Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: squamous cell NSCLC TKI Erlotinib Docetaxel VeriStrat protein signature
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 81
Healthy volunteers: no

Brief summary:
Using a laboratory test (VeriStrat), patients with relapsed squamous cell lung cancer are assigned to two strata, VSG (VeriStrat Good) and VSP (VeriStrat Poor). They are then randomized between an EGFR-TK inhibitor (erlotinib) and chemotherapy (Docetaxel).

It is hypothesized that the VeriStrat test results are able to predict the benefit of treatment with erlotinib vs docetaxel. This would suggest a significant improvement in progression-free survival for VSG patients when treated with Erlotinib, and no significant improvement in VSP patients who receive the same treatment.

Detailed description:
Goals of the study:

1. Explore the predictive ability of the VeriStrat signature, by testing for interaction between treatment arms (Arm A: erlotinib vs Arm B: docetaxel) and VeriStrat status (VSG vs VSP) using as outcome progression free survival.
2. Explore whether treatment with erlotinib provides progression free survival benefit as compared to docetaxel in the VSG group.
3. Compare progression free survival in the two treatment arms (Arm A: erlotinib vs Arm B: docetaxel) in the VSP group.
4. Explore the prognostic ability of the VeriStrat signature by testing for an overall difference in progression free survival between the two VeriStrat groups (in case of no significant interaction).
5. Explore the predictive ability of the VeriStrat signature using the secondary measures of clinical efficacy including overall survival, objective response rate, and disease control rate.
6. Compare overall survival, objective response rate and disease control rate between treatment groups separately in the VSG and VSP groups.
7. Explore the prognostic ability of the VeriStrat signature by testing for an overall difference in overall survival, objective response rate and disease control rate between the two VeriStrat groups (in case of no significant interaction).
8. Assess the safety and the tolerability of the two treatments separately in each VeriStrat group and overall.

Recruitment period: 18 months Sample Size: 500

Arms:
arm 1: Erlotinib in standard dose. Until progression (clinical or radiological) or unacceptable toxicity. arm 2: Docetaxel in standard dose. Until progression (clinical or radiological) or unacceptable toxicity.

Interventions: intervention 1: Erlotinib intervention 2: Docetaxel
Intervention descriptions: intervention 1: Erlotinib 150 mg/day p.o. continuously with 21 days cycle. intervention 2: Docetaxel 75 mg/m2 as an IV infusion every 21 days.

Protocol document:
SAP_002.pdf: 
Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 1 of 20 
 
EMPHASIS-lung 
ETOP 3-12 
 
A randomized phase III trial of erlotinib versus docetaxel in patients with advanced 
squamous cell non-small cell lung cancer who failed first line platinum-based doublet 
chemotherapy stratified by VeriStrat Good vs VeriStrat Poor 
 
Erlotinib Maldi TOF Phase III Signature in Squamous cell non-small cell lung cancer 
 
A clinical trial of ETOP 
 
 
NCT01652469 
 
 
SAP VERSION 
V.1 
SAP VERSION DATE 
07.01.2015 
TRIAL STATISTICIAN 
Urania Dafni 
TRIAL PRIMARY INVESTIGATORS 
Egbert Smit, Solange Peters 
SAP AUTHOR 
Marie Kassapian 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 2 of 20 
TABLE OF CONTENTS 
1. 
Abbreviations........................................................................................................................................3 
2. 
Introduction...........................................................................................................................................4    
   2.1 
Preface......................................................................................................................................................4 
   2.2 
Hypotheses.............................................................................................................................................4 
3. 
Study Objectives and Endpoints....................................................................................................4 
   3.1 
Study Objectives...................................................................................................................................4 
   3.2 
Endpoints................................................................................................................................................5 
   3.3 
Statistical Hypotheses........................................................................................................................6 
4. 
Study Methods......................................................................................................................................7 
   4.1 
General Study Design and Plan......................................................................................................7 
   4.2 
Patient Selection...................................................................................................................................8 
   4.3 
Patient Randomization......................................................................................................................8 
   4.4 
Study Variables.....................................................................................................................................8 
   4.5 
Primary Comparisons.....................................................................................................................10 
5. 
Planned Analysis...............................................................................................................................11 
6. 
Sample Size..........................................................................................................................................11 
7. 
General Considerations..................................................................................................................11 
   7.1 
Timing of Analyses...........................................................................................................................11 
   7.2 
Analysis Populations.......................................................................................................................12 
   7.3 
Missing Data........................................................................................................................................12 
8. 
Efficacy Analysis................................................................................................................................12 
9. 
Safety Analysis....................................................................................................................................13 
   9.1 
Adverse Events...................................................................................................................................13 
   9.2 
Severity Grade....................................................................................................................................13 
   9.3 
Serious Adverse Events..................................................................................................................14 
10. 
Reporting Conventions...................................................................................................................15 
11. 
Technical Details...............................................................................................................................15 
12. 
Listing of Tables and Figures.......................................................................................................16 
 
 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 3 of 20 
1. 
ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
EGFR 
Epidermal Growth Factor Receptor 
HR 
Hazard Ratio 
KM 
Kaplan - Meier 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PFS 
Progression Free Survival 
PH 
Proportional Hazards 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
TKI 
Tyrosine Kinase Inhibitor 
ULN 
Upper Limit of Normal lab value 
VSG 
VeriStrat Good 
VSP 
VeriStrat Poor 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 4 of 20 
2. 
INTRODUCTION 
2.1 
Preface 
The current project aims to assess the predictive ability of the VeriStrat signature, a recently 
developed blood-based proteomic test that appears to be both predictive and prognostic for 
outcome in patients with non-small cell lung cancer (NSCLC). VeriStrat assigns each sample a 
“good” (VSG) or “poor” (VSP) label and previous studies have confirmed that patients 
classified as VSG had better progression free survival (PFS) and overall survival (OS) than 
patients classified as VSP. In the present trial, patients with relapsed squamous cell lung 
cancer in both strata of the VeriStrat signature (VSG and VSP) are randomized between an 
EGFR-TKI and chemotherapy. As both erlotinib and docetaxel are currently approved for this 
indication, these drugs are used in the trial. Our main purpose is to explore the predictive 
ability of the VeriStrat signature regarding the benefit of treatment with erlotinib vs 
docetaxel. 
2.2 
Hypotheses  
The VeriStrat signature is expected to be able to predict the benefit of treatment with erlotinib 
vs docetaxel as measured by a significant improvement in median PFS for VSG patients with 
squamous cell advanced NSCLC, when treated with an EGFR-TKI, and without significant 
improvement in VSP patients who receive the same treatment. 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
Primary Objective 
Explore the predictive ability of the VeriStrat signature, by testing for interaction between 
treatment arms (Arm A: erlotinib vs Arm B: docetaxel) and VeriStrat status (Good vs Poor) 
using progression free survival as outcome. 
 
Secondary Objectives 
i. 
Explore whether treatment with erlotinib provides progression free survival benefit as 
compared to docetaxel in the VSG group.  
ii. 
Compare progression free survival in the two treatment arms (Arm A: erlotinib vs Arm 
B: docetaxel) in the VSP group. 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 5 of 20 
iii. 
Explore the prognostic ability of the VeriStrat signature by testing for an overall 
difference in progression free survival between the two VeriStrat groups (in case of no 
significant interaction). 
iv. 
Explore the predictive ability of the VeriStrat signature using the secondary measures 
of clinical efficacy including overall survival, objective response rate, and disease 
control rate. 
v. 
Compare overall survival, objective response rate and disease control rate between 
treatment groups separately in the VSG and VSP groups. 
vi. 
Explore the prognostic ability of the VeriStrat signature by testing for an overall 
difference in overall survival, objective response rate and disease control rate between 
the two VeriStrat groups (in case of no significant interaction). 
vii. 
Assess the safety and the tolerability of the two treatments separately in each VeriStrat 
group and overall. 
3.2 
Endpoints 
Primary Endpoint 
The primary endpoint of the study is Progression-free Survival (PFS), defined as the time from 
randomization until documented progression or death without documented progression or 
up to last day of follow-up if event has not occurred. 
 
Secondary Endpoints 
Secondary endpoints include Overall Survival (OS), Time to Treatment Discontinuation (TTD), 
Objective Response (OR), Disease Control (DC) and toxicities of treatment. More specifically 
OS is defined as the time from randomization until death, or up to last day of follow-up if 
event has not occurred. Regarding TTD, two different definitions of treatment discontinuation 
are considered:  
i) all cause treatment discontinuation, and 
ii) discontinuation of treatment for patient decision.  
In addition, OR is defined as the best overall response (CR or PR) across all assessment time-
points according to RECIST Criteria 1.1, during the period from randomization to termination 
of trial treatment. DC is defined as achieving objective response or stable disease for at least 6 
weeks. Finally, toxicities of treatment refer to all adverse events classified according to NCI 
CTCAE version 4.  
 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 6 of 20 
3.3 
Statistical Hypotheses 
The specific statistical hypotheses that are to be tested in order to assess the primary and 
secondary objectives of the study, as described in Section 3.1, are listed below. 
All tests will be performed using a 2-sided significance level of 0.05. 
 
Primary Objective 
H0: 
The difference on median PFS when treated with erlotinib vs docetaxel is independent 
of VeriStrat status. 
H1: 
The difference on median PFS when treated with erlotinib vs docetaxel is not 
independent of VeriStrat status. 
It is assumed that the PFS Hazard Ratio of erlotinib versus docetaxel will be HR=0.675 for the 
VSG patients (median PFS of 4 months for erlotinib and of 2.7 months for docetaxel), while 
HR=1.23 for the VSP patients (median PFS of 2.2 and 2.7 months, respectively). 
 
Secondary Objectives 
i. 
H0: 
The median PFS does not differ significantly between the two treatment arms in 
the VSG group. 
H1: 
There is a significant difference in the median PFS between the two treatment 
arms in the VSG group. 
 
ii. 
H0: 
The median PFS does not differ significantly between the two treatment arms in 
the VSP group. 
H1: 
There is a significant difference in the median PFS between the two treatment 
arms in the VSP group. 
 
iii. 
H0: 
The median PFS does not differ significantly between the two VeriStrat groups.  
H1: 
There is a significant difference in the median PFS between the two VeriStrat 
groups. 
 
iv. 
H0: 
The difference on median OS (ORR / DCR) when treated with erlotinib vs 
docetaxel is independent of VeriStrat status. 
H1: 
The difference on median OS (ORR / DCR) when treated with erlotinib vs 
docetaxel is not independent of VeriStrat status. 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 7 of 20 
v. 
H0: 
The median OS (ORR / DCR) does not differ significantly between the two 
treatment arms in the VSG group. 
H1: 
There is a significant difference in the median OS (ORR / DCR) between the two 
treatment arms in the VSG group. 
 
H0: 
The median OS (ORR / DCR) does not differ significantly between the two 
treatment arms in the VSP group. 
H1: 
There is a significant difference in the median OS (ORR / DCR) between the two 
treatment arms in the VSP group. 
 
vi. 
H0: 
The median OS (ORR / DCR) does not differ significantly between the two 
VeriStrat groups.  
H1: 
There is a significant difference in the median OS (ORR / DCR) between the two 
VeriStrat groups. 
 
4. 
STUDY METHODS 
4.1 
General Study Design and Plan 
The study is designed as a Phase III trial to explore the differential activity of erlotinib vs 
docetaxel in VSG vs VSP squamous cell NSCLC patients who relapsed after first line platinum-
based chemotherapy. Patients in both VeriStrat strata, i.e. VSG and VSP, will be randomized to 
receive erlotinib or docetaxel, and treatment must start within 7 days after randomization. 
The investigator will be blinded to the result of the VeriStrat test. 
Patient accrual is expected to be completed within 18 months after first patient 
randomization. The combined run period, treatment and follow-up for PFS (primary 
endpoint) is expected to extend the study duration to a total of 24 months (i.e., 6 months after 
the last patient is randomized). All patients will be followed for survival status every 12 
weeks thereafter, until death or up to 24 months after the last patient is randomized, at which 
time the study will formally end. 
The preparation of the study report is scheduled for 26 months after the first patient is 
enrolled. 
 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 8 of 20 
4.2 
Patient Selection 
Patients should only be selected and consented for screening if they fulfill the inclusion and 
exclusion criteria (EMPHASIS Protocol, Sections 7.1 – 7.2), within 14 days prior to 
registration, except where otherwise noted. Written informed consent needs to be obtained 
prior to undertaking any study-specific procedure, including blood collection for VeriStrat 
testing. 
4.3 
Patient Randomization 
This trial will use the web-based randomization and RDE (Remote Data Entry) system called 
ETOPdata. Each participating center will access the system directly. Specific details for 
randomization of patients are described in the document “EMPHASIS Randomization 
Procedure”. 
Block stratified randomization balanced by center using a minimization algorithm (Pocock 
and Simon, 1975; Pocock, 1979) will be used in the study. Patients will be stratified based on 
VeriStrat status (VSG vs VSP) and Performance Status (0-1 vs 2). 
4.4 
Study Variables 
Trial schedule of events 
 
Baseline evaluations (within 14 days prior to registration) 
▪ Medical history including symptoms, smoking history, medications, comorbidities and 
allergies. 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 9 of 20 
▪ Physical examination including blood pressure [mmHg], ECOG performance status (see 
definition in EMPHASIS-lung procedures manual), and body weight [kg] and height 
[cm]. 
▪ Hematology: hemoglobin, neutrophils, platelets. 
▪ Renal function: serum creatinine and creatinine clearance calculated according to 
Cockroft-Gault. 
▪ Hepatic function: ALT, AP, Bilirubin. 
▪ Serum or urine pregnancy test for women of reproductive potential, within 7 days 
prior to registration. 
▪ CT scan of thorax and abdomen, within 2 weeks before registration, with i.v. contrast 
(alone or in combination with PET) to determine measurable disease according to 
RECIST v1.1 (at least one lesion outside of irradiated areas that can be measured in at 
least one dimension as ≥ 10 mm, or ≥ 15 mm in case of lymph nodes). In the presence 
of clinically suspected metastases outside of these fields, additional imaging of the 
affected body part is recommended. 
▪ CT scan of brain is not mandatory and only recommended in case of clinically 
suspected brain metastasis. 
 
Before Randomization 
For VeriStrat testing collect, process and ship serum sample according instructions in the kits 
and in the EMPHASIS-lung Procedures Manual. 
 
Routine evaluations before and during trial treatment 
On day 1 of every 3-week treatment cycle: 
▪ Recording of symptoms / adverse events 
▪ Physical examination including blood pressure, performance status, and body weight 
▪ Hematology: hemoglobin, neutrophils, platelets 
▪ Serum creatinine 
▪ Hepatic function: ALT, AP, Bilirubin 
 
Tumor evaluations during treatment 
These evaluations will occur prior to the start of odd cycles (3, 5, 7, 9, ...) until progression. 
They should be performed within 5 days before the start of the subsequent cycle: 
▪ CT thorax and abdomen 
 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 10 of 20 
Evaluations in the follow-up phase before progression 
Patients who discontinue treatment before progression should have the following 
assessments 30-45 days after study treatment stop and every 6 weeks thereafter: 
▪ Physical examination 
▪ CT thorax and abdomen (plus further imaging, repeating former disease evaluation 
imaging techniques, if applicable) 
▪ Documentation of further treatments 
 
Evaluations at progression 
Each patient will receive trial treatment until documented progression. At progression, do the 
following: 
▪ CT thorax and abdomen, document progression on the respective CRF 
▪ Documentation of further treatments 
 
End of treatment visit 
At the end of the trial treatment and irrespective of the reason for stopping treatment, a 
post treatment visit at the center is to be scheduled after 30 to 45 days following last 
treatment day. The following procedures should be performed: 
▪ Recording of symptoms 
▪ Physical examination including blood pressure 
▪ Hematology: hemoglobin, neutrophils, platelets 
▪ Hepatic function: ALT, AP, Bilirubin 
▪ Serum creatinine 
▪ CT thorax and abdomen, if not done within the last 30 days 
 
Evaluations after progression 
Patients with progression will end trial treatment and should have documented survival every 
12 weeks until death. Survival status can be collected by patient visit or documented phone 
calls. 
4.5 
Primary Comparisons 
The main comparison involves exploring the ability of the VeriStrat signature to predict 
response to treatment (Arm A: erlotinib vs Arm B: docetaxel). The primary comparison will be 
based on PFS, and in particular the predictive ability of the VeriStrat signature will be tested 
by studying the interaction between VeriStrat status and treatment arm in a Cox proportional 
hazards (PH) model. 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 11 of 20 
5. 
PLANNED ANALYSIS 
The total study duration will be approximately 23 months: 18 months recruitment period, and 
at least 2 months treatment and follow-up period for the last randomized patient. The final 
evaluation will be done within 6 months after the two-month visit of the last entered patient, 
approximately 26 months after the inclusion of the first patient. The planned analysis in terms 
of methods, reporting conventions and formats is described in detail in Sections 9-13. 
6. 
SAMPLE SIZE 
For a sample size of 500, accrued in 18 months and an additional follow-up of 2 months, 86% 
power is achieved for testing at a two-sided significance level of 0.05, the null hypothesis that 
the difference on median PFS when treated with erlotinib vs docetaxel is independent of 
VeriStrat status, under the above stated assumptions of HR=0.675 for VSG patients and 
HR=1.23 for VSP patients, assuming a hazard for censoring of 0.01 (power of 82% is achieved 
for a hazard for censoring of 0.05). 
In the case the median PFS for erlotinib treated VeriStrat Poor patients is as high as 2.4, 
(HR=1.125), with all other assumptions the same, we retain a power of 74%. 
Simulations are run with the R software package and used for sample size calculations, along 
with the Interaction Survival Power/Sample Size program from the Southwest Oncology 
Group, SWOG (http://www.swogstat.org/stat/public/Help/survivalint.html). 
Secondary objective: Test for significant difference in PFS between treatment arms in the VSG 
group. 
For the sample size of 250 patients accrued in 18 months in the VSG group, and with a total 
study duration of 20 months (total events 204), a power of 80% is achieved to detect with a 
two-sided logrank test at a significance level of 0.05, a 32.5% difference in median PFS 
(HR=0.675) between the two treatment groups. 
The EAST software package is used for sample size calculations in the VSG patient group 
(EAST 5, Version 5.4.0.0, Cytel Inc. 2010). 
7. 
GENERAL CONSIDERATIONS 
7.1 
Timing of Analyses 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 12 of 20 
The preparation of the study report is scheduled for 26 months after the first patient is 
enrolled.  
7.2 
Analysis Populations 
Efficacy Cohort 
The efficacy cohort will include all eligible patients with a VSG or VSP signature entering the 
study (see Figure 1). 
 
Figure 1. Predictive signature representation 
 
Safety Cohort 
The safety cohort will encompass all patients who have received at least one dose of trial 
treatment. 
 
7.3 
Missing Data 
Missing values will not be replaced by any statistics calculated over non-missing data. 
 
8. 
EFFICACY ANALYSIS 
The primary efficacy analysis will include all eligible patients with a VSG or VSP signature 
entering the study (efficacy cohort – see Figure 1).   
Baseline characteristics will be summarized and presented both overall and by treatment 
arm. All continuous variables will be summarised using the following descriptive statistics: n 
(non-missing sample size), mean, 95% CI for the mean, median, maximum and minimum. The 
frequency and percentages (based on the non-missing sample size) of observed levels will be 
reported for all categorical measures.  
In general, all data will be listed, sorted by site, treatment and subject, and when appropriate 
by visit number within subject. All summary tables will be structured with a column for each 
treatment in the order (Treatment A: erlotinib, Treatment B: docetaxel) and a column for the 
total population. 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 13 of 20 
Information on outcome (PFS & OS) will be as well presented, overall and within the two 
treatment groups. Observed differences by i) treatment arm and ii) VeriStrat status will be 
graphically depicted via Kaplan-Meier curves. Moreover, the median follow-up time will be 
calculated using the reverse censoring method for OS. Clinical efficacy will be further 
described by objective response rate (ORR) and disease control rate (DCR). 
9. 
SAFETY ANALYSIS 
The safety cohort will encompass all patients who have received at least one dose of trial 
treatment. Safety and tolerability of the docetaxel and erlotinib treatments will be described 
overall and separately in each VeriStrat subgroup (Figure 1) by tabulation of the CTCAE V4 
grade and graphical representation of the corresponding distributions using bar charts. In 
particular, safety analysis will include assessment of the experience of adverse events (AE) 
and serious adverse events (SAE), the frequency of AEs (overall and separately for targeted 
and non-targeted AEs) and their distribution by CTCAE V4 grade. The numbers of patients 
experiencing specific number of adverse events will also be reported. 
For a closer investigation and for purposes of medical review, information on AEs will also be 
provided by patient. This information will consist of AE description and grade, date of AE 
onset and its relation to treatment, the treatment arm each patient belongs to and his/ her 
specific outcome. Bar charts will be used to depict the maximum severity of AE per patient, 
overall and by treatment arm. 
9.1 
Adverse Events (AE) 
An adverse event is defined as any untoward medical occurrence that occurs from the first 
dose of study medication until 30 days after the final dose, regardless of whether it is 
considered related to a medication. In addition, any known untoward event that occurs 
subsequent to the adverse event reporting period that the investigator assesses as possibly 
related to the protocol treatment should be considered an adverse event.  
 
9.2 
Severity Grade 
The adverse events severity grade (NCI CTCAE Version 4) provides a qualitative assessment 
of the extent or intensity of an adverse event, as determined by the investigator or as reported 
by the subject. The severity grade does not reflect the clinical seriousness of the event, only 
the degree or extent of the affliction or occurrence (e.g. severe nausea, mild seizure), and does 
not reflect the relationship to study drug. 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 14 of 20 
Severity grade for other adverse events not covered in the toxicity grading scale: 
1=Grade 1 
Mild 
2=Grade 2 
Moderate 
3=Grade 3 
Severe 
4=Grade 4 
Life- threatening 
5=Grade 5 
Fatal 
  
9.3 
Serious Adverse Events (SAE) 
SAEs during trial treatment 
A SAE is defined in general as any undesirable medical occurrence/adverse drug experience 
that occur during or within 30 days after stopping study treatment and which, at any dose, 
results in any of the following: 
▪ is fatal (any cause), 
▪ life-threatening, 
▪ requires or prolongs inpatient hospitalization, 
▪ results in persistent or significant disability/incapacity, 
▪ is a congenital anomaly or birth defect 
▪ is a secondary malignancy, 
▪ requires significant medical intervention. 
Second (non-NSCLC) malignancies are always considered SAEs, no matter when they are 
diagnosed. These events should be reported on the Serious Adverse Event Forms. Other 
significant/important medical events which may jeopardize the patient are also considered 
serious adverse events. 
Serious also includes any other event that the investigator or the ETOP Safety Office judges to 
be serious or which is defined as serious by the regulatory agency in the country in which the 
event occurred. An unexpected adverse event is one that is not listed as a known toxicity in 
the summary of product characteristics. 
A related adverse event is one for which the investigator assesses that there is a reasonable 
possibility that the event is related to the drug. All adverse events judged as having a 
reasonable suspected causal relationship to the trial medication qualify as adverse reactions. 
Events not considered to be serious adverse events are hospitalizations occurring under the 
following circumstances: 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 15 of 20 
▪ elective surgery; 
▪ occur on an outpatient basis and do not result in admission (hospitalization<24h); 
▪ are part of the normal treatment or monitoring of the studied treatment; 
▪ progression of disease. 
 
SAEs after end of trial treatment 
During the follow-up phase (starting 30 days after end of trial treatment), the following 
events have to be reported as SAE: 
▪ fatal, life-threatening and other medically significant events possibly, probably or 
definitely related to late effects of trial treatment 
▪ disabling events 
▪ second primary cancer 
▪ congenital anomaly 
▪ pregnancy 
In the case of pregnancy (involving a treated female or male patient) occurring during trial 
treatment or within 1 year after treatment discontinuation, the investigator shall immediately 
notify the ETOP Safety Office by completing the pregnancy reporting form. The investigator 
shall ensure that the case is followed up to the end of the pregnancy and supply a final report 
on the outcome. 
 
10. 
REPORTING CONVENTIONS 
P-values ≥0.001 will be reported to 3 decimal places; p-values >0.010 will be reported with 
two significant digits; p-values less than 0.001 will be reported as “<0.001”. The mean, 95% 
confidence limits, quantiles, and any other statistics, will be reported to one decimal. Hazard 
ratios (HRs) and their 95% CI’s will be reported to two decimals. Estimated parameters, not 
on the same scale as raw observations (e.g. regression coefficients) will be reported to 3 
significant figures.  
 
11. 
TECHNICAL DETAILS 
Data will be analyzed using the SAS software package (version 9.3).  
A second review statistician will independently reproduce all analysis and summary 
statistics. The reviewing statistician will have an overview of the entire analysis and will 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 16 of 20 
explicitly check the code producing tables and figures as well as any other pieces of code 
as desired. 
 
12. 
LISTING OF TABLES AND FIGURES 
Table 1 gives a tabulation of the following aspects unique to each table: 
▪ Title 
▪ Numbering 
▪ Population 
▪ Endpoint(s) 
▪ Time Points or details of how to conglomerate multiple observations 
▪ Covariates or Subgroups used to break down summary statistics 
▪ Which summary statistics will be calculated 
For figures the equivalent information is summarized in Table 2 and includes the following: 
▪ Title 
▪ Numbering 
▪ Population 
▪ Type of figure  
▪ Endpoint(s), and which is used for horizontal and vertical co-ordinates 
▪ Statistic(s) used in calculating co-ordinate values used in the figure 
▪ Covariates used within the figure used to determine colours or symbols 
▪ Covariates used to define facets or sub-plots 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 17 of 20 
Table 1. Listing of Tables 
Table title 
Number 
Population 
Endpoint 
Time Points or how 
to conglomerate 
Covariates or Subgroups 
Summary Statistics 
Accrual by center 
1 
Efficacy 
cohort 
Accrual 
NA 
center 
n (%) 
Balance of treatment allocation per 
stratification factor combination 
2 
Efficacy 
cohort 
Treatment allocation 
NA 
Treatment arm, ECOG 
performance status, 
VeriStrat status 
n (%) 
Patient baseline characteristics 
3a, 3b 
Efficacy 
cohort 
Gender 
Baseline  
Treatment arm 
n (%) 
 
 
 
Smoking status 
Baseline 
Treatment arm 
n (%) 
 
 
 
Tumor histology 
Baseline 
Treatment arm 
n (%) 
 
 
 
ECOG performance status 
Baseline 
Treatment arm 
n (%) 
 
 
 
VeriStrat status 
Baseline 
Treatment arm 
n (%) 
 
 
 
Age 
Baseline 
Treatment arm 
Mean, 95% CI, median, 
min, max 
Time on follow-up & time on treatment 
4a, 4b 
Efficacy 
cohort 
No. of patients still on f-up, 
no. of discontinuations 
End of f-up 
Treatment arm 
n (%) 
median, iterq. range 
Adverse event overview 
5a, 5b 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) of persons who 
have experienced >=1 AE 
Serious adverse event overview 
6a, 6b 
Safety 
cohort 
SAE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) of persons who 
have experienced >=1 
SAE 
Serious adverse events overview by center 
7 
Safety 
cohort 
SAE 
On day 1 of every 3-
week treatment cycle 
Center 
n (%) of persons who 
have experienced >=1 
SAE, incidence 
Frequency of serious adverse events 
8a, 8b 
Safety 
cohort 
SAE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) 
Frequency of serious adverse events 
according to CTCAE Version 4 
9a, 9b 
Safety 
cohort 
SAE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) 
Number of patients experiencing specific 
number of serious adverse events 
10 
Safety 
cohort 
SAE 
On day 1 of every 3-
week treatment cycle 
 
n 
Number of patients experiencing specific 
number of serious adverse events 
according to CTCAE Version 4 
11 
Safety 
cohort 
SAE 
On day 1 of every 3-
week treatment cycle 
 
n 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 18 of 20 
Table title 
Number 
Population 
Endpoint 
Time Points or how 
to conglomerate 
Covariates or Subgroups 
Summary Statistics 
Distribution of adverse events by Grade 
12 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Severity grade 
n (%) 
Distribution of adverse events by Grade 
according to CTCAE Version 4 
13 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Severity grade 
n (%) 
Frequency of adverse events 
14a, 14b 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) 
Frequency of adverse events according to 
CTCAE Version 4 
15a, 15b 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) 
Number of patients experiencing specific 
number of adverse events 
16 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) 
Number of patients experiencing specific 
number of adverse events according to 
CTCAE Version 4 
17 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) 
Frequency of targeted adverse events 
18a 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) 
Frequency of non-targeted adverse events 
18b 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) 
Frequency of targeted adverse events 
according to CTCAE Version 4 
19a 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) 
Frequency of non-targeted adverse events 
according to CTCAE Version 4 
19b 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
Treatment arm 
n (%) 
Treatment A: Adverse event information by 
patient (any AE & SAE) 
20a 
Safety 
cohort 
AE / SAE 
On day 1 of every 3-
week treatment cycle 
Treatment A 
NA 
Treatment B: Adverse event information by 
patient (any AE & SAE) 
20b 
Safety 
cohort 
AE / SAE 
On day 1 of every 3-
week treatment cycle 
Treatment B 
NA 
Narratives of patients with a SAE 
21 
Safety 
cohort 
SAE 
On day 1 of every 3-
week treatment cycle 
 
NA 
Adverse events experienced by patients 
with progression of disease / death 
22 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
 
NA 
Adverse events experienced by patients 
with progression of disease / death 
according to CTCAE Version 4 
23 
Safety 
cohort 
AE 
On day 1 of every 3-
week treatment cycle 
 
NA 
 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 19 of 20 
Table 2. Listing of Figures 
Title 
Number 
Population 
Type of 
graph 
Horizontal 
Variables 
Vertical Variables 
Groupings 
Statistics 
Patients flowchart 
1 
Efficacy 
cohort 
Flowchart 
NA 
NA 
 
NA 
Expected vs observed accrual 
2a 
Efficacy 
cohort 
Line 
graph 
time 
cumulative number 
of patients 
 
NA 
Cumulative accrual by treatment arm 
 2b 
Efficacy 
cohort 
Line 
graph 
time 
cumulative number 
of patients 
Treatment arm 
NA 
Time on follow-up by treatment arm 
3 
Efficacy 
cohort 
KM 
time 
probability 
Treatment arm 
Survival 
estimates 
Time on treatment by treatment arm 
4 
Efficacy 
cohort 
KM 
time 
probability 
Treatment arm 
Survival 
estimates 
Distribution of adverse events 
5a, 5b 
Safety cohort 
Bar chart 
NA 
percentage 
Treatment arm 
percentage 
Distribution of serious adverse events 
6a, 6b 
Safety cohort 
Bar chart 
NA 
percentage 
Treatment arm 
percentage 
Distribution of serious adverse events 
(nominal) 
7a, 7b 
Safety cohort 
Bar chart 
NA 
percentage 
Treatment arm 
percentage 
Distribution of serious adverse events 
according to CTCAE Version 4 (nominal) 
8a, 8b 
Safety cohort 
Bar chart 
NA 
percentage 
Treatment arm 
percentage 
Severity of adverse events 
9a, 9b 
Safety cohort 
Bar chart 
NA 
percentage 
Severity grade, Treatment arm  
percentage 
Severity of adverse events according to 
CTCAE Version 4 
10a, 10b 
Safety cohort 
Bar chart 
NA 
percentage 
Severity grade, Treatment arm 
percentage 
Maximum severity of adverse events per 
patient 
11a, 11b 
Safety cohort 
Bar chart 
NA 
percentage 
Severity grade, Treatment arm 
percentage 
Distribution of adverse events (nominal) 
12a, 12b 
Safety cohort 
Bar chart 
NA 
percentage 
Treatment arm 
percentage 
Distribution of adverse events according 
to CTCAE Version 4 (nominal) 
13a, 13b 
Safety cohort 
Bar chart 
NA 
percentage 
Treatment arm 
percentage 
Progression-free survival 
14, 15 
Efficacy 
cohort 
KM 
time 
probability 
VeriStrat status 
Survival 
estimates 
Overall survival 
16, 17 
Efficacy 
cohort 
KM 
time 
probability 
VeriStrat status 
Survival 
estimates 
 
 
 
 


Statistical Analysis Plan                                                                                                                                                                             ETOP 3-12 EMPHASIS-lung 
 
 
Page 20 of 20 
References 
SJ Pocock (1979). Allocation of patients to treatment in clinical trials. Biometrics, 35: 183 - 187. 
 
SJ Pocock and R Simon (1975). Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trials. Biometrics, 31: 103 -115. 
 

SAP_004.pdf: 
EMPHASIS-lung 
ETOP 3-12 
 
A randomized phase III trial of erlotinib versus docetaxel in patients 
with advanced squamous cell non-small cell lung cancer who failed 
first line platinum-based doublet chemotherapy stratified by VeriStrat 
Good vs VeriStrat Poor 
 
Erlotinib Maldi TOF Phase III Signature in Squamous cell non-small cell lung 
cancer 
 
A clinical trial of ETOP 
 
 
NCT01652469 
 
 
SAP VERSION 
V.1 
SAP VERSION DATE 
07.01.2015 
TRIAL STATISTICIAN 
Urania Dafni 
TRIAL PRIMARY INVESTIGATORS 
Egbert Smit, Solange Peters 
DSMB SAP AUTHOR 
Marie Kassapian 
 
 


Table 1: Accrual by center 
Center    
n (%) 
BEL063 Institut Jules Bordet, Brussels 
xxx (xx.x) 
CHE005 University Hospital Zürich, Zürich 
xxx (xx.x) 
CHE021 Centre Hospitalier Universitaire Vaudois, Lausanne 
xxx (xx.x) 
CHE022 Kantonsspital Luzern, Luzern 
xxx (xx.x) 
CHE024 Onkologiezentrum Thun - Berner Oberland, Thun 
xxx (xx.x) 
CHE105 Kantonsspital Graubünden, Chur 
xxx (xx.x) 
DNK003 Aarhus University Hospital, Aarhus 
xxx (xx.x) 
ESP052 Hospital Universitario 12 Octubre, Madrid 
xxx (xx.x) 
... 
xxx (xx.x) 
... 
xxx (xx.x) 
Total 
xxx 
 
 
 
Table 2: Balance of treatment allocation per stratification factor combination 
VeriStrat status=Good 
VeriStrat status=Poor 
PS=0&1 
PS=2 
PS=0&1 
PS=2 
Treatment 
A 
Treatment 
B 
Treatment 
A 
Treatment 
B 
Treatment 
A 
Treatment 
B 
Treatment 
A 
Treatment 
B 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
 
 
 


Table 3a: Patient baseline characteristics (N=xx) 
Categorical characteristics 
Gender - n (%) 
Male 
xxx (xx.x) 
Female 
xxx (xx.x) 
Smoking history - n (%) 
Never 
xxx (xx.x) 
Former (>=100 cig & >=12 months smoke-free) 
xxx (xx.x) 
Current 
xxx (xx.x) 
Unknown 
xxx (xx.x) 
Histology - n (%) 
Squamous 
xxx (xx.x) 
Predominantly squamous with minor adenocarcinoma 
component 
xxx (xx.x) 
Predominantly squamous with adenocarcinoma 
component>10% 
xxx (xx.x) 
Unknown 
xxx (xx.x) 
Performance status - n (%) 
0 
xxx (xx.x) 
1 
xxx (xx.x) 
2 
xxx (xx.x) 
Veristrat status - n (%) 
Good 
xxx (xx.x) 
Poor 
xxx (xx.x) 
Continuous characteristics 
Age (yrs) 
Mean (95% CI) 
xx.x (xx.x, xx.x) 
Median (Min-Max) 
xx.x (xx.x - xx.x) 
 
 
 


Table 3b: Patient baseline characteristics by treatment arm (N=xx) 
 
Treatment A 
(n=37) 
Treatment B 
(n=40) 
 
Categorical characteristics 
Gender - n (%) 
Male 
xxx (xx.x) 
xxx (xx.x) 
 
Female 
xxx (xx.x) 
xxx (xx.x) 
 
Smoking history - n (%) 
Never 
xxx (xx.x) 
xxx (xx.x) 
 
Former (≥100 cig & ≥12 months smoke-free) 
xxx (xx.x) 
xxx (xx.x) 
 
Current 
xxx (xx.x) 
xxx (xx.x) 
 
Unknown 
xxx (xx.x) 
xxx (xx.x) 
 
Histology - n (%) 
Squamous 
xxx (xx.x) 
xxx (xx.x) 
 
Predominantly squamous with minor adenocarcinoma 
component 
xxx (xx.x) 
xxx (xx.x) 
 
Predominantly squamous with adenocarcinoma 
component>10% 
xxx (xx.x) 
xxx (xx.x) 
 
Unknown 
xxx (xx.x) 
xxx (xx.x) 
 
Performance status - n (%) 
0 
xxx (xx.x) 
xxx (xx.x) 
 
1 
xxx (xx.x) 
xxx (xx.x) 
 
2 
xxx (xx.x) 
xxx (xx.x) 
 
Veristrat status - n (%) 
Good 
xxx (xx.x) 
xxx (xx.x) 
 
Poor 
xxx (xx.x) 
xxx (xx.x) 
 
Continuous characteristics 
Age (yrs) 
Mean (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
Median (Min-Max) 
xx.x (xx.x - xx.x) 
xx.x (xx.x - xx.x) 
 
 
 
 


Table 4a: Time on follow-up & time on treatment (N=xxx) 
Time on follow-up (in months) 
All pts (xxx) 
No. of pts still on f-up (%) 
xxx (xx.x) 
Median (Interq. Range) 
 xx.x (xx.x - xx.x) 
Time-on treatment (in months)  
 
No. of discontinuations (%) 
xxx (xx.x) 
Median (Interq. Range) 
xx.x (xx.x – xx.x) 
 
 
 
Table 4b: Time on follow-up & time on treatment by treatment arm (N=xxx) 
Time on follow-up (in months) 
Treatment A 
(n=xxx) 
Treatment B 
(n=xxx) 
No. of pts still on f-up (%) 
xxx (xx.x) 
Xxx (xx.x) 
Median (Interq. Range) 
xx.x (xx.x - xx.x) 
xx.x (xx.x – xx.x) 
Time-on treatment (in months)  
 
 
No. of discontinuations (%) 
xxx (xx.x) 
xxx (xx.x) 
Median (Interq. Range) 
xx.x (xx.x – xx.x) 
xx.x (xx.x – xx.x) 
 
 
 
 
 
 
 
 
 
 
 


Table 5a: Adverse event overview 
 
N 
% 
Experienced AE 
xxx 
xx.x 
No AE 
xxx 
xx.x 
Total subjects 
xxx 
 
 
 
Table 5b: Adverse event overview by treatment arm 
 
Treatment A 
Treatment B 
 
N 
% 
N 
% 
Experienced AE 
xxx 
xx.x 
xxx 
xx.x 
No AE 
xxx 
xx.x 
xxx 
xx.x 
Total subjects 
xxx 
 
xxx 
 
 
 
Table 6a: Serious adverse event overview 
 
N 
% 
Experienced SAE 
xxx 
xx.x 
No SAE 
xxx 
xx.x 
Total subjects 
xxx 
 
 
 
Table 6b: Serious adverse event overview by treatment arm 
 
Treatment A 
Treatment B 
 
N 
% 
N 
% 
Experienced SAE 
xxx 
xx.x 
xxx 
xx.x 
No SAE 
xxx 
xx.x 
xxx 
xx.x 
Total subjects 
xxx 
 
xxx 
 
 
 
 


Table 7:  Serious adverse events overview by center 
Center 
No. of 
patients 
Experienced 
SAE 
Total 
follow-up  
SAE 
incidence 
 
 
N 
% 
(months) 
 
BEL063 Institut Jules Bordet 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
CHE005 University Hospital Zürich 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
CHE021 Centre Hospitalier Universitaire Vaudois 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
CHE022 Kantonsspital Luzern 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
CHE024 Onkologiezentrum Thun - Berner 
Oberland 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
CHE105 Kantonsspital Graubünden 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
DNK003 Aarhus University Hospital 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
ESP052 Hospital Universitario 12 Octubre 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
ESP055 Hospital General Universitario Alicante 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
... 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
... 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
 
 
 


Table 8a: Frequency of serious adverse events 
Adverse event description 
Total 
Febrile neutropenia 
xxx 
Pain 
xxx 
Respiratory failure 
xxx 
Respiratory, thoracic and mediastinal disorder 
xxx 
Bronchial infection 
xxx 
Bronchial obstruction 
xxx 
Bronchopulmonary hemorrhage 
xxx 
... 
xxx 
... 
xxx 
Total 
xxx 
 
 
 
Table 8b: Frequency of serious adverse events by treatment arm 
Adverse event description 
Treatment A 
Treatment B 
Total 
Bronchial infection 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Bronchial obstruction 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Bronchopulmonary hemorrhage 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Dehydration 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Endocrine disorders  
xxx (xx.x) 
xxx (xx.x) 
xxx 
Febrile neutropenia 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Fever 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Gastrointestinal disorders  
xxx (xx.x) 
xxx (xx.x) 
xxx 
... 
xxx (xx.x) 
xxx (xx.x) 
xxx 
... 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Total 
xxx 
xxx 
xxx 
 
 


Table 9a: Frequency of serious adverse events according to CTCAE Version 4 
Adverse event description 
Total 
% 
Respiratory, thoracic and mediastinal disorders 
xxx 
xx.x 
General disorders and administration site conditions 
xxx 
xx.x 
Blood and lymphatic system disorders 
xxx 
xx.x 
Infections and infestations 
xxx 
xx.x 
Endocrine disorders 
xxx 
xx.x 
Gastrointestinal disorders 
xxx 
xx.x 
... 
xxx 
xx.x 
... 
xxx 
xx.x 
Total 
xxx 
 
 
 
Table 9b: Frequency of serious adverse events by treatment arm according to 
CTCAE Version 4 
Adverse event description 
Treatment A 
Treatment B 
Total 
Blood and lymphatic system disorders 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Endocrine disorders 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Gastrointestinal disorders 
xxx (xx.x) 
xxx (xx.x) 
xxx 
General disorders and administration site conditions 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Infections and infestations 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Injury, poisoning and procedural complications 
xxx (xx.x) 
xxx (xx.x) 
xxx 
... 
xxx (xx.x) 
xxx (xx.x) 
xxx 
... 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Total 
xxx 
xxx 
xxx 
 
 
 


Table 10: Number of patients experiencing specific number of serious adverse 
events 
 
SAEs 
Frequency of SAEs 
1 
2 
3 
No. of patients 
xxx 
xxx 
xxx 
 
 
Table 11: Number of patients experiencing specific number of serious adverse 
events according to CTCAE Version 4 
 
SAEs  
Frequency of SAEs 
1 
2 
3 
No. of patients 
xxx 
xxx 
xxx 
 
 
 


Table 12: Distribution of adverse events by Grade 
Adverse event description 
Grade=1 Grade=2 Grade=3 Grade=4 Grade=5 Total 
Abdominal distension 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Abdominal pain 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Alanine aminotransferase increase 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Allergic rhinitis 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Alopecia 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Amnesia 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Anemia 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
... 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
... 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Total 
xxx  
xxx  
xxx  
xxx  
xxx  
xxx 
 
Table 13: Distribution of adverse events by Grade according to CTCAE Version 4 
Adverse event description 
Grade=1 
Grade=2 Grade=3 
Grade=4 
Grade=5 Total 
Blood and lymphatic system disorders 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Cardiac disorders 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Endocrine disorders 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Eye disorders 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Gastrointestinal disorders 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Hepatobiliary disorders 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Infections and infestations 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
... 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
... 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx 
Total 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 


Table 14a: Frequency of adverse events 
Adverse event description 
Total 
Adverse event description 
Total 
Fatigue 
xxx 
Amnesia 
xxx 
Rash maculo papular 
xxx 
Anemia 
xxx 
Dyspnea 
xxx 
Back pain 
xxx 
Cough 
xxx 
Bronchial obstruction 
xxx 
Diarrhea 
xxx 
Bronchospasm 
xxx 
Mucositis oral 
xxx 
Death NOS 
xxx 
Anorexia 
xxx 
Dehydration 
xxx 
Febrile neutropenia 
xxx 
Dry mouth 
xxx 
Neutrophil count decreased 
xxx 
Endocrine disorders  
xxx 
... 
xxx 
... 
xxx 
 
Table 14b: Frequency of adverse events by treatment arm 
Adverse event description 
Treatment A 
Treatment B 
Total 
Abdominal distension 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Abdominal pain 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Alanine aminotransferase increase 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Allergic rhinitis 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Alopecia 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Amnesia 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Anemia 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Anorexia 
xxx (xx.x) 
xxx (xx.x) 
xxx 
... 
xxx (xx.x) 
xxx (xx.x) 
xxx 
... 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Total 
xxx 
xxx 
xxx 
 
 
 


Table 15a: Frequency of adverse events according to CTCAE Version 4 
Adverse event description 
Total 
% 
General disorders and administration site conditions 
xxx 
xx.x 
Skin and subcutaneous tissue disorders 
xxx 
xx.x 
Respiratory, thoracic and mediastinal disorders 
xxx 
xx.x 
Gastrointestinal disorders 
xxx 
xx.x 
Blood and lymphatic system disorders 
xxx 
xx.x 
Infections and infestations 
xxx 
xx.x 
... 
xxx 
xx.x 
... 
xxx 
xx.x 
Total 
xxx 
 
 
 
Table 15b: Frequency of adverse events by treatment arm according to CTCAE 
Version 4 
Adverse event description 
Treatment A 
Treatment B 
Total 
Blood and lymphatic system disorders 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Cardiac disorders 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Endocrine disorders 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Eye disorders 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Gastrointestinal disorders 
xxx (xx.x) 
xxx (xx.x) 
xxx 
General disorders and administration site conditions 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Hepatobiliary disorders 
xxx (xx.x) 
xxx (xx.x) 
xxx 
... 
xxx (xx.x) 
xxx (xx.x) 
xxx 
... 
xxx (xx.x) 
xxx (xx.x) 
xxx 
Total 
xxx 
xxx 
xxx 
 
 
 
 
 


Table 16: Number of patients experiencing specific number of adverse events 
 
AEs 
Frequency of AEs 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 12 
13 
14 
No. of patients 
xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx 
 
 
Table 17: Number of patients experiencing specific number of adverse events 
according to CTCAE Version 4 
 
AEs 
Frequency of AEs 
1 
2 
3 
4 
5 
6 
7 
8 
9 
No. of patients 
xxx xxx xxx xxx xxx xxx xxx xxx xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Table 18a: Frequency of targeted adverse events 
Adverse event description 
N 
% 
Fatigue 
xxx 
xx.x 
Rash maculo papular 
xxx 
xx.x 
Dyspnea 
xxx 
xx.x 
Diarrhea 
xxx 
xx.x 
Mucositis oral 
xxx 
xx.x 
Neutrophil count decreased 
xxx 
xx.x 
Febrile neutropenia 
xxx 
xx.x 
Alanine aminotransferase increase 
xxx 
xx.x 
Pain 
xxx 
xx.x 
Peripheral sensory neuropathy 
xxx 
xx.x 
... 
xxx 
xx.x 
... 
xxx 
xx.x 
Total 
xxx 
 
 
Table 18b: Frequency of non-targeted adverse events 
Adverse event description 
N 
% 
Adverse event description 
N 
% 
Cough 
xxx 
xx.x 
Fatigue 
xxx 
xx.x 
Anorexia 
xxx 
xx.x 
Gastrointestinal disorders  
xxx 
xx.x 
Alopecia 
xxx 
xx.x 
Glucose intolerance 
xxx 
xx.x 
Pain 
xxx 
xx.x 
Hepatic pain 
xxx 
xx.x 
Conjunctivitis 
xxx 
xx.x 
Hypertriglyceridemia 
xxx 
xx.x 
Constipation 
xxx 
xx.x 
Hyponatremia 
xxx 
xx.x 
Dizziness 
xxx 
xx.x 
Infections and infestations  
xxx 
xx.x 
Lung infection 
xxx 
xx.x 
Keratitis 
xxx 
xx.x 
Nausea 
xxx 
xx.x 
Laryngeal hemorrhage 
xxx 
xx.x 
Abdominal pain 
xxx 
xx.x 
Leukocytosis 
xxx 
xx.x 
Bone pain 
xxx 
xx.x 
Mucosal infection 
xxx 
xx.x 
Creatinine increased 
xxx 
xx.x 
Mucositis oral 
xxx 
xx.x 
Total=xxx 
 


Table 19a: Frequency of targeted adverse events according to CTCAE Version 4 
Adverse event description 
N 
% 
General disorders and administration site 
conditions 
xxx 
xx.x 
Skin and subcutaneous tissue disorders 
xxx 
xx.x 
Respiratory, thoracic and mediastinal disorders 
xxx 
xx.x 
Blood and lymphatic system disorders 
xxx 
xx.x 
Gastrointestinal disorders 
xxx 
xx.x 
Infections and infestations 
xxx 
xx.x 
Investigations 
xxx 
xx.x 
... 
xxx 
xx.x 
... 
xxx 
xx.x 
Total 
xxx 
 
 
 
Table 19b: Frequency of non-targeted adverse events according to CTCAE 
Version 4 
Adverse event description 
N 
% 
Gastrointestinal disorders 
xxx 
xx.x 
Respiratory, thoracic and mediastinal disorders 
xxx 
xx.x 
Skin and subcutaneous tissue disorders 
xxx 
xx.x 
Metabolism and nutrition disorders 
xxx 
xx.x 
General disorders and administration site conditions 
xxx 
xx.x 
Musculoskeletal and connective tissue disorders 
xxx 
xx.x 
Nervous system disorders 
xxx 
xx.x 
Eye disorders 
xxx 
xx.x 
... 
xxx 
xx.x 
... 
xxx 
xx.x 
Total 
xxx 
 
 
 
 


Table 20a: Treatment A: Adverse event information by patient (any AE & SAE) 
ID 
Adverse event 
(CTCAE V.4) 
Adverse event 
description 
AE/ 
SAE 
Grade 
Date of 
onset 
Relate
d cycle 
Relation to 
treatment 
Outcome 
4101 
Respiratory, thoracic and 
mediastinal disorders 
Allergic rhinitis 
AE 
2 
. 
2 
4-probable 
PD (15/04/2013)  
&  
Death 
(26/09/2013) 
 
Metabolism and nutrition 
disorders 
Anorexia 
AE 
2 
. 
4 
3-possible 
 
Respiratory, thoracic and 
mediastinal disorders 
Bronchospasm 
AE 
1 
. 
4 
1-unrelated 
 
Eye disorders 
Conjunctivitis 
AE 
1 
. 
4 
3-possible 
 
Skin and subcutaneous tissue 
disorders 
Rash maculo 
papular 
AE 
2 
01/02/2013 
4 
5-definite 
4243 
Skin and subcutaneous tissue 
disorders 
Rash maculo 
papular 
AE 
2 
17/04/2013 
1 
5-definite 
On Follow-up 
 
Respiratory, thoracic and 
mediastinal disorders 
Cough 
AE 
2 
. 
3 
1-unrelated 
 
Metabolism and nutrition 
disorders 
Anorexia 
AE 
3 
. 
4 
3-possible 
 
Musculoskeletal and 
connective tissue disorders 
Back pain 
AE 
1 
. 
4 
1-unrelated 
 
 
Table 20b: Treatment B: Adverse event information by patient (any AE & SAE) 
ID 
Adverse event 
(CTCAE V.4) 
Adverse event 
description 
AE/ 
SAE 
Grad
e 
Date of 
onset 
Relate
d cycle 
Relation to 
treatment 
Outcome 
4270 
General disorders and 
administration site 
conditions 
Fatigue 
AE 
1 
09/05/2013 
2 
3-possible 
PD (19/09/2013)  
& 
Death 
(30/11/2013) 
 
Skin and subcutaneous 
tissue disorders 
Alopecia 
AE 
2 
. 
3 
5-definite 
 
Nervous system disorders 
Amnesia 
AE 
2 
. 
3 
1-unrelated 
 
Vascular disorders 
Hypertension 
AE 
2 
. 
3 
3-possible 
4411 
Blood and lymphatic 
system disorders 
Febrile 
neutropenia 
SAE 
4 
10/05/2013 
1 
5-definite 
Death (30/05/2013) 
4413 
Infections and 
infestations 
Bronchial 
infection 
SAE 
3 
15/06/2013 
2 
3-possible 
On Follow-up 
 
Infections and 
infestations 
Sepsis 
SAE 
4 
27/06/2013 
2 
5-definite 
 
 


Table 21: Narratives of patients with a SAE 
ID 
SAE 
Date of 
onset 
Narrative 
4411 
Febrile neutropenia 
10/05/2013 
63 year old formerly smoking man with medical history of asthma and urothelial carcinoma (2009) was 
diagnosed with advanced, progressing (adrenal, bone, brain, liver and lung metastases) squamous cell NSCLC 
after surgery. ........ 
4413 
Bronchial infection 
15/06/2013 
56 year old smoking man with medical history of hypertension and diabetes was diagnosed with advanced, 
progressing (liver and lymph node metastases) squamous cell NSCLC after radiotherapy and 
chemoradiotherapy. .......... 


Table 22: Adverse events experienced by patients with Progression of disease and/or Death 
 
ID number 
Adverse event 
4101 4270 4290 4411 4432 4434 4435 4441 4442 4459 4461 4471 4475 4477 4496 4506 4509 4511 4515 
Allergic rhinitis 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alopecia 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amnesia 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anorexia 
✓ 
 
 
 
✓ 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
Bone pain 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
Bronchial 
infection 
 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
Table 23: Adverse events experienced by patients with Progression of disease and/or Death according to CTCAE Version 4 
 
 
ID number 
Adverse event 
 4101 4270 4290 4411 4432 4434 4435 4441 4442 4459 4461 4471 4475 4477 4496 4506 4509 4511 4515 
Endocrine 
disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
 
 
 
 
Eye disorders 
 ✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gastrointestinal 
disorders 
 
 
 
 
 
✓ 
 
✓ 
✓ 
 
 
 
 
 
 
 
✓ 
 
✓ 
 
Hepatobiliary 
disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
Infections and 
infestations 
 
 
 
✓ 
 
 
 
 
✓ 
✓ 
 
 
 
 
 
 
 
 
 
 
Investigations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
 
 
✓ 
 


 

ICF_001.pdf: 
EMPHASIS Appendix 1: Patient Information (English) 
page 1 of 11 
V1.0  01.May.2012  <insert center name> 
 
 
EMPHASIS-lung 
 
ETOP 3-12 
1) This template Patient Information Sheet and Informed Consent has been written 
according to International Conference on Harmonization (ICH) guidelines which state 
the Informed Consent Form (ICF) should adhere to Good Clinical Practices (GCP) 
and to the ethical principles that have origin in the Declaration of Helsinki. 
2) This template can be edited to incorporate information specific to your institution. 
Please forward the edited version to the ETOP Coordinating Office for approval prior 
to submission to Ethics Committee(EC)/IRB. The final version should receive the 
Local EC/IRB approval in advance of use. 
3) Following the ICH-GCP guidelines, the ICF should contain information about the 
following items: 
a) The trial involves research 
b) Purpose of the trial 
c) Trial treatment(s) and the probability of random assignment 
d) The subject’s responsibilities 
e) The aspects of the trial that are experimental 
f) Risks 
g) Benefits 
h) Alternative treatments available 
i) Compensation/expenses 
j) Subject’s participation is voluntary/right to withdraw 
k) Confidentiality 
l) Information about course of the trial 
m) Circumstance under which trial may be terminated 
n) Contact persons for further information or in case of injury 
o) The approximate number of subjects involved in the trial 
p) Duration of subject’s participation in the trial 
4) This template has been designed to cover the above items. If the Local EC/IRB 
requires modifications, none of the above items should be completely excluded, nor 
should the meaning of the highlighted areas be modified. Such modifications must be 
submitted to ETOP for approval. 
5) In order to assist in the preparation of your customized version, an electronic file in 
MS Word will be distributed via e-mail to all Principal Investigators and ETOP 
members may download it from the ETOP web site (www.etop-eu.org). 


EMPHASIS Appendix 1: Patient Information (English) 
page 2 of 11 
V1.0  01.May.2012  <insert center name> 
PATIENT INFORMATION SHEET AND INFORMED CONSENT APPENDIX I 
 
ETOP PATIENT INFORMATION SHEET FOR CLINICAL RESEARCH 
Dear Patient 
You are being asked to participate in a clinical research study. The doctors at 
different centers of the European Thoracic Oncology Platform (ETOP) and in other 
cooperative groups or centers throughout the world study the nature of lung cancer 
and attempt to develop improved methods of diagnosis and treatment. This is called 
clinical research. In order to decide whether or not you should agree to be part of this 
clinical research study you should understand enough about its risks and benefits to 
make an informed judgment. Your participation in this research study is entirely 
voluntary and you will be given sufficient time to decide whether you wish to 
participate. This process is known as Informed Consent. 
This Patient Information Sheet gives detailed information about the research study, 
which your doctor will discuss with you. Once you understand the study, if you wish 
to participate, you will be asked to sign the Patient Informed Consent Form. You will 
have a copy of this document and of the signed Patient Informed Consent Form to 
keep as a record. 
 
The clinical research study being proposed to you is: 
 
 
EMPHASIS-lung 
 
ETOP 3-12 
A randomized phase III trial of erlotinib versus docetaxel in patients 
with advanced squamous cell non-small cell lung cancer who failed 
first line platinum based doublet chemotherapy stratified by 
VeriStrat Good vs VeriStrat Poor 
 
Erlotinib Maldi TOF Phase III Signature in Squamous cell non-small cell 
lung cancer 
 
PURPOSE OF THE RESEARCH STUDY 
You have been diagnosed with a type of lung cancer that is called “non small cell 
lung cancer (NSCLC)”. Your lung cancer has recently recurred despite previous 
treatment with chemotherapy. Your doctor has decided that further treatment of your 
cancer is necessary.  
In previous clinical studies of NSCLC, treatment with Taxotere® (Docetaxel) showed 
a survival advantage in patient with advanced, relapsed NSCLC. Relapsed means 
that despite treatment, the cancer is growing. Similar results have been reported the 
treatment with Tarceva® (Erlotinib). 
 
The aim of the current study is to compare the efficacy (how well the treatment 
works) and tolerability (how severe the side effects are) of these two treatments in 
patients with advanced NSCLC. Also, the aim is to explore how well the VeriStrat® 


EMPHASIS Appendix 1: Patient Information (English) 
page 3 of 11 
V1.0  01.May.2012  <insert center name> 
test is able to predict the response of NSCLC to one of the two drugs, Docetaxel and 
Erlotinib. 
VeriStrat is a test that will look for certain proteins in your blood that are related to 
your cancer, prior to receiving treatment with drugs such as Erlotinib. The results of 
the test have been shown to correlate with how well a tumour responds to treatments 
such as Erlotinib. VeriStrat is currently marketed in the USA as a test for patients with 
advanced NSCLC whose tumour has grown after previous treatment.  
Docetaxel and Tarceva are both approved by the Health Authorities in Europe and 
Switzerland for the treatment of NSCLC.  
 
EMPHASIS is an international clinical research study. A total of 500 patients from 
centers throughout Europe and Switzerland are expected to be enrolled in this study 
over a period of 18 months. In country it is planned that xx patients will take part. The 
study will take approximately 42 months to be completed. 
 
This clinical trial is conducted according to all applicable national laws and 
international guidelines. The trial has been approved by the independent Ethics 
Committee concerned insert name of the Ethics Committee.  
 
VOLUNTARY PARTICIPATION/RIGHT TO REFUSE OR WITHDRAW 
 
Your participation in this clinical research study is entirely voluntary. If you decide not 
to participate in the study, this will not affect your medical care in any way. If you 
begin the study, you will have the right to withdraw at any time without giving any 
reason. This will not affect your future medical care. You will be asked to have a final 
examination before you withdraw and you will be advised for other available care 
which suits your needs and medical condition. If you should withdraw, data already 
collected until then will be used for analysis. 
 
If you participate in the study, you should follow the instructions of your treating 
physician, follow the schedule of treatment visits, inform your physician of any new 
signs and symptoms you have, and about any non-study medication or supplement 
you take.  
 
 
DESCRIPTION OF THE CLINICAL RESEARCH STUDY 
Veristrat testing: If you decide to participate, a 3.5 mL blood sample will be collected 
for VeriStrat testing before randomization and will be sent to a central laboratory, 
called Biodesix, in Aurora, Colorado, USA. Neither you nor your doctor will be 
informed about the result of the test.There is a small possibility that your sample 
cannot be analyzed due to technical reasons. In this case you will be asked to give 
one additional blood sample. If this can also not be analyzed you will not be able to 
participate in this study. 
You will have a full medical history taken, physical examination, radiological and lab 
workout performed at the time you enter the study. If you are a female of child-
bearing potential, a pregnancy test will be done on your blood serum within 7 days 
prior to receiving study treatment. 


EMPHASIS Appendix 1: Patient Information (English) 
page 4 of 11 
V1.0  01.May.2012  <insert center name> 
If you decide to participate in the study and meet the criteria to take part in the study 
described above, you will receive one of the following treatments: 
A: Tarceva®: 150 mg orally, daily. You will take Tarceva tablets every day. Tablets 
should be taken at a fixed time each day and at least 1 hour before or 2 hours after 
you eat.  
B: Docetaxel: 75mg/m2 intravenous (IV) infusion received on one day every 3 weeks. 
Each period of 3 weeks is called a 3-week cycle. To reduce the risk of fluid retention 
and allergic reaction to this treatments, all patients will receive corticosteroids for 3 
days starting one day before every Docetaxel administration. 
It is not clear at this time which treatment schedule would be better for you. For this 
reason, the treatment offered to you will be chosen by a method called 
randomization. Randomization is a method similar to the “flip of a coin” to assign at 
random (by chance) a treatment for you. Neither you nor your doctor can choose to 
which treatment arm you will be allocated: You will have an equal chance of being 
placed in one of the two groups. 
  
During the study treatment, you must visit your treating physician every 3 weeks for a 
physical examination. If you have been randomized to receive Tarceva, please bring 
with you all empty, full and partly used boxes of Tarceva® tablets. Routine blood 
analyses including liver and kidney function will be carried out every 3 weeks as part 
of standard medical routine. If you develop side effects, more frequent examinations 
may be necessary.  
Inpatient admission into a hospital is not foreseen, but can potentially become 
necessary.  
Your treating physician will document your general condition and all hospital stays 
during the clinical research study. He/she will similarly ask you about all side effects 
you have experienced and about all medications, supplements or treatments you 
have taken/received since your last visit. 
To determine the status of your NSCLC and effects from the treatment, radiological 
examinations (computer tomography [CT] of the chest) will be conducted at study 
entry and every 6 weeks thereafter (at the beginning of cycles 3,5,7,9 etc) until your 
tumour grows again. These examinations are carried out as part of medical routine 
and may be carried out more frequently, if your treating physician considers this 
appropriate. 
Your doctor may suggest other tests, such as CT of the brain. The regular doctor’s 
visits are part of your standard medical care and are handled the same way as if you 
did not take part in the study. 
 
ALTERNATIVE TREATMENTS 
Instead of being in this study, your doctor may recommend that you receive Tarceva 
or another form of treatment (for example chemotherapy and/or radiotherapy) not 
given as part of this study. 
 
BENEFITS 


EMPHASIS Appendix 1: Patient Information (English) 
page 5 of 11 
V1.0  01.May.2012  <insert center name> 
The ultimate goal of conducting clinical research studies in lung cancer patients is to 
better understand the behaviour of cancer and to find better ways of treatment. We 
hope that the treatment under this clinical research study will be of benefit to you 
and/or that it will help others, although we cannot guarantee this.  
 
RISKS AND DISCOMFORTS 
While you receive treatment with the medications being used in the protocol, you are 
at risk of the side effects of these treatments. Your physician will be checking you 
closely to see if any of the side effects are occurring. You should report any side 
effect or symptom that you experience to your physician. Other drugs may be given 
to make some of these side effects less serious and uncomfortable. 
 
Tarceva® 
Very common (≥ 10%): 
 Diarrhoea  
 Vomiting 
 Rash which may occur or worsen in sun exposed areas 
 Eye irritation due to conjunctivitis/keratoconjunctivitis and keratitis 
 Infection 
 Loss of appetite, decreased weight 
 Depression 
 Headache, altered skin sensation or numbness in the extremities 
 Difficulty in breathing, cough 
 Nausea 
 Mouth irritation 
 Stomach pain, indigestion and flatulence 
 Abnormal blood tests for the liver function 
 Itching, dry skin and loss of hair 
 Tiredness, fever, rigors 
Common (1 – 10%):  
 Bleeding from the nose 
 Bleeding from the stomach or the intestines 
 Inflammatory reactions around the fingernail 
 Cracked skin (skin fissures) 
Rare (< 1%) 
 Eyelash changes 
 Excess body and facial hair of a male distribution pattern 
 Eyebrow changes 
 Brittle and loose nails 
Very rare (< 0.1%) 
 Perforation or ulceration of the cornea 
 Severe blistering or peeling of skin  
Your physician will be checking you closely to see if any of these side effects are 
occurring. Your doctor may prescribe medication to keep these side effects under 
control.  
You should tell your doctor: 


EMPHASIS Appendix 1: Patient Information (English) 
page 6 of 11 
V1.0  01.May.2012  <insert center name> 
 if you have sudden difficulty in breathing associated with cough or fever 
because your doctor may need to treat you with other medicines and interrupt 
your Tarceva treatment 
 if you have diarrhoea; 
 immediately, if you have severe or persistent diarrhoea, nausea, loss of 
appetite, or vomiting; 
 if you have severe pain in the abdomen, severe blistering or peeling of skin, or 
acute or worsening eye problems (for example eye pain).  
 if you are also taking a statin and experience unexplained muscle pain, 
tenderness, weakness or cramps.  
 
Docetaxel 
Very common (≥ 10%): 
During the infusion at the hospital 
 flushing, skin reactions, itching 
 chest tightness; difficulty in breathing 
 fever or chills 
 back pain 
 low blood pressure 
After the infusion: 
 infections, decrease in the number of red (anaemia), or white blood cells and 
platelets 
 fever: if this happens you must tell your doctor immediately 
 allergic reactions as described above 
 loss of appetite (anorexia) 
 insomnia 
 feeling of numbness or pins and needles or pain in the joints of muscles 
 headache 
 alteration in sense of taste 
 inflammation of the eye or increased tearing of the eyes 
 swelling caused by faulty lymphatic drainage 
 shortness of breath 
 nasal drainage; inflammation of the throat and nose; cough 
 bleeding from the nose 
 sores in the mouth 
 stomach upsets including nausea, vomiting and diarrhoea, constipation 
 abdominal pain 
 indigestion 
 short term hair loss (in most cases normal hair growth should return) 
 redness and swelling of the palms of your hands or soles of your feet which 
may cause your 
 skin to peel (this may also occur on the arms, face, or body) 
 change in the colour of your nails, which may detach 
 muscle aches and pains; back pain or bone pain 
 change or absence of menstrual period 
 swelling of the hands, feet, legs 
 tiredness; or flu-like symptoms 
 weight gain or loss 
Common (1 – 10%):  


EMPHASIS Appendix 1: Patient Information (English) 
page 7 of 11 
V1.0  01.May.2012  <insert center name> 
 fungal infection of the mouth (oral candidiasis) 
 dehydration 
 dizziness 
 hearing impaired 
 decrease in blood pressure; irregular or rapid heart beat 
 heart failure 
 oesophagitis 
 dry mouth 
 difficulty or painful swallowing 
 haemorrhage 
 raised liver enzymes (hence the need for regular blood tests) 
Rare (< 1%) 
 fainting 
 at the injection site, skin reactions, phlebitis (inflammation of the vein) or 
swelling 
 inflammation of the colon, small intestine; intestinal perforation 
 blood clots. 
 
Pregnancy/Birth Control: 
All women who participate in the trial and are able to become pregnant must use 
effective contraception while they receive study medication and 12 months thereafter.  
If you are female and are pregnant, or plan to become pregnant, or if you are 
breastfeeding. you will not be allowed to enter this study. This is because the effects 
of the drug used in this study to an unborn baby or nursing infant are uncertain. You 
will also be asked to use a proven contraceptive method (a way to prevent you from 
becoming pregnant) while you are in this study. Your doctor will discuss with you 
which methods constitute effective contraception.  
If you are a man whose partner can get pregnant, you and your partner will need to 
use a proven contraceptive method while you are in this study. 
If you are female and become pregnant, or if you are male and a partner becomes 
pregnant, you must tell your study doctor immediately. For female patients, your 
doctor may discuss with you the possibility of stopping study treatment. Your doctor 
will need to report this information and the outcome of you or your partner’s 
pregnancy to the ETOP safety office.   
 
NEW INFORMATION ARISING FROM THIS AND OTHER STUDIES 
 
You have the right to be informed of the progress of the clinical research study and of 
its final results. You have also the right to be informed of all additional results of other 
studies, which might be important for your treatment or might affect your willingness 
to continue. 
 
CONFIDENTIALITY 
The researchers will need to collect personal information from you such as your age, 
gender and relevant health information. All information collected is coded in a way 
that without a key, it will not be possible to link the information to your person. 


EMPHASIS Appendix 1: Patient Information (English) 
page 8 of 11 
V1.0  01.May.2012  <insert center name> 
Any personal or health information that is collected will be kept private and 
confidential. It will be stored securely. Only authorised persons, who understand that 
it must be kept confidential, will be able to get access to it. In any report of the 
research made available to the public you will not be referred to by name. 
Representatives of ETOP, Biodesix Inc., health authorities or drug regulatory 
agencies may require access to personal or health information contained in your 
medical records to verify clinical trial procedures and/or data. Your personal data will 
be stored in a database and evaluated at the Data Centre of ETOP. ETOP 
guarantees that the national and international data protection guidelines are 
respected. 
 
COLLECTION OF BIOLOGICAL MATERIAL 
About blood samples 
Blood samples (3.5 mL or 1 teaspoon) will be collected for VeriStrat testing and will 
be sent to a central laboratory called Biodesix in Aurora, CO, USA. After performing 
the test the sample will be destroyed (no collection). 
 
EXPENSES / REMUNERATION 
VeriStrat will be provided free of charge by Biodesix, Inc. 
Tarceva® and Docetaxel as well as all other expenses, for example, routine standard 
examinations, will be handled as if you were receiving standard treatment and not 
participating in the clinical study. 
You will receive no payment for taking part in this study.  
 
TERMINATION OF THE STUDY 
You might stop receiving study treatment without your consent for the following 
reasons: 
a) If your lung cancer worsens or a new tumour develops. 
b) If the doctors treating you detect side effects that they consider dangerous. 
c) If you refuse to have the treatments or follow-up examinations and tests 
needed to determine whether the treatment is safe and effective. 
d) If the early analyses of study data show insufficient benefit or a significant 
potential harm of the treatment. 
 
INSURANCE 
 
The ETOP will compensate you for any damage you may suffer during the course of 
the clinical trial. For this purpose the ETOP has arranged insurance for clinical trials 
with XX. 
If you notice any health problems or other damage during or after the clinical trial, 
please contact the responsible doctor without delay. He/She is familiar with the valid 
legislation, has the relevant documentation and will take the necessary steps for you. 


EMPHASIS Appendix 1: Patient Information (English) 
page 9 of 11 
V1.0  01.May.2012  <insert center name> 
 
CONTACT PERSONS 
The physician in charge of this study is (give name, telephone number of PI). If you need 
more information about this study before you decide to join, or at any other time, you 
may wish to contact him/her. In the event that you do decide to participate, he/she 
should also be called if there are severe side effects from the treatment. 
 
 
 
 


EMPHASIS Appendix 1: Patient Information (English) 
page 10 of 11 
V1.0  01.May.2012  <insert center name> 
PATIENT INFORMED CONSENT FOR CLINICAL RESEARCH 
 
 Please read this form carefully. 
 Please ask if there is anything you do not understand or would like to know. 
 
Clinical trial number: EMPHASIS-lung/ ETOP 3-12 
Title of clinical trial: A randomized phase III trial of erlotinib versus docetaxel in 
patients with advanced squamous cell non-small cell lung cancer who failed first line 
platinum based doublet chemotherapy stratified by VeriStrat Good vs VeriStrat Poor  
Location of clinical trial: 
Trial investigator: 
Surname and forename: 
Patient: 
Surname and forename: 
Date of birth: 
 
 The undersigned doctor has explained to me verbally and in writing the 
objectives, the procedure of the trial with Tarceva® or Docetaxel, the expected 
effects, possible advantages and disadvantages and potential risks.  
 I have read and understood the written Patient Information Leaflet issued for 
the above-mentioned trial (see footer for date). My questions related to the 
participation in this trial have been answered to my satisfaction. I may retain 
the written information leaflet and have been given a copy of my informed 
consent form.  
 Other possible treatments and treatment methods have been explained to me. 
 I have had enough time to make my decision. 
 I have been informed that there is insurance to cover any damage that may 
arise during the course of the trial. 
 I agree that my GP is being informed of my participation in the trial. 
 I take note that my blood sample will be used for VeriStrat® testing. 
 I know that my personal details and sample will only be used in anonymised 
form for research purposes. I give my consent for the relevant experts from the 
ETOP, the authorities and the ethics committee to have access to my original 
data for inspection and review purposes, but provided that strict confidentiality 
is maintained. 
 I am participating voluntarily in this clinical trial. I may withdraw my consent to 
participate at any time without giving reasons and without any disadvantage to 
my continued medical care. If I do withdraw my consent, I will undergo a final 
medical examination. 
 I am aware that the requirements and restrictions detailed in the patient 
information leaflet must be observed during the clinical trial. In the interests of 
my health, the trial investigator may exclude me from the trial at any time. 
Furthermore I will report to the investigator any concurrent treatment I receive 
and any medication I am taking (whether it was prescribed by the doctor or I 
bought it myself). 
 


EMPHASIS Appendix 1: Patient Information (English) 
page 11 of 11 
V1.0  01.May.2012  <insert center name> 
Place, Date 
Patient’s signature: 
 
 
Confirmation by trial investigator: 
 
I hereby confirm that I have explained the nature, significance and implications of the 
trial to this patient. I undertake to meet all the obligations arising in connection with 
this clinical trial. If at any time during the conduct of the trial I learn of aspects that 
might influence the patient’s willingness to participate in the trial, I will notify her of 
these immediately. 
 
Place, Date 
Investigator’s signature: 
 
 
 
 
PLEASE RETAIN A COPY OF THE SIGNED INFORMED CONSENT FORM. DO NOT SEND 
THE SIGNED INFORMED CONSENT FORM TO ETOP. 
 
 
 

SAP_003.pdf: 
 
EMPHASIS-lung 
ETOP 3-12 
 
A randomized phase III trial of erlotinib versus docetaxel in patients with 
advanced squamous cell non-small cell lung cancer who failed first line platinum-
based doublet chemotherapy stratified by VeriStrat Good vs VeriStrat Poor 
 
Erlotinib Maldi TOF Phase III Signature in Squamous cell non-small cell lung cancer 
 
A clinical trial of ETOP 
 
NCT01652469 
 
 
SAP VERSION 
V.1 
SAP VERSION DATE 
07.01.2015 
TRIAL STATISTICIAN 
Urania Dafni 
TRIAL PRIMARY INVESTIGATORS 
Egbert Smit, Solange Peters 
DSMB SAP AUTHOR 
Marie Kassapian 
 
 


 
 
 
Figure 1: Patient flowchart 
 
 
 
 
 


 
Figure 2a: expected vs observed accrual 
 


 
Figure 2b: Cumulative accrual by treatment arm 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Figure 3: Time on follow-up by treatment arm (N=xxx) 
 
 
 
 
 
 
 
 
 


 
 
 
 
Figure 4: Time on treatment by treatment arm (N=xxx) 


 
Figure 5a: Distribution of adverse events 
 


 
Figure 5b: Distribution of adverse events by treatment arm 
 
 
 


 
Figure 6a: Distribution of serious adverse events 
 


 
Figure 6b: Distribution of serious adverse events by treatment arm 
 


 
Figure 7a: Distribution of serious adverse events 
 


 
Figure 7b: Distribution of serious adverse events by treatment arm 
 


 
Figure 8a: Distribution of serious adverse events according to CTCAE Version 4 
 
 
 
 
 
 


 
Figure 8b: Distribution of serious adverse events by treatment arm according to CTCAE Version 4 
 
 
 


 
Figure 9a: Severity of adverse events  
 


 
Figure 9b: Severity of adverse events by treatment arm 
 
 
 


 
Figure 10a: Severity of adverse events according to CTCAE Version 4  
 


 
Figure 10b: Severity of adverse events by treatment arm according to CTCAE Version 4 
 
 
 
 


 
Figure 11a: Maximum severity of adverse event per patient 


 
Figure 11b: Maximum severity of adverse event per patient by treatment arm 
 


 
Figure 12a: Distribution of adverse events 
 


 
Figure 12b: Distribution of adverse events by treatment arm 
 
 


 
Figure 13a: Distribution of adverse events according to CTCAE Version 4 
 
 


Figure 13b: Distribution of adverse events by treatment arm according to CTCAE Version 4 
 


 
Figure 14:  Progression-free Survival (N=xxx) 
 
 


 
Figure 15:  Progression-free Survival by VeriStrat status (N=xxx) 
 
 


 
Figure 16:  Overall Survival (N=xxx) 
 


 
Figure 17:  Overall Survival by VeriStrat status (N=xxx) 

Prot_000.pdf: 
ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
1/38
EMPHASIS-lung
ETOP 3-12
A randomized phase III trial of erlotinib versus docetaxel in patients with
advanced squamous cell non-small cell lung cancer who failed first line
platinum based doublet chemotherapy stratified by VeriStrat Good vs
VeriStrat Poor
Erlotinib Maldi TOF Phase III Signature in Squamous cell non-small cell
lung cancer
A clinical trial of ETOP
EudraCT number:
2012-001896-35
ETOP c/o IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern
Phone: +41 31 389 93 91
Fax: +41 31 389 93 92
Version 1.0


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
2/38
Contacts
Trial Co-Chair
Egbert Smit. MD-
PhD
Address
Tel:
Fax:
Email:
Vrije Universiteit VU
Medical Centre,
PO Box 7057
1007MB Amsterdam, The Netherlands
+31204444782
+31204444328
ef.smit@vumc.nl
Trial Co-Chair
Solange Peters, MD-
PhD
Address
Tel:
Fax:
Email:
Centre Pluridisciplinaire d'Oncologie
Centre Hospitalier Universitaire Vaudois
1011 Lausanne, Switzerland
+41 79 556 01 92
+41 21 314 67 89 (assistant)
+41 21 314 01 67
solange.peters@etop-eu.org
Chairman ETOP
Rolf Stahel, MD
Address
Tel:
Fax:
Email:
Laboratory of Molecular Oncology
Clinic of Oncology
University Hospital Zuerich
Häldeliweg 4
8044 Zürich, Switzerland
+41 44 634 28 71
+41 44 634 28 72
rolf.stahel@usz.ch
Statistics
Urania Dafni, ScD
Address
Tel:
Fax:
Email:
Frontier Science Foundation - Hellas
70 Mikras Asias Str.
11527, Athens, Greece
+302107710902
+302107710903
udafni@frontier-science.gr
Data Management
ETOP Coordinating
Office
Address
Tel:
Fax:
Email:
ETOP Coordinating Office
c/o IBCSG Coordinating Center
Effingerstrasse 40
3008 Bern, Switzerland
+41 31 389 93 91
+41 31 389 92 29
EMPHASIS@etop-eu.org
Safety and Regulatory
Affairs
Barbara Ruepp, PhD
Address
Tel:
Fax:
Email:
ETOP Safety and Regulatory Office
c/o IBCSG Coordinating Center
Effingerstrasse 40
3008 Bern, Switzerland
+41 31 389 93 91
+41 31 389 92 29
regulatoryoffice@etop-eu.org
ETOP Coordinating
Office Team
Anita Hiltbrunner
Rudolf Maibach,
PhD
Susanne Roux
Marc Marbot
Address
Tel:
Fax:
Email:
c/o IBCSG Coordinating Center
Effingerstrasse 40
3008 Bern, Switzerland
+41 31 389 93 91
+41 31 389 92 29
anita.hiltbrunner@etop-eu.org
rudolf.maibach@etop-eu.org
susanne.roux@etop-eu.org
marc.marbot@etop-eu.org
In collaboration with Biodesix, Inc.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
3/38
Protocol Signature Page
ETOP 3-12
EMPHASIS-lung
A randomized phase III trial of erlotinib versus docetaxel in patients with
advanced squamous cell non-small cell lung cancer who failed first line
platinum based doublet chemotherapy stratified by VeriStrat Good vs
VeriStrat Poor
Approved by:
Egbert Smit
Trial Co-Chair
__________signature on file__________________________
Solange Peters
Trial Co-Chair
__________signature on file__________________________
Rolf Stahel
Chairman of ETOP
__________signature on file__________________________


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
4/38
Principal Investigator Protocol Signature Page
ETOP 3-12
EMPHASIS-lung
A randomized phase III trial of erlotinib versus docetaxel in patients with
advanced squamous cell non-small cell lung cancer who failed first line
platinum based doublet chemotherapy stratified by VeriStrat Good vs
VeriStrat Poor
I have read the protocol and agree that it contains all necessary details for conducting this
trial. I will conduct the trial as outlined in the following protocol and in compliance with
International Conference on Harmonization (ICH) Good Clinical Practices (GCP). I will
provide copies of this protocol version, furnished to me by ETOP, to all physicians
responsible to me who participate in this trial. I will discuss this material with them to
assure that they are fully informed regarding the study drugs and VeriStrat, and the conduct
of the trial. I agree to keep accurate records on all patient information including patient's
informed consent statement, VeriStrat kit and sample shipment and all other information
collected during the trial for a minimum period of 15 years after trial closure.
Printed Name of Principal Investigator:
___________________________________________
Printed Name and Place of Institution:
___________________________________________
_____________________________________________________ ______________
Signature
Date


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
5/38
TABLE OF CONTENTS
Section
Page
1.
Protocol Summary............................................................................................................7
2.
Trial Design and Schedule..............................................................................................12
2.1.
Graphical trial design ..............................................................................................12
2.2.
Trial schedule of events...........................................................................................13
3.
List of abbreviations .......................................................................................................14
4.
Background and Rationale..............................................................................................15
4.1.
Non-small cell lung cancer......................................................................................15
4.2.
Treatment of non-small cell lung cancer.................................................................15
4.3.
VeriStrat Test ..........................................................................................................16
4.4.
Hypothesis for a prospective evaluation .................................................................16
5.
Objectives and endpoints................................................................................................17
5.1.
Primary objective ....................................................................................................17
5.2.
Secondary objectives...............................................................................................17
5.3.
Primary endpoint.....................................................................................................17
5.4.
Secondary endpoints ...............................................................................................17
6.
Trial design, duration and termination ...........................................................................17
7.
Patient selection..............................................................................................................18
7.1.
Inclusion criteria......................................................................................................18
7.2.
Exclusion criteria.....................................................................................................19
8.
Patient Randomization....................................................................................................19
8.1.
Randomization principles........................................................................................19
8.2.
Randomization steps ...............................................................................................20
9.
Central VeriStrat testing.................................................................................................20
9.1.
Collection of the serum sample for VeriStrat..........................................................20
9.2.
Shipping of samples to central laboratory...............................................................20
9.3.
Central laboratory evaluation..................................................................................20
9.4.
Indeterminate VeriStrat result.................................................................................21
9.5.
VeriStrat test not feasible........................................................................................21
10.
Trial treatments ...........................................................................................................21
10.1.
Sequence of treatments........................................................................................21
10.2.
Dosage, administration and schedule ..................................................................21
10.3.
Precautions...........................................................................................................22
10.4.
Concomitant treatment ........................................................................................22
10.5.
Treatment delay and dose modification for toxicity............................................22
10.6.
Treatment duration ..............................................................................................23
11.
Safety ..........................................................................................................................24
11.1.
Docetaxel.............................................................................................................24
11.2.
Erlotinib...............................................................................................................25
12.
Adverse events and reporting......................................................................................27
12.1.
Adverse event reporting.......................................................................................27
12.2.
Definition of Serious Adverse Event (SAE)........................................................28
12.3.
Definition of Serious Adverse Drug Reaction (SADR) ......................................29
12.4.
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR)........29
12.5.
Reporting SAEs ...................................................................................................29
13.
Endpoints definition....................................................................................................30


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
6/38
13.1.
Progression free survival .....................................................................................30
13.2.
Overall survival ...................................................................................................30
13.3.
Objective response...............................................................................................30
13.4.
Disease control ....................................................................................................30
13.5.
Toxicities of treatment.........................................................................................30
14.
Trial procedures ..........................................................................................................30
14.1.
Trial stages...........................................................................................................30
14.2.
Baseline evaluations (within 14 days prior to registration).................................31
14.3.
Before Randomization.........................................................................................31
14.4.
Routine evaluations before and during trial treatment ........................................31
14.5.
Tumor evaluations during treatment....................................................................32
14.6.
Evaluations in the follow-up phase before progression.......................................32
14.7.
Evaluations at progression...................................................................................32
14.8.
End of treatment visit ..........................................................................................32
14.9.
Evaluations after progression ..............................................................................32
15.
Case report forms and documentation ........................................................................33
15.1.
Case report forms schedule..................................................................................33
16.
Statistical considerations.............................................................................................33
16.1.
Primary objective.................................................................................................34
16.2.
Secondary objective.............................................................................................34
16.3.
Sample size determination...................................................................................34
16.4.
Evaluation of primary and secondary objectives.................................................35
17.
Criteria for termination of the trial..............................................................................35
17.1.
Discontinuation of protocol treatment for individual patients.............................35
17.2.
General criteria for termination of the trial .........................................................36
18.
Ethics approval procedures and Patient Informed Consent........................................36
18.1.
Ethical Review Board/Ethics Committee............................................................36
18.2.
Regulatory approval procedures..........................................................................36
18.3.
Informed consent .................................................................................................37
18.4.
Confidentiality.....................................................................................................37
18.5.
Duration of study.................................................................................................37
19.
Governance and administrative issues........................................................................37
19.1.
Steering Committee.............................................................................................37
19.2.
Publication...........................................................................................................37
19.3.
Clinical trial insurance.........................................................................................37
20.
References...................................................................................................................37
Appendices:
1. Template for patient information and informed consent form
2. RECIST criteria V1.1
3. NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4
4. ETOP Publication Policy


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
7/38
1.
Protocol Summary
A randomized phase III trial of erlotinib versus docetaxel in patients with
advanced squamous cell non-small cell lung cancer who failed first line
platinum based doublet chemotherapy stratified by VeriStrat Good vs
VeriStrat Poor
Rationale:
In the Western world lung cancer remains the first cause of cancer related deaths in men and
is surpassing the deaths due to breast cancer in women. About 20% of non-small cell lung
cancer (NSCLC) patients present with localized disease amenable to therapy with curative
intent, while the remaining patients suffer from advanced disease for which treatment with
palliative intent is delivