achieved after 89 deaths are 
observed for a pairwise comparison. 
 
Study Design: 
This study has 2 parts.   
Part 1 is a multi-center, open-label dose de-escalation phase 1b segment of AMG 479 in 
combination with etoposide plus carboplatin (Cohort 1) or cisplatin (Cohort 2), and of AMG 102 
in combination with etoposide plus carboplatin (Cohort 3) or cisplatin (Cohort 4). Once 
respective doses of AMG 479 and of AMG 102 have been identified that are safe and tolerated 
based on the incidence of DLT, Part 2 will open for enrollment.  
Part 2 is a randomized, double-blind, placebo-controlled phase 2 segment of AMG 479 (at the 
dose selected in Part 1), and of AMG 102 (at the dose selected in Part 1), and of placebo plus 
platinum-based chemotherapy (etoposide plus carboplatin and/or etoposide plus cisplatin, as 
determined in part 1) as first-line treatment for subjects with extensive stage SCLC. Subjects 
(n = 180) will be randomized in a 1:1:1 ratio to each treatment arm (n = 60 per arm). 
Randomization will be stratified according to gender (female; male) and chemotherapy (etoposide 
and cisplatin; etoposide and carboplatin).  


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 April 2009 
Page 5 of 190 
 
In both parts of the study, chemotherapy (etoposide plus carboplatin or cisplatin) will be 
administered on day 1 of each 21-day (Q3W) cycle. Etoposide will also be administered on day 2 
and 3 of each Q3W cycle. Premedication (see Section 6.2.2.3), vigorous hydration and diuresis 
(see Section 6.2.2.4) will be required for chemotherapy treatment. Investigational product (IP; 
AMG 479 [Part 1, Cohorts 1 and 2; Part 2, Arm A] or AMG 102 [Part 1, Cohorts 3 and 4; Part 2, 
Arm B] or placebo [Part 2, Arm C]) will be administered after the chemotherapy infusion on day 2 
of the initial cycle, and day 1 of each Q3W cycle thereafter. Four to six cycles of chemotherapy 
will be given. Determination of the number of cycles of chemotherapy to be administered 
(between 4 to 6) will be left to the investigator’s discretion. Subjects who complete 4 to 6 
cycles of chemotherapy or who discontinue chemotherapy early will continue to receive IP 
(AMG 479, or AMG 102, or placebo) single agent maintenance therapy on day 1 of each Q3W 
cycle for up to  24 months from the date of first study treatment administration (study day 1). 
 Subjects who have completed 24 months of IP may be eligible for continued treatment with IP by 
extension protocol or as provided for by the local country’s regulatory mechanism (see 
Section 13).  Study treatment will cease if a subject experiences progressive disease (PD), death, 
unacceptable toxicity, withdraws consent, or due to an administrative decision (by the investigator 
or Amgen).   
Radiological imaging to assess PD (per modified RECIST) will be performed every 6 weeks (± 7 
days) during the first 6 months of the study, from Study Day 1 and every 9 weeks (± 7 days) 
thereafter, until subjects develop PD (per modified RECIST) or begin a new cancer treatment.  
A follow-up visit will occur 30 days (+ 7 days) and 60 days (+ 14 days) after the last dose of 
protocol-specified treatment. Subjects will be contacted every 3 months (± 2 weeks) in the 
long-term follow-up, for up to 36 months from the date of the last subject randomized, to assess 
survival. Please refer to the Study Schema for an overview of the 2-part study design.  
 
Primary and Secondary Endpoints:  See Section 10 for details 
 
Primary Endpoints 
 
Part 1:    ▪  The incidence of adverse events and clinical laboratory abnormalities defined as DLT 
 
Part 2:    ▪  OS  
 
Secondary Endpoints 
 
 
Part 1: 
 
The incidence of adverse events and laboratory abnormalities not defined as DLT 
 
The incidence of anti-AMG 479 and anti-AMG 102 antibody formation  
 
PK (Cmax and Cmin for AMG 479 and AMG 102)  
 
Part 2: 
 
ORR, DOR, TTP, PFS, mOS, and OS rates at 10,12, 24, and 36 months 
 
The incidence of adverse events and laboratory abnormalities 
 
The incidence of anti-AMG 479 and anti-AMG 102 antibody formation  
 
PK (Cmax and Cmin) for AMG 479 and AMG 102 
 
EORTC QLQ-C30 and EORTC QLQ-LC13 scores 
 
Exploratory Endpoints 
Part 1 and Part 2: 
 
PK (AUC and Cmax) for etoposide, cisplatin and carboplatin  
 
Relationship between AMG 479 and AMG 102 PK and treatment outcomes (including 
clinical and pharmacodynamic endpoints)  
 
Baseline biomarker profile and pharmacodynamic response, as assessed by AMG 479 
and AMG 102 biomarkers, and correlation with treatment outcomes  
 
Biochemical levels and abundance of drug targets and other biomarkers in blood 
samples and tumor tissue (if available), and correlation with treatment outcomes  


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 April 2009 
Page 6 of 190 
 
 
Genetic variations in cancer genes, drug target and pathway genes, and other biomarker 
genes, and correlation with treatment outcomes   
Sample Size:  Part 1: 24 to 108 subjects; Part 2: 180 subjects 
 
Summary of Subject Eligibility Criteria:  See Section 4 for details 
 
Key Inclusion Criteria 
 
Histologically or cytologically confirmed SCLC 
 
Extensive disease, defined by at least one of the following criteria: 
 
No limited disease (ie, no disease confined to the ipsilateral hemithorax, which can 
be safely encompassed within a tolerable radiation field) 
 
Extrathoracic metastases  
 
Malignant pericardial or pleural effusion 
 
Contralateral hilar adenopathy 
 
Measurable or non-measurable disease, as defined by modified RECIST 
 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
 
≥ 18 years old 
 
Life expectancy (with therapy) ≥ 3 months 
 
Adequate hematologic, hepatic, coagulation, renal, and metabolic function  
 
Fasting blood glucose ≤ 160 mg/dL 
Key Exclusion Criteria 
 
Prior chemotherapy, chemo-radiation, or investigational agent for SCLC 
 
Prior radiotherapy to > 25% of the bone marrow 
 
Symptomatic or untreated central nervous system (CNS) metastasis (with exceptions) 
 
Currently or previously treated with biological, immunological or other therapies for SCLC 
 
Current serious or non-healing wound or ulcer           
 
History of prior or concurrent other malignancy (with exceptions) 
 
Any clinically significant medical condition other than cancer (eg, cardiovascular disease 
or chronic obstructive pulmonary disease), which could interfere with the safe delivery of 
study treatment or increase risk of toxicity 
Study Drug Dosage and Administration:  See Section 6 for details. 
Investigational Product: 
Part 1:   Cohorts 1a and 2a:   
 
AMG 479 18 mg/kg intravenous (IV) on day 2 of the initial cycle, and day 1 of each Q3W 
 
cycle thereafter  
 
AMG 479 18 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment  
 
              Cohort 3a and 4a:   
 
AMG 102 15 mg/kg IV on day 2 of the initial cycle, and day 1 of each Q3W cycle 
 
thereafter 
 
AMG 102 15 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment  
 
Lower doses of AMG 479 and/or AMG 102 may be explored based on safety and PK data, 
to determine the maximum tolerated dose. Refer to Section 6.1.1.1 for details. 
 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 April 2009 
Page 7 of 190 
 
Part 2:  AMG 479 (Arm A), AMG 102 (Arm B), at the respective doses selected in Part 1, 
 
or matching placebo (Arm C), IV Q3W:  
 
 
day 2 of the initial cycle, and day 1 of each Q3W cycle thereafter 
 
IP dose will be calculated based on the subject’s actual body weight at baseline, and the dose 
must be recalculated if the actual body weight changes by > 10%.  IP will be diluted in 0.9% 
normal saline.   
IP will be administered Q3W, after completion of the chemotherapy infusion (if administered).  IP 
will be administered over 60 minutes (min) (± 10 min).  If a dose of IP is well tolerated (ie, without 
serious infusion-related reactions), then subsequent IV infusions may be given over 30 min (± 10 
min).  Infusion time can be extended up to 120 min for subjects deemed unable to tolerate the 60 
min infusion. 
Chemotherapy (Part 1 and Part 2):    
Etoposide 100 mg/m2 to be administered IV over 90 min (± 30 min) on days 1, 2, and 3 of each 
Q3W cycle, or per institutional guidelines.  
Carboplatin (AUC = 5 mg/mL • min) will be administered IV over 30 min (+ 10 min) on day 1 of 
each Q3W cycle after the etoposide infusion is complete, per institutional guidelines. Infusion time 
can be extended up to 60 min for subjects deemed unable to tolerate the 30 min infusion. 
Cisplatin 75 mg/m2 will be administered IV over 60 min (± 15 min) on day 1 of each Q3W cycle 
after the etoposide infusion is complete, per institutional guidelines. Infusion time can be 
extended up to 120 min for subjects deemed unable to tolerate the 60 min infusion.  
Subjects must receive adequate premedication (see Section 6.2.2.3), vigorous hydration and 
diuresis, and monitoring of fluid status (see Section 6.2.2.4).  
 
Control Group:   
Part 1: there is no control group 
 
Part 2: Arm C: Placebo in combination with etoposide plus carboplatin or cisplatin Q3W  
 
Key Study Procedures:  See Section 7.1 and Schedule of Assessments (Appendix A) for details.  
 
Screening Procedures  
 • Review of inclusion and exclusion criteria  
 • Medication and medical history, concomitant medications/treatment(s), adverse events  
 • Vital signs: resting pulse, respiration, blood pressure, and temperature  
 • Physical examination, including height and weight  
 • ECOG performance status assessment  
 • Laboratory tests; including hematology, chemistry, coagulation, urinalysis, pregnancy test  
 • If available, submission of paraffin-embedded tumor tissue (paraffin tumor block, or slides) and     
all available pathology reports 
 • 12-lead electrocardiogram (ECG)  
 • Radiological imaging to assess disease extent (CT scan or MRI of the brain, chest, abdomen, 
and all other sites of disease; within 28 days prior to enrollment)  
 
Treatment and Follow-Up Procedures 
 • Recording of adverse events and concomitant medications  
 • Patient completion of EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires (Part 2)  
 • Vital signs: resting pulse, respiration, blood pressure, and temperature  
 • Physical examination, including weight, and ECOG performance status assessment  
 • Laboratory tests; including hematology, chemistry, pregnancy test  


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 April 2009 
Page 8 of 190 
 
 • Samples for biomarkers and anti-AMG 479 or anti-AMG 102 antibodies  
 • Samples for AMG 479, AMG 102, carboplatin, cisplatin and etoposide PK (Part 1) 
 • ECG  
 • Radiological imaging to assess disease extent  (CT scan or MRI [same modality throughout 
the study] of the chest, abdomen, and all other sites of disease [except: brain imaging only as 
clinically indicated] every 6 weeks [± 7 days] from Study Day 1 during the first 6 months of the 
study, and every 9 weeks [± 7 days] thereafter)  
Statistical Considerations: See Section 10 for details.  
Analyses will be presented separately for Part 1 and Part 2 of the study.  The HR for OS will be 
estimated using a Cox regression model stratified by randomization stratification factors and 
controlled for the LDH level as an important covariate.  A Wald chi-square test will provide a 
descriptive p-value for the HR.  Overall survival between the respective pair of treatment arms 
(Arm A/Arm C and Arm B/Arm C) will use a stratified log-rank test for a descriptive comparison. 
 
DRT Safety Reviews and Interim Analysis 
For the protection of subjects, in Part 1 of the study, Safety Review Team (SRT) meetings will be 
held to review safety, laboratory, dosing information and PK data (when available) from each 
AMG 479 and AMG 102 dose cohort, to make recommendations regarding dose selection for 
Part 2, dose de-escalation, or dose stopping.   
In Part 2, an Amgen Data Review Team (DRT) independent of the study team will perform two 
unblinded reviews of the safety data after at least 30 and 60 subjects have been randomized and 
had the opportunity to complete the first cycle of study treatment (safety interim analyses).  
One interim efficacy analysis is planned to review both OS and PFS data 10 months after the last 
subject is randomized.  Approximately 100 OS events are estimated (69 OS events per 
comparison: Arm A/Arm C and Arm B/Arm C) for the interim analysis assuming approximately 
half of the planned enrollment will occur at 15 months. Review of safety data will also occur 
during the interim efficacy analysis. The interim efficacy analysis will provide a preliminary 
assessment of the overall risk/benefit profile. Unless safety concerns arise, the study will not be 
discontinued or modified due to the results of the interim efficacy analysis.  
The primary analysis of Part 2 will be event-driven and will occur after a total of approximately 
130 deaths (89 deaths per planned comparison: Arm A/Arm C and Arm B/Arm C), which is 
anticipated to occur 18 months after end of enrollment.  A final analysis is planned after a 
minimum expected follow-up of 36 months, at which time approximately 163 deaths are expected 
overall (110 per planned comparison).  
Sponsor/Licensee:  Amgen Inc


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 April 2009 
Page 9 of 190 
 
Study Design and Treatment Schema 
 
PART 1 ENROLLMENT 
Safety Follow-Up 
Long-Term Follow-Up
(Every 3 months for up to 36 months from last subject randomized)
PART 1
PHASE 1B DOSE SELECTION SEGMENT
PART 2
PHASE 2 SEGMENT
PART 2  RANDOMIZATION 1:1:1
END OF TREATMENT
Platin/Etoposide
PLACEBO
BLINDED
Platin/Etoposide
AMG 102
BLINDED
Platin/Etoposide
ARM A (n=60)
Cisplatin/Etoposide
AMG 479 18 mg/kg
Cohort 1a (n=6 to 9)
Cisplatin/Etoposide
AMG 102 15 mg/kg
Carboplatin/Etoposide
AMG 102 15 mg/kg
SAFETY REVIEW TEAM REVIEWS DOSE COHORTS, RECOMMENDS PART 2 REGIMEN(S)
AMG 479 AND AMG 102 AT DOSES IDENTIFIED IN PART 1 
STUDY TREATMENT (3 Week Cycles)  
Chemotherapy: Etoposide (100 mg/m 2 Days 1, 2, 3) and Carboplatin (AUC = 5 mg/mL•min Day 1) or Cisplatin (75 mg/m 2 Day 1)
- Chemotherapy for 4 Cycles (6 Cycles, if best tumor response [maximum tumor regression, per RECIST]) 
Investigational Product: AMG 479 or AMG 102 or Placebo (Part 2 only)
- Day 2 of initial Cycle 
- Day 1 of Cycle = 2, up to 24 months from Study Day 1
Prophylactic Cranial Irradiation (for responding subjects, if not previously administered) prior to IP maintenance treatment
ARM B (n=60)
ARM C (n=60)
Cohort 3a (n=6 to 9)
Cohort 2a (n=6 to 9)
Cohort 4a (n=6 to 9)
AMG 479 
BLINDED
Carboplatin/Etoposide
AMG 479 18 mg/kg
 Dose Cohort  
 Review:
 Determine 
 AMG 479 MTD
Pre-Phase 2 Review
                        Physician’s Choice: Carboplatin or Cisplatin
                        Sequential Assignment: AMG 479 or AMG 102
           Physician’s Choice: Carboplatin or Cisplatin
           Stratification: Gender; Platinum Agent (Carboplatin; Cisplatin)
 Dose Cohort  
 Review:
 Determine 
 AMG 479 MTD
 Dose Cohort  
 Review:
 Determine 
 AMG 102 MTD
 Dose Cohort  
 Review:
 Determine 
 AMG 102 MTD


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  28 September 2009 
Page 1 of 153 
A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based 
Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer 
AMG 479 and AMG 102 
Amgen Protocol Number 20060534 
 
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 
Clinical Research Medical Director  
Amgen Inc 
Phone:  650.244.2634 
Fax:  650.837.9716  
jessem@amgen.com 
 
Megan Ingram 
Clinical Research Study Manager - Primary 
Amgen SF LLC 
Phone:  650.244.2867 
Fax:  650.837.9602 
mingram@amgen.com
 
Jennifer Sampson 
Clinical Research Study Manager - Europe 
Amgen Limited 
Phone:  +44 1895 525313 
Fax:  +44 1895 525101  
Jennifer.Sampson@amgen.com   
Amendment 2 Date: 
28 September 2009 
Amendment 1 Date: 
01 April 2009 
Date: 
07 June 2008 
EudraCT Number: 
2008-003292-42 
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: 1-805-447-5000 
For all other study-related questions, continue to contact the Key Sponsor Contact. 
 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  28 September 2009 
Page 2 of 153
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in 
Combination with Platinum-based Chemotherapy as First-Line Treatment for Extensive 
Stage Small Cell Lung Cancer dated Amendment 2, 28 September 2009, 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) 
 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  28 September 2009 
Page 3 of 153 
Protocol Synopsis 
Title:  A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based 
Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer 
Study Phase:  1b/ 2  
Indication:  Previously Untreated Extensive Stage Small Cell Lung Cancer (SCLC) 
Primary Objective:   
Part 1: To identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin, and of AMG 102 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin that can be administered safely and is tolerated as determined by the 
incidence of dose-limiting toxicity (DLT) 
Part 2: To estimate the relative treatment effect of AMG 479 (at the dose selected in Part 1) in 
combination with chemotherapy (etoposide plus carboplatin and/or etoposide plus cisplatin, as 
determined in part 1), and of AMG 102 (at the dose selected in Part 1) in combination with 
chemotherapy, compared with placebo plus chemotherapy, as measured by the respective 
hazard ratios (HR) for overall survival (OS).   
 
Secondary Objectives:  
Part 1: 
 
To evaluate safety as assessed by the incidence of adverse events and laboratory 
abnormalities not defined as DLT 
 
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody 
formation and anti-AMG 102 antibody formation  
 
To evaluate pharmacokinetics (PK) as assessed by the maximum observed serum 
concentration (Cmax) and the minimum observed serum concentration (Cmin) for 
AMG 479 and for AMG 102  
Part 2:  
 
To evaluate clinical benefit as assessed by the objective response rate (ORR) as 
measured by modified Response Evaluation Criteria in Solid Tumors (RECIST), 
duration of response (DOR), time to progression (TTP), progression-free survival 
(PFS), median OS (mOS), and OS rates at 10, 12, 24 and 36 months 
 
To evaluate safety as assessed by the incidence of adverse events and laboratory 
abnormalities 
 
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody 
formation and anti-AMG 102 antibody formation  
 
To evaluate PK as assessed by Cmax and Cmin for AMG 479 and for AMG 102  
 
To estimate the effect of AMG 479 and of AMG 102 on subject’s health related 
quality of life (HRQoL) using the European Organisation for Research and 
Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and its lung cancer 
module (QLQ-LC13) 
Exploratory Objectives: 
Part 1 and Part 2: 
 
To evaluate PK as assessed by area under the curve (AUC) and Cmax for 
etoposide, cisplatin and carboplatin  
 
To investigate the relationship between AMG 479 and AMG 102 PK and treatment 
outcomes (including clinical and pharmacodynamic endpoints)  
 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  28 September 2009 
Page 4 of 153
 
To investigate the biomarker profile at baseline, and the pharmacodynamic 
response, as assessed by biomarkers for AMG 479 (eg, serum IGF-1, IGF-BP3, 
GH, and other factors involved in regulating the IGF-1/IGF-1R pathway) and for 
AMG 102 (eg, HGF/SF:c-Met pathway markers, tumor apoptosis markers, 
angiogenic cytokines and other biomarkers), and correlate with treatment outcomes 
 
To investigate other potential biomarker development (eg, biochemical levels and 
abundance of drug targets, tumor somatic mutations in drug target, pathway, and 
cancer genes) by biochemical analysis of blood samples and tumor tissue (if 
available), and correlate with treatment outcomes  
 
To investigate the effect of genetic variations in cancer genes, drug target and 
pathway genes, and other biomarker genes, and correlate with treatment outcomes 
(optional for subjects; requires separate informed consent) 
Hypotheses:   
Part 1 will identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin and of AMG 102 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin that is safe and tolerated as determined by the incidence of DLT.   
Part 2 will estimate the relative efficacy of AMG 479 (at the dose selected in Part 1), and of 
AMG 102 (at the dose selected in Part 1), and of placebo plus platinum-based chemotherapy 
(etoposide plus carboplatin and/or etoposide plus cisplatin, as determined in part 1) as measured 
by the respective OS HR.  Given a hypothesized HR of 0.74 for each comparison, the target 
maximum half width of 0.22 for the OS HR 2-sided 80% CI will be achieved after 89 deaths are 
observed for a pairwise comparison. 
 
Study Design: 
This study has 2 parts.   
Part 1 is a multi-center, open-label dose de-escalation phase 1b segment of AMG 479 in 
combination with etoposide plus carboplatin (Cohort 1) or cisplatin (Cohort 2), and of AMG 102 in 
combination with etoposide plus carboplatin (Cohort 3) or cisplatin (Cohort 4). Once respective 
doses of AMG 479 and of AMG 102 have been identified that are safe and tolerated based on the 
incidence of DLT, Part 2 will open for enrollment.  
Part 2 is a randomized, double-blind, placebo-controlled phase 2 segment of AMG 479 (at the 
dose selected in Part 1), and of AMG 102 (at the dose selected in Part 1), and of placebo plus 
platinum-based chemotherapy (etoposide plus carboplatin and/or etoposide plus cisplatin, as 
determined in part 1) as first-line treatment for subjects with extensive stage SCLC. Subjects 
(n = 180) will be randomized in a 1:1:1 ratio to each treatment arm (n = 60 per arm). 
Randomization will be stratified according to gender (female; male) and chemotherapy (etoposide 
and cisplatin; etoposide and carboplatin).  
In both parts of the study, chemotherapy (etoposide plus carboplatin or cisplatin) will be 
administered on day 1 of each 21-day (Q3W) cycle. Etoposide will also be administered on day 2 
and 3 of each Q3W cycle. Premedication (see Section 6.2.2.3), vigorous hydration and diuresis 
(see Section 6.2.2.4) will be required for chemotherapy treatment. Investigational product (IP; 
AMG 479 [Part 1, Cohorts 1 and 2; Part 2, Arm A] or AMG 102 [Part 1, Cohorts 3 and 4; Part 2, 
Arm B] or placebo [Part 2, Arm C]) will be administered after the chemotherapy infusion on day 2 
of the initial cycle, and day 1 of each Q3W cycle thereafter. Four to six cycles of chemotherapy 
will be given. Determination of the number of cycles of chemotherapy to be administered 
(between 4 to 6) will be left to the investigator’s discretion. Subjects who complete 4 to 6 cycles of 
chemotherapy or who discontinue chemotherapy early will continue to receive IP (AMG 479, or 
AMG 102, or placebo) single agent maintenance therapy on day 1 of each Q3W cycle for up to  
24 months from the date of first study treatment administration (study day 1).  Subjects who have 
completed 24 months of IP may be eligible for continued treatment with IP by extension protocol 
or as provided for by the local country’s regulatory mechanism (see Section 13).  Study treatment 
will cease if a subject experiences progressive disease (PD), death, unacceptable toxicity, 
withdraws consent, or due to an administrative decision (by the investigator or Amgen).   
 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  28 September 2009 
Page 5 of 153 
Radiological imaging to assess PD (per modified RECIST) will be performed every 6 weeks (± 7 
days) during the first 6 months of the study, from Study Day 1 and every 9 weeks (± 7 days) 
thereafter, until subjects develop PD (per modified RECIST) or begin a new cancer treatment.  
A follow-up visit will occur 30 days (+ 7 days) and 60 days (+ 14 days) after the last dose of 
protocol-specified treatment. Subjects will be contacted every 3 months (± 2 weeks) in the 
long-term follow-up, for up to 36 months from the date of the last subject randomized, to assess 
survival. Please refer to the Study Schema for an overview of the 2-part study design.  
 
Primary and Secondary Endpoints:  See Section 10 for details 
 
Primary Endpoints 
 
Part 1:    ▪  The incidence of adverse events and clinical laboratory abnormalities defined as DLT 
 
Part 2:    ▪  OS  
 
Secondary Endpoints 
 
 
Part 1: 
 
The incidence of adverse events and laboratory abnormalities not defined as DLT 
 
The incidence of anti-AMG 479 and anti-AMG 102 antibody formation  
 
PK (Cmax and Cmin for AMG 479 and AMG 102)  
 
Part 2: 
 
ORR, DOR, TTP, PFS, mOS, and OS rates at 10,12, 24, and 36 months 
 
The incidence of adverse events and laboratory abnormalities 
 
The incidence of anti-AMG 479 and anti-AMG 102 antibody formation  
 
PK (Cmax and Cmin) for AMG 479 and AMG 102 
 
EORTC QLQ-C30 and EORTC QLQ-LC13 scores 
 
Exploratory Endpoints 
Part 1 and Part 2: 
 
PK (AUC and Cmax) for etoposide, cisplatin and carboplatin  
 
Relationship between AMG 479 and AMG 102 PK and treatment outcomes (including 
clinical and pharmacodynamic endpoints)  
 
Baseline biomarker profile and pharmacodynamic response, as assessed by AMG 479 
and AMG 102 biomarkers, and correlation with treatment outcomes  
 
Biochemical levels and abundance of drug targets and other biomarkers in blood 
samples and tumor tissue (if available), and correlation with treatment outcomes  
 
Genetic variations in cancer genes, drug target and pathway genes, and other biomarker 
genes, and correlation with treatment outcomes   
Sample Size:  Part 1: 24 to 108 subjects; Part 2: 180 subjects 
 
Summary of Subject Eligibility Criteria:  See Section 4 for details 
 
Key Inclusion Criteria 
 
Histologically or cytologically confirmed SCLC 
 
Extensive disease, defined by at least one of the following criteria: 
 
No limited disease (ie, no disease confined to the ipsilateral hemithorax, which can 
be safely encompassed within a tolerable radiation field) 
 
Extrathoracic metastases  
 
Malignant pericardial or pleural effusion 
 
Contralateral hilar adenopathy 
 
Measurable or non-measurable disease, as defined by modified RECIST 
 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  28 September 2009 
Page 6 of 153 
 
≥ 18 years old 
 
Life expectancy (with therapy) ≥ 3 months 
 
Adequate hematologic, hepatic, coagulation, renal, and metabolic function  
 
Fasting blood glucose ≤ 160 mg/dL 
Key Exclusion Criteria 
 
Prior chemotherapy, chemo-radiation, or investigational agent for SCLC 
 
Prior radiotherapy to > 25% of the bone marrow 
 
Symptomatic or untreated central nervous system (CNS) metastasis (with exceptions) 
 
Currently or previously treated with biological, immunological or other therapies for SCLC 
 
Current serious or non-healing wound or ulcer           
 
History of prior or concurrent other malignancy (with exceptions) 
 
Thrombosis or vascular ischemic events within the last twelve months, such as 
deep venous thrombosis, pulmonary embolism, transient ischemic attack, cerebral 
infarction, or myocardial infarction 
 
Any clinically significant medical condition other than cancer (eg, cardiovascular disease 
or chronic obstructive pulmonary disease), which could interfere with the safe delivery of 
study treatment or increase risk of toxicity 
Study Drug Dosage and Administration:  See Section 6 for details. 
Investigational Product: 
Part 1:   Cohorts 1a and 2a:   
 
AMG 479 18 mg/kg intravenous (IV) on day 2 of the initial cycle, and day 1 of each Q3W 
 
cycle thereafter  
 
AMG 479 18 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment  
 
              Cohort 3a and 4a:   
 
AMG 102 15 mg/kg IV on day 2 of the initial cycle, and day 1 of each Q3W cycle 
 
thereafter 
 
AMG 102 15 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment  
 
Lower doses of AMG 479 and/or AMG 102 may be explored based on safety and PK data, 
to determine the maximum tolerated dose. Refer to Section 6.1.1.1 for details. 
 
 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  28 September 2009 
Page 7 of 153 
Part 2:  AMG 479 (Arm A), AMG 102 (Arm B), at the respective doses selected in Part 1, 
 
or matching placebo (Arm C), IV Q3W:  
 
 
day 2 of the initial cycle, and day 1 of each Q3W cycle thereafter 
 
IP dose will be calculated based on the subject’s actual body weight at baseline, and the dose 
must be recalculated if the actual body weight changes by > 10%.  IP will be diluted in 0.9% 
normal saline.   
IP will be administered Q3W, after completion of the chemotherapy infusion (if administered).  IP 
will be administered over 60 minutes (min) (± 10 min).  If a dose of IP is well tolerated (ie, without 
serious infusion-related reactions), then subsequent IV infusions may be given over 30 min (± 10 
min).  Infusion time can be extended up to 120 min for subjects deemed unable to tolerate the 60 
min infusion. 
Chemotherapy (Part 1 and Part 2):    
Etoposide 100 mg/m2 to be administered IV over 90 min (± 30 min) on days 1, 2, and 3 of each 
Q3W cycle, or per institutional guidelines.  
Carboplatin (AUC = 5 mg/mL • min) will be administered IV over 30 min (+ 10 min) on day 1 of 
each Q3W cycle after the etoposide infusion is complete, per institutional guidelines. Infusion time 
can be extended up to 60 min for subjects deemed unable to tolerate the 30 min infusion. 
Cisplatin 75 mg/m2 will be administered IV over 60 min (± 15 min) on day 1 of each Q3W cycle 
after the etoposide infusion is complete, per institutional guidelines. Infusion time can be 
extended up to 120 min for subjects deemed unable to tolerate the 60 min infusion.  
Subjects must receive adequate premedication (see Section 6.2.2.3), vigorous hydration and 
diuresis, and monitoring of fluid status (see Section 6.2.2.4).  
 
Control Group:   
Part 1: there is no control group 
 
Part 2: Arm C: Placebo in combination with etoposide plus carboplatin or cisplatin Q3W  
 
Key Study Procedures:  See Section 7.1 and Schedule of Assessments (Appendix A) for details.  
 
Screening Procedures  
 • Review of inclusion and exclusion criteria  
 • Medication and medical history, concomitant medications/treatment(s), adverse events  
 • Vital signs: resting pulse, respiration, blood pressure, and temperature  
 • Physical examination, including height and weight  
 • ECOG performance status assessment  
 • Laboratory tests; including hematology, chemistry, coagulation, urinalysis, pregnancy test  
 • If available, submission of paraffin-embedded tumor tissue (paraffin tumor block, or slides) and 
all available pathology reports 
 • 12-lead electrocardiogram (ECG)  
 • Radiological imaging to assess disease extent (CT scan or MRI of the brain, chest, abdomen, 
and all other sites of disease; within 28 days prior to enrollment)  
 
Treatment and Follow-Up Procedures 
 • Recording and reporting of adverse events and concomitant medications  
 • Patient completion of EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires (Part 2)  
 • Vital signs: resting pulse, respiration, blood pressure, and temperature  
 • Physical examination, including weight, and ECOG performance status assessment  
 • Laboratory tests; including hematology, chemistry, pregnancy test  
 


Products:  AMG 479 an
Protocol Nu
Date:  28 Se
d AMG 102 
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ptember 2009 
Page 8 of 153 
 
 • Samples for biomarkers and anti-AMG 479 or anti-AMG 102 antibodies  
 • Samples for AMG 479, AMG 102, carboplatin, cisplatin and etoposide PK (Part 1) 
 • ECG  
 • Radiological imaging to assess disease extent  (CT scan or MRI [same modality throughout 
the study] of the chest, abdomen, and all other sites of disease [except: brain imaging only as 
clinically indicated] every 6 weeks [± 7 days] from Study Day 1 during the first 6 months of the 
study, and every 9 weeks [± 7 days] thereafter)  
Statistical Considerations: See Section 10 for details.  
Analyses will be presented separately for Part 1 and Part 2 of the study.  The HR for OS will be 
estimated using a Cox regression model stratified by randomization stratification factors and 
controlled for the LDH level as an important covariate.  A Wald chi-square test will provide a 
descriptive p-value for the HR.  Overall survival between the respective pair of treatment arms 
(Arm A/Arm C and Arm B/Arm C) will use a stratified log-rank test for a descriptive comparison. 
 
DRT Safety Reviews and Interim Analysis 
For the protection of subjects, in Part 1 of the study, Safety Review Team (SRT) meetings will be 
held to review safety, laboratory, dosing information and PK data (when available) from each 
AMG 479 and AMG 102 dose cohort, to make recommendations regarding dose selection for 
Part 2, dose de-escalation, or dose stopping.   
 
In Part 2. and Amgen Data Review Team (DRT), independent of the study team will perform 
unblinded reviews of the safety data after at least 30 and 60 subjects have been randomized and 
had the opportunity to complete cycle 1 of the study treatment (safety interim analyses). In 
addition, unblinded SAE information for thrombosis or vascular ischemic events will be 
made available to the DRT on an ongoing basis 
   
One interim efficacy analysis is planned to review both OS and PFS data 10 months after the last 
subject is randomized.  Approximately 100 OS events are estimated (69 OS events per 
comparison: Arm A/Arm C and Arm B/Arm C) for the interim analysis assuming approximately 
half of the planned enrollment will occur at 15 months. Review of safety data will also occur 
during the interim efficacy analysis. The interim efficacy analysis will provide a preliminary 
assessment of the overall risk/benefit profile. Unless safety concerns arise, the study will not be 
discontinued or modified due to the results of the interim efficacy analysis 
The primary analysis of Part 2 will be event-driven and will occur after a total of approximately 
130 deaths (89 deaths per planned comparison: Arm A/Arm C and Arm B/Arm C), which is 
anticipated to occur 18 months after end of enrollment.  A final analysis is planned after a 
minimum expected follow-up of 36 months, at which time approximately 163 deaths are expected 
overall (110 per planned comparison).  
Sponsor/Licensee:  Amgen Inc


d AMG 102 
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Study Design and Treatment Schema  
Products:  AMG 479 an
Protocol Nu
Date:  28 Se


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 February 2011 
Page 1 of 147 
 
A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based 
Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer 
AMG 479 and AMG 102 
Amgen Protocol Number 20060534 
 
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 
Clinical Research Medical Director  
Amgen Inc 
Phone:  650.244.2634 
Fax:  650.837.9716  
jessem@amgen.com 
 
Cat Goodall 
Clinical Research Study Manager - Primary 
Amgen Limited 
Phone:  +44 1895 525327 
Fax:  +44 1895 525101  
cgoodall@amgen.com   
 
Nancy Kenyon 
Clinical Research Study Manager – U.S 
Amgen Inc 
Phone:  805.447.5737 
Fax:  805. 
nkenyon@amgen.com 
 
Amendment 3 Date: 
01 February 2011 
Amendment 2 Date: 
24 September 2010 
Amendment 1 Date: 
01 April 2009 
Date: 
07 June 2008 
EudraCT Number: 
2008-003292-42 
 
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: 1-805-447-5000 
For all other study-related questions, continue to contact the Key Sponsor Contact. 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 February 2011 
Page 2 of 147 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in 
Combination with Platinum-based Chemotherapy as First-Line Treatment for Extensive 
Stage Small Cell Lung Cancer dated Amendment 3, 01 February 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) 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 February 2011 
Page 3 of 147 
 
Protocol Synopsis 
Title:  A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based 
Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer 
Study Phase:  1b/ 2  
Indication:  Previously Untreated Extensive Stage Small Cell Lung Cancer (SCLC) 
Primary Objective:   
Part 1: To identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin, and of AMG 102 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin that can be administered safely and is tolerated as determined by the 
incidence of dose-limiting toxicity (DLT) 
Part 2:
Secondary Objectives:  
 To estimate the relative treatment effect of AMG 479 (at the dose selected in Part 1) in 
combination with chemotherapy (etoposide plus carboplatin and/or etoposide plus cisplatin, as 
determined in part 1), and of AMG 102 (at the dose selected in Part 1) in combination with 
chemotherapy, compared with placebo plus chemotherapy, as measured by the respective 
hazard ratios (HR) for overall survival (OS).   
Part 1
• 
To evaluate safety as assessed by the incidence of adverse events and laboratory 
abnormalities not defined as DLT 
: 
• 
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody formation and 
anti-AMG 102 antibody formation  
• 
To evaluate pharmacokinetics (PK) as assessed by the maximum observed serum 
concentration (Cmax) and the minimum observed serum concentration (Cmin) for AMG 479 and 
for AMG 102  
Part 2
• 
To evaluate clinical benefit as assessed by the objective response rate (ORR) as measured 
by modified Response Evaluation Criteria in Solid Tumors (RECIST), duration of response 
(DOR), time to progression (TTP), progression-free survival (PFS), median OS (mOS), and 
OS rates at 10, 12, 24, and 36 months 
:  
• 
To evaluate safety as assessed by the incidence of adverse events and laboratory 
abnormalities 
• 
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody formation and 
anti-AMG 102 antibody formation  
• 
To evaluate PK as assessed by Cmax and Cmin for AMG 479 and for AMG 102  
• 
To estimate the effect of AMG 479 and of AMG 102 on subject’s health-related quality of life 
(HRQoL) using the European Organisation for Research and Treatment of Cancer (EORTC) 
core questionnaire (QLQ-C30) and its lung cancer module (QLQ-LC13) 
Exploratory Objectives: 
Part 1 and Part 2
• 
To evaluate PK as assessed by area under the curve (AUC) and Cmax for etoposide, 
cisplatin and carboplatin  
: 
• 
To investigate the relationship between AMG 479 and AMG 102 PK and treatment outcomes 
(including clinical and pharmacodynamic endpoints)  


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 February 2011 
Page 4 of 147 
 
• 
To investigate the biomarker profile at baseline, and the pharmacodynamic response, as 
assessed by biomarkers for AMG 479 (eg, serum IGF-1, IGF-BP3, GH, and other factors 
involved in regulating the IGF-1/IGF-1R pathway) and for AMG 102 (eg, HGF/SF:c-Met 
pathway markers, tumor apoptosis markers, angiogenic cytokines and other biomarkers), and 
correlate with treatment outcomes 
• 
To investigate other potential biomarker development (eg, biochemical levels and abundance 
of drug targets, tumor somatic mutations in drug target, pathway, and cancer genes) by 
biochemical analysis of blood samples and tumor tissue (if available), and correlate with 
treatment outcomes  
• 
To investigate the effect of genetic variations in cancer genes, drug target and pathway 
genes, and other biomarker genes, and correlate with treatment outcomes (optional for 
subjects; requires separate informed consent) 
Hypotheses:   
• 
Part 1 will identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin and of AMG 102 in combination with etoposide plus carboplatin 
and/or etoposide plus cisplatin that is safe and tolerated as determined by the incidence of 
DLT.   
• 
Part 2 will estimate the relative efficacy of AMG 479 (at the dose selected in Part 1), and of 
AMG 102 (at the dose selected in Part 1), and of placebo plus platinum-based chemotherapy 
(etoposide plus carboplatin and/or etoposide plus cisplatin, as determined in part 1) as 
measured by the respective OS HR.  Given a hypothesized HR of 0.74 for each comparison, 
the target maximum half width of 0.22 for the OS HR 2-sided 80% CI will be achieved after 
89 deaths are observed for a pairwise comparison. 
Study Design: 
This study has 2 parts.   
Part 1 is a multi-center, open-label dose de-escalation phase 1b segment of AMG 479 in 
combination with etoposide plus carboplatin (Cohort 1) or cisplatin (Cohort 2), and of AMG 102 in 
combination with etoposide plus carboplatin (Cohort 3) or cisplatin (Cohort 4). Once respective 
doses of AMG 479 and of AMG 102 have been identified that are safe and tolerated based on the 
incidence of DLT, Part 2 will open for enrollment.  
Part 2
In both parts of the study, chemotherapy (etoposide plus carboplatin or cisplatin) will be 
administered on day 1 of each 21-day (Q3W) cycle. Etoposide will also be administered on day 2 
and 3 of each Q3W cycle. Premedication (see 
 is a randomized, double-blind, placebo-controlled phase 2 segment of AMG 479 (at the 
dose selected in Part 1), and of AMG 102 (at the dose selected in Part 1), and of placebo plus 
platinum-based chemotherapy (etoposide plus carboplatin and/or etoposide plus cisplatin, as 
determined in part 1) as first-line treatment for subjects with extensive stage SCLC. Subjects 
(n = 180) will be randomized in a 1:1:1 ratio to each treatment arm (n = 60 per arm). 
Randomization will be stratified according to gender (female; male) and chemotherapy (etoposide 
and cisplatin; etoposide and carboplatin).  
Section 6.2.2.3), vigorous hydration and diuresis 
(see Section 6.2.2.4) will be required for chemotherapy treatment. Investigational product (IP; 
AMG 479 [Part 1, Cohorts 1 and 2; Part 2, Arm A] or AMG 102 [Part 1, Cohorts 3 and 4; Part 2, 
Arm B] or placebo [Part 2, Arm C]) will be administered after the chemotherapy infusion on day 2 
of the initial cycle, and day 1 of each Q3W cycle thereafter. Four to six cycles of chemotherapy 
will be given. Determination of the number of cycles of chemotherapy to be administered 
(between 4 to 6) will be left to the investigator’s discretion. Subjects who complete 4 to 6 cycles of 
chemotherapy or who discontinue chemotherapy early will continue to receive IP (AMG 479, or 
AMG 102, or placebo) single agent maintenance therapy on day 1 of each Q3W cycle for up to  
24 months from the date of first study treatment administration (study day 1).  Subjects who have 
completed 24 months of IP may be eligible for continued treatment with IP by extension protocol 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 February 2011 
Page 5 of 147 
 
or as provided for by the local country’s regulatory mechanism (see Section 13).  Study treatment 
will cease if a subject experiences progressive disease (PD), death, unacceptable toxicity, 
withdraws consent, or due to an administrative decision (by the investigator or Amgen).   
Radiological imaging to assess PD (per modified RECIST) will be performed every 6 weeks  
(± 7 days) during the first 6 months of the study, from Study Day 1 and every 9 weeks (± 7 days) 
thereafter, until subjects develop PD (per modified RECIST) or begin a new cancer treatment.  
A follow-up visit will occur 30 days (+ 7 days) and 60 days (+ 14 days) after the last dose of 
protocol-specified treatment. Subjects will be contacted every 3 months (± 2 weeks) in the 
long-term follow-up, for up to 36 months from the date of the last subject randomized, to assess 
survival. Please refer to the Study Schema for an overview of the 2-part study design.  
Primary and Secondary Endpoints:  See Section 10 for details 
Primary Endpoints 
Part 1
• 
The incidence of adverse events and clinical laboratory abnormalities defined as DLT 
:     
Part 2
• 
OS  
:     
Secondary Endpoints 
• 
The incidence of adverse events and laboratory abnormalities not defined as DLT 
Part 1: 
• 
The incidence of anti-AMG 479 and anti-AMG 102 antibody formation  
• 
PK (Cmax and Cmin for AMG 479 and AMG 102)  
• 
ORR, DOR, TTP, PFS, mOS, and OS rates at 10,12, 24, and 36 months 
Part 2: 
• 
The incidence of adverse events and laboratory abnormalities 
• 
The incidence of anti-AMG 479 and anti-AMG 102 antibody formation  
• 
PK (Cmax and Cmin) for AMG 479 and AMG 102 
• 
EORTC QLQ-C30 and EORTC QLQ-LC13 scores 
Exploratory Endpoints 
• 
PK (AUC and Cmax) for etoposide, cisplatin and carboplatin  
Part 1 and Part 2: 
• 
Relationship between AMG 479 and AMG 102 PK and treatment outcomes (including clinical 
and pharmacodynamic endpoints)  
• 
Baseline biomarker profile and pharmacodynamic response, as assessed by AMG 479 and 
AMG 102 biomarkers, and correlation with treatment outcomes  
• 
Biochemical levels and abundance of drug targets and other biomarkers in blood samples 
and tumor tissue (if available), and correlation with treatment outcomes  
• 
Genetic variations in cancer genes, drug target and pathway genes, and other biomarker 
genes, and correlation with treatment outcomes   
Sample Size:  Part 1: 24 to 108 subjects; Part 2: 180 subjects 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 February 2011 
Page 6 of 147 
 
Summary of Subject Eligibility Criteria:  See Section 4 for details 
• 
Histologically or cytologically confirmed SCLC 
Key Inclusion Criteria 
• 
Extensive disease, defined by at least one of the following criteria: 
− 
No limited disease (ie, no
− 
Extrathoracic metastases  
 disease confined to the ipsilateral hemithorax, which can 
be safely encompassed within a tolerable radiation field) 
− 
Malignant pericardial or pleural effusion 
− 
Contralateral hilar adenopathy 
• 
Measurable or non-measurable disease, as defined by modified RECIST 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
• 
≥ 18 years old 
• 
Life expectancy (with therapy) ≥ 3 months 
• 
Adequate hematologic, hepatic, coagulation, renal, and metabolic function  
• 
Fasting blood glucose ≤ 160 mg/dL 
• 
Prior chemotherapy, chemo-radiation, or investigational agent for SCLC 
Key Exclusion Criteria 
• 
Prior radiotherapy to > 25% of the bone marrow 
• 
Symptomatic or untreated central nervous system (CNS) metastasis (with exceptions) 
• 
Currently or previously treated with biological, immunological or other therapies for SCLC 
• 
Current serious or non-healing wound or ulcer           
• 
History of prior or concurrent other malignancy (with exceptions) 
• 
Thrombosis or vascular ischemic events within the last twelve months, such as deep venous 
thrombosis, pulmonary embolism, transient ischemic attack, cerebral infarction, or myocardial 
infarction 
• 
Any clinically significant medical condition other than cancer (eg, cardiovascular disease or 
chronic obstructive pulmonary disease), which could interfere with the safe delivery of study 
treatment or increase risk of toxicity 
Study Drug Dosage and Administration:  See Section 6 for details. 
Investigational Product: 
Part 1:   Cohorts 1a and 2a
 
AMG 479 18 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment  
:   
 
AMG 479 18 mg/kg intravenous (IV) on day 2 of the initial cycle, and day 1 of each Q3W 
 
cycle thereafter  
              Cohort 3a and 4a
 
AMG 102 15 mg/kg IV on day 2 of the initial cycle, and day 1 of each Q3W cycle 
 
thereafter 
:   
 
AMG 102 15 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment  
Lower doses of AMG 479 and/or AMG 102 may be explored based on safety and PK 
data, to determine the maximum tolerated dose. Refer to Section 6.1.1.1 for details. 


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 February 2011 
Page 7 of 147 
 
Part 2
 
or matching placebo (Arm C), IV Q3W:  
 
:  AMG 479 (Arm A), AMG 102 (Arm B), at the respective doses selected in Part 1, 
 
day 2 of the initial cycle, and day 1 of each Q3W cycle thereafter 
IP dose will be calculated based on the subject’s actual body weight at baseline, and the dose 
must be recalculated if the actual body weight changes by > 10%.  IP will be diluted in 0.9% 
normal saline.   
IP will be administered Q3W, after completion of the chemotherapy infusion (if administered).  IP 
will be administered over 60 minutes (min) (± 10 min).  If a dose of IP is well tolerated (ie, without 
serious infusion-related reactions), then subsequent IV infusions may be given over 30 min 
(± 10 min).  Infusion time can be extended up to 120 min for subjects deemed unable to tolerate 
the 60 min infusion. 
Chemotherapy (Part 1 and Part 2)
Etoposide 100 mg/m2 to be administered IV over 90 min (± 30 min) on days 1, 2, and 3 of each 
Q3W cycle, or per institutional guidelines.  
:    
Carboplatin (AUC = 5 mg/mL • min) will be administered IV over 30 min (+ 10 min) on day 1 of 
each Q3W cycle after the etoposide infusion is complete, per institutional guidelines. Infusion time 
can be extended up to 60 min for subjects deemed unable to tolerate the 30 min infusion. 
Cisplatin 75 mg/m2 will be administered IV over 60 min (± 15 min) on day 1 of each Q3W cycle 
after the etoposide infusion is complete, per institutional guidelines. Infusion time can be 
extended up to 120 min for subjects deemed unable to tolerate the 60 min infusion.  
Subjects must receive adequate premedication (see Section 6.2.2.3), vigorous hydration and 
diuresis, and monitoring of fluid status (see Section 6.2.2.4).  
Control Group:   
Part 1: there is no control group 
Part 2: Arm C: Placebo in combination with etoposide plus carboplatin or cisplatin Q3W  
Key Study Procedures:  See Section 7.1 and Schedule of Assessments (Appendix A) for 
details.  
• 
Review of inclusion and exclusion criteria  
Screening Procedures  
• 
Medication and medical history, concomitant medications/treatment(s), adverse events  
• 
Vital signs: resting pulse, respiration, blood pressure, and temperature  
• 
Physical examination, including height and weight  
• 
ECOG performance status assessment  
• 
Laboratory tests; including hematology, chemistry, coagulation, urinalysis, pregnancy test  
• 
If available, submission of paraffin-embedded tumor tissue (paraffin tumor block, or slides) 
and all available pathology reports 
• 
12-lead electrocardiogram (ECG)  
• 
Radiological imaging to assess disease extent (CT scan or MRI of the brain, chest, abdomen, 
and all other sites of disease; within 28 days prior to enrollment)  
• 
Recording and reporting of adverse events and concomitant medications  
Treatment and Follow-Up Procedures 
• 
Patient completion of EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires (Part 2)  
• 
Vital signs: resting pulse, respiration, blood pressure, and temperature  


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 February 2011 
Page 8 of 147 
 
• 
Physical examination, including weight, and ECOG performance status assessment  
• 
Laboratory tests; including hematology, chemistry, pregnancy test  
• 
Samples for biomarkers and anti-AMG 479 or anti-AMG 102 antibodies  
• 
Samples for AMG 479, AMG 102, carboplatin, cisplatin and etoposide PK (Part 1) 
• 
ECG  
• 
Radiological imaging to assess disease extent  (CT scan or MRI [same modality throughout 
the study] of the chest, abdomen, and all other sites of disease [except: brain imaging only as 
clinically indicated] every 6 weeks [± 7 days] from Study Day 1 during the first 6 months of the 
study, and every 9 weeks [± 7 days] thereafter)  
Statistical Considerations: See Section 10 for details.  
Analyses will be presented separately for Part 1 and Part 2 of the study.  The HR for OS will be 
estimated using a Cox regression model stratified by randomization stratification factors and 
controlled for the LDH level as an important covariate.  A Wald chi-square test will provide a 
descriptive p-value for the HR.  Overall survival between the respective pair of treatment arms 
(Arm A/Arm C and Arm B/Arm C) will use a stratified log-rank test for a descriptive comparison. 
DRT Safety Reviews and Interim Analysis 
For the protection of subjects, in Part 1 of the study, Safety Review Team (SRT) meetings will be 
held to review safety, laboratory, dosing information and PK data (when available) from each 
AMG 479 and AMG 102 dose cohort, to make recommendations regarding dose selection for 
Part 2, dose de-escalation, or dose stopping.   
In Part 2. and Amgen Data Review Team (DRT), independent of the study team will perform 
unblinded reviews of the safety data after at least 30 and 60 subjects have been randomized and 
had the opportunity to complete cycle 1 of the study treatment (safety interim analyses).  In 
addition, unblinded SAE information for thrombosis or vascular ischemic events will be made 
available to the DRT on an ongoing basis 
One interim efficacy analysis is planned to review both OS and PFS data 10 months after the last 
subject is randomized.  Approximately 100 OS events are estimated (69 OS events per 
comparison: Arm A/Arm C and Arm B/Arm C) for the interim analysis assuming approximately 
half of the planned enrollment will occur at 15 months.  Review of safety data will also occur 
during the interim efficacy analysis.  The interim efficacy analysis will provide a preliminary 
assessment of the overall risk/benefit profile.  Unless safety concerns arise, the study will not be 
discontinued or modified due to the results of the interim efficacy analysis 
The primary analysis of Part 2 will be event-driven and will occur after a total of approximately 
130 deaths (89 deaths per planned comparison: Arm A/Arm C and Arm B/Arm C), which is 
anticipated to occur 18 months after end of enrollment.  A final analysis is planned after a 
minimum expected follow-up of 36 months, at which time approximately 163 deaths are expected 
overall (110 per planned comparison).  
Sponsor/Licensee:  Amgen Inc


Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  01 February 2011 
Page 9 of 147 
 
Study Design and Treatment Schema  


Approved 
 
 
Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  05 April 2011 
Page 1 of 142 
 
A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based 
Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer 
AMG 479 and AMG 102 
Amgen Protocol Number 20060534 
 
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 
Clinical Research Medical Director  
Amgen Inc 
Phone:  650.244.2634 
Fax:  650.837.9716  
jessem@amgen.com 
 
Cat Goodall 
Clinical Research Study Manager - Primary 
Amgen Limited 
Phone:  +44 1895 525327 
Fax:  +44 1895 525101  
cgoodall@amgen.com   
 
Nancy Kenyon 
Clinical Research Study Manager – U.S 
Amgen Inc 
Phone:  805.447.5737 
Fax:  805. 
nkenyon@amgen.com 
 
Amendment 4 Date: 
05 April 2011 
Amendment 3 Date: 
01 February 2011 
Amendment 2 Date: 
24 September 2010 
Amendment 1 Date: 
01 April 2009 
Date: 
07 June 2008 
EudraCT Number: 
2008-003292-42 
 
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: 1-805-447-5000 
For all other study-related questions, continue to contact the Key Sponsor Contact. 


Approved 
 
 
Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  05 April 2011 
Page 2 of 142 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in 
Combination with Platinum-based Chemotherapy as First-Line Treatment for Extensive 
Stage Small Cell Lung Cancer dated Amendment 4, 05 April 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 
 
 
Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  05 April 2011 
Page 3 of 142 
 
Protocol Synopsis 
Title:  A Phase 1b/ 2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based 
Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer 
Study Phase:  1b/ 2  
Indication:  Previously Untreated Extensive Stage Small Cell Lung Cancer (SCLC) 
Primary Objective:   
Part 1: To identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin, and of AMG 102 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin that can be administered safely and is tolerated as determined by the 
incidence of dose-limiting toxicity (DLT) 
Part 2:
Secondary Objectives:  
 To estimate the relative treatment effect of AMG 479 (at the dose selected in Part 1) in 
combination with chemotherapy (etoposide plus carboplatin and/or etoposide plus cisplatin, as 
determined in part 1), and of AMG 102 (at the dose selected in Part 1) in combination with 
chemotherapy, compared with placebo plus chemotherapy, as measured by the respective 
hazard ratios (HR) for overall survival (OS).   
Part 1
• 
To evaluate safety as assessed by the incidence of adverse events and laboratory 
abnormalities not defined as DLT 
: 
• 
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody formation and 
anti-AMG 102 antibody formation  
• 
To evaluate pharmacokinetics (PK) as assessed by the maximum observed serum 
concentration (Cmax) and the minimum observed serum concentration (Cmin) for AMG 479 and 
for AMG 102  
Part 2
• 
To evaluate clinical benefit as assessed by the objective response rate (ORR) as measured 
by modified Response Evaluation Criteria in Solid Tumors (RECIST), duration of response 
(DOR), time to progression (TTP), progression-free survival (PFS), median OS (mOS), and 
OS rates at 10, 12, 24, and 36 months 
:  
• 
To evaluate safety as assessed by the incidence of adverse events and laboratory 
abnormalities 
• 
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody formation and 
anti-AMG 102 antibody formation  
• 
To evaluate PK as assessed by Cmax and Cmin for AMG 479 and for AMG 102  
• 
To estimate the effect of AMG 479 and of AMG 102 on subject’s health-related quality of life 
(HRQoL) using the European Organisation for Research and Treatment of Cancer (EORTC) 
core questionnaire (QLQ-C30) and its lung cancer module (QLQ-LC13) 
Exploratory Objectives: 
Part 1 and Part 2
• 
To evaluate PK as assessed by area under the curve (AUC) and Cmax for etoposide, 
cisplatin and carboplatin  
: 
• 
To investigate the relationship between AMG 479 and AMG 102 PK and treatment outcomes 
(including clinical and pharmacodynamic endpoints)  


Approved 
 
 
Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  05 April 2011 
Page 4 of 142 
 
• 
To investigate the biomarker profile at baseline, and the pharmacodynamic response, as 
assessed by biomarkers for AMG 479 (eg, serum IGF-1, IGF-BP3, GH, and other factors 
involved in regulating the IGF-1/IGF-1R pathway) and for AMG 102 (eg, HGF/SF:c-Met 
pathway markers, tumor apoptosis markers, angiogenic cytokines and other biomarkers), and 
correlate with treatment outcomes 
• 
To investigate other potential biomarker development (eg, biochemical levels and abundance 
of drug targets, tumor somatic mutations in drug target, pathway, and cancer genes) by 
biochemical analysis of blood samples and tumor tissue (if available), and correlate with 
treatment outcomes  
• 
To investigate the effect of genetic variations in cancer genes, drug target and pathway 
genes, and other biomarker genes, and correlate with treatment outcomes (optional for 
subjects; requires separate informed consent) 
Hypotheses:   
• 
Part 1 will identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or 
etoposide plus cisplatin and of AMG 102 in combination with etoposide plus carboplatin 
and/or etoposide plus cisplatin that is safe and tolerated as determined by the incidence of 
DLT.   
• 
Part 2 will estimate the relative efficacy of AMG 479 (at the dose selected in Part 1), and of 
AMG 102 (at the dose selected in Part 1), and of placebo plus platinum-based chemotherapy 
(etoposide plus carboplatin and/or etoposide plus cisplatin, as determined in part 1) as 
measured by the respective OS HR.  Given a hypothesized HR of 0.74 for each comparison, 
the target maximum half width of 0.22 for the OS HR 2-sided 80% CI will be achieved after 
89 deaths are observed for a pairwise comparison. 
Study Design: 
This study has 2 parts.   
Part 1 is a multi-center, open-label dose de-escalation phase 1b segment of AMG 479 in 
combination with etoposide plus carboplatin (Cohort 1) or cisplatin (Cohort 2), and of AMG 102 in 
combination with etoposide plus carboplatin (Cohort 3) or cisplatin (Cohort 4). Once respective 
doses of AMG 479 and of AMG 102 have been identified that are safe and tolerated based on the 
incidence of DLT, Part 2 will open for enrollment.  
Part 2
In both parts of the study, chemotherapy (etoposide plus carboplatin or cisplatin) will be 
administered on day 1 of each 21-day (Q3W) cycle. Etoposide will also be administered on day 2 
and 3 of each Q3W cycle. Premedication (see 
 is a randomized, double-blind, placebo-controlled phase 2 segment of AMG 479 (at the 
dose selected in Part 1), and of AMG 102 (at the dose selected in Part 1), and of placebo plus 
platinum-based chemotherapy (etoposide plus carboplatin and/or etoposide plus cisplatin, as 
determined in part 1) as first-line treatment for subjects with extensive stage SCLC. Subjects 
(n = 180) will be randomized in a 1:1:1 ratio to each treatment arm (n = 60 per arm). 
Randomization will be stratified according to gender (female; male) and chemotherapy (etoposide 
and cisplatin; etoposide and carboplatin).  
Section 6.2.2.3), vigorous hydration and diuresis 
(see Section 6.2.2.4) will be required for chemotherapy treatment. Investigational product (IP; 
AMG 479 [Part 1, Cohorts 1 and 2; Part 2, Arm A] or AMG 102 [Part 1, Cohorts 3 and 4; Part 2, 
Arm B] or placebo [Part 2, Arm C]) will be administered after the chemotherapy infusion on day 2 
of the initial cycle, and day 1 of each Q3W cycle thereafter. Four to six cycles of chemotherapy 
will be given. Determination of the number of cycles of chemotherapy to be administered 
(between 4 to 6) will be left to the investigator’s discretion. Subjects who complete 4 to 6 cycles of 
chemotherapy or who discontinue chemotherapy early will continue to receive IP (AMG 479, or 
AMG 102, or placebo) single agent maintenance therapy on day 1 of each Q3W cycle for up to  
24 months from the date of first study treatment administration (study day 1).  Subjects who have 
completed 24 months of IP may be eligible for continued treatment with IP by extension protocol 


Approved 
 
 
Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  05 April 2011 
Page 5 of 142 
 
or as provided for by the local country’s regulatory mechanism (see Section 13).  Study treatment 
will cease if a subject experiences progressive disease (PD), death, unacceptable toxicity, 
withdraws consent, or due to an administrative decision (by the investigator or Amgen).   
Radiological imaging to assess PD (per modified RECIST) will be performed every 6 weeks  
(± 7 days) during the first 6 months of the study, from Study Day 1 and every 9 weeks (± 7 days) 
thereafter, until subjects develop PD (per modified RECIST) or begin a new cancer treatment.  
A follow-up visit will occur 30 days (+ 7 days) and 60 days (+ 14 days) after the last dose of 
protocol-specified treatment. Subjects will be contacted every 3 months (± 2 weeks) in the 
long-term follow-up, for up to 36 months from the date of the last subject randomized, to assess 
survival. Please refer to the Study Schema for an overview of the 2-part study design.  
Primary and Secondary Endpoints:  See Section 10 for details 
Primary Endpoints 
Part 1
• 
The incidence of adverse events and clinical laboratory abnormalities defined as DLT 
:     
Part 2
• 
OS  
:     
Secondary Endpoints 
• 
The incidence of adverse events and laboratory abnormalities not defined as DLT 
Part 1: 
• 
The incidence of anti-AMG 479 and anti-AMG 102 antibody formation  
• 
PK (Cmax and Cmin for AMG 479 and AMG 102)  
• 
ORR, DOR, TTP, PFS, mOS, and OS rates at 10,12, 24, and 36 months 
Part 2: 
• 
The incidence of adverse events and laboratory abnormalities 
• 
The incidence of anti-AMG 479 and anti-AMG 102 antibody formation  
• 
PK (Cmax and Cmin) for AMG 479 and AMG 102 
• 
EORTC QLQ-C30 and EORTC QLQ-LC13 scores 
Exploratory Endpoints 
• 
PK (AUC and Cmax) for etoposide, cisplatin and carboplatin  
Part 1 and Part 2: 
• 
Relationship between AMG 479 and AMG 102 PK and treatment outcomes (including clinical 
and pharmacodynamic endpoints)  
• 
Baseline biomarker profile and pharmacodynamic response, as assessed by AMG 479 and 
AMG 102 biomarkers, and correlation with treatment outcomes  
• 
Biochemical levels and abundance of drug targets and other biomarkers in blood samples 
and tumor tissue (if available), and correlation with treatment outcomes  
• 
Genetic variations in cancer genes, drug target and pathway genes, and other biomarker 
genes, and correlation with treatment outcomes   
Sample Size:  Part 1: 24 to 108 subjects; Part 2: 180 subjects 


Approved 
 
 
Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  05 April 2011 
Page 6 of 142 
 
Summary of Subject Eligibility Criteria:  See Section 4 for details 
• 
Histologically or cytologically confirmed SCLC 
Key Inclusion Criteria 
• 
Extensive disease, defined by at least one of the following criteria: 
− 
No limited disease (ie, no
− 
Extrathoracic metastases  
 disease confined to the ipsilateral hemithorax, which can 
be safely encompassed within a tolerable radiation field) 
− 
Malignant pericardial or pleural effusion 
− 
Contralateral hilar adenopathy 
• 
Measurable or non-measurable disease, as defined by modified RECIST 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
• 
≥ 18 years old 
• 
Life expectancy (with therapy) ≥ 3 months 
• 
Adequate hematologic, hepatic, coagulation, renal, and metabolic function  
• 
Fasting blood glucose ≤ 160 mg/dL 
• 
Prior chemotherapy, chemo-radiation, or investigational agent for SCLC 
Key Exclusion Criteria 
• 
Prior radiotherapy to > 25% of the bone marrow 
• 
Symptomatic or untreated central nervous system (CNS) metastasis (with exceptions) 
• 
Currently or previously treated with biological, immunological or other therapies for SCLC 
• 
Current serious or non-healing wound or ulcer           
• 
History of prior or concurrent other malignancy (with exceptions) 
• 
Thrombosis or vascular ischemic events within the last twelve months, such as deep venous 
thrombosis, pulmonary embolism, transient ischemic attack, cerebral infarction, or myocardial 
infarction 
• 
Any clinically significant medical condition other than cancer (eg, cardiovascular disease or 
chronic obstructive pulmonary disease), which could interfere with the safe delivery of study 
treatment or increase risk of toxicity 
Study Drug Dosage and Administration:  See Section 6 for details. 
Investigational Product: 
Part 1:   Cohorts 1a and 2a
 
AMG 479 18 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment  
:   
 
AMG 479 18 mg/kg intravenous (IV) on day 2 of the initial cycle, and day 1 of each Q3W 
 
cycle thereafter  
              Cohort 3a and 4a
 
AMG 102 15 mg/kg IV on day 2 of the initial cycle, and day 1 of each Q3W cycle 
 
thereafter 
:   
 
AMG 102 15 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment  
Lower doses of AMG 479 and/or AMG 102 may be explored based on safety and PK 
data, to determine the maximum tolerated dose. Refer to Section 6.1.1.1 for details. 


Approved 
 
 
Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  05 April 2011 
Page 7 of 142 
 
Part 2
 
or matching placebo (Arm C), IV Q3W:  
 
:  AMG 479 (Arm A), AMG 102 (Arm B), at the respective doses selected in Part 1, 
 
day 2 of the initial cycle, and day 1 of each Q3W cycle thereafter 
IP dose will be calculated based on the subject’s actual body weight at baseline, and the dose 
must be recalculated if the actual body weight changes by > 10%.  IP will be diluted in 0.9% 
normal saline.   
IP will be administered Q3W, after completion of the chemotherapy infusion (if administered).  IP 
will be administered over 60 minutes (min) (± 10 min) 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.  If a dose of IP is well tolerated (ie, without serious infusion-
related reactions), then subsequent IV infusions may be given over 30 min (± 10 min).  Infusion 
time can be extended up to 120 min for subjects deemed unable to tolerate the 60 min infusion. 
Chemotherapy (Part 1 and Part 2)
Etoposide 100 mg/m2 to be administered IV over 90 min (± 30 min) on days 1, 2, and 3 of each 
Q3W cycle, or per institutional guidelines.  
:    
Carboplatin (AUC = 5 mg/mL • min) will be administered IV over 30 min (+ 10 min) on day 1 of 
each Q3W cycle after the etoposide infusion is complete, per institutional guidelines. Infusion time 
can be extended up to 60 min for subjects deemed unable to tolerate the 30 min infusion. 
Cisplatin 75 mg/m2 will be administered IV over 60 min (± 15 min) on day 1 of each Q3W cycle 
after the etoposide infusion is complete, per institutional guidelines. Infusion time can be 
extended up to 120 min for subjects deemed unable to tolerate the 60 min infusion.  
Subjects must receive adequate premedication (see Section 6.2.2.3), vigorous hydration and 
diuresis, and monitoring of fluid status (see Section 6.2.2.4).  
Control Group:   
Part 1: there is no control group 
Part 2: Arm C: Placebo in combination with etoposide plus carboplatin or cisplatin Q3W  
Key Study Procedures:  See Section 7.1 and Schedule of Assessments (Appendix A) for 
details.  
• 
Review of inclusion and exclusion criteria  
Screening Procedures  
• 
Medication and medical history, concomitant medications/treatment(s), adverse events  
• 
Vital signs: resting pulse, respiration, blood pressure, and temperature  
• 
Physical examination, including height and weight  
• 
ECOG performance status assessment  
• 
Laboratory tests; including hematology, chemistry, coagulation, urinalysis, pregnancy test  
• 
If available, submission of paraffin-embedded tumor tissue (paraffin tumor block, or slides) 
and all available pathology reports 
• 
12-lead electrocardiogram (ECG)  
• 
Radiological imaging to assess disease extent (CT scan or MRI of the brain, chest, abdomen, 
and all other sites of disease; within 28 days prior to enrollment)  
• 
Recording and reporting of adverse events and concomitant medications  
Treatment and Follow-Up Procedures 
• 
Patient completion of EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires (Part 2)  


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Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  05 April 2011 
Page 8 of 142 
 
• 
Vital signs: resting pulse, respiration, blood pressure, and temperature  
• 
Physical examination, including weight, and ECOG performance status assessment  
• 
Laboratory tests; including hematology, chemistry, pregnancy test  
• 
Samples for biomarkers and anti-AMG 479 or anti-AMG 102 antibodies  
• 
Samples for AMG 479, AMG 102, carboplatin, cisplatin and etoposide PK (Part 1) 
• 
ECG  
• 
Radiological imaging to assess disease extent  (CT scan or MRI [same modality throughout 
the study] of the chest, abdomen, and all other sites of disease [except: brain imaging only as 
clinically indicated] every 6 weeks [± 7 days] from Study Day 1 during the first 6 months of the 
study, and every 9 weeks [± 7 days] thereafter)  
Statistical Considerations: See Section 10 for details.  
Analyses will be presented separately for Part 1 and Part 2 of the study.  The HR for OS will be 
estimated using a Cox regression model stratified by randomization stratification factors and 
controlled for the LDH level as an important covariate.  A Wald chi-square test will provide a 
descriptive p-value for the HR.  Overall survival between the respective pair of treatment arms 
(Arm A/Arm C and Arm B/Arm C) will use a stratified log-rank test for a descriptive comparison. 
DRT Safety Reviews and Interim Analysis 
For the protection of subjects, in Part 1 of the study, Safety Review Team (SRT) meetings will be 
held to review safety, laboratory, dosing information and PK data (when available) from each 
AMG 479 and AMG 102 dose cohort, to make recommendations regarding dose selection for 
Part 2, dose de-escalation, or dose stopping.   
In Part 2. and Amgen Data Review Team (DRT), independent of the study team will perform 
unblinded reviews of the safety data after at least 30 and 60 subjects have been randomized and 
had the opportunity to complete cycle 1 of the study treatment (safety interim analyses).  In 
addition, unblinded SAE information for thrombosis or vascular ischemic events will be made 
available to the DRT on an ongoing basis 
One interim efficacy analysis is planned to review both OS and PFS data 10 months after the last 
subject is randomized.  Approximately 100 OS events are estimated (69 OS events per 
comparison: Arm A/Arm C and Arm B/Arm C) for the interim analysis assuming approximately 
half of the planned enrollment will occur at 15 months.  Review of safety data will also occur 
during the interim efficacy analysis.  The interim efficacy analysis will provide a preliminary 
assessment of the overall risk/benefit profile.  Unless safety concerns arise, the study will not be 
discontinued or modified due to the results of the interim efficacy analysis 
The primary analysis of Part 2 will be event-driven and will occur after a total of approximately 
130 deaths (89 deaths per planned comparison: Arm A/Arm C and Arm B/Arm C), which is 
anticipated to occur 18 months after end of enrollment.  A final analysis is planned after a 
minimum expected follow-up of 36 months, at which time approximately 163 deaths are expected 
overall (110 per planned comparison).  
Sponsor/Licensee:  Amgen Inc


 
Approved 
 
 
 
Products:  AMG 479 and AMG 102 
Protocol Number:  20060534 
Date:  05 April 2011 
Page 9 of 142 
 
Study Design and Treatment Schema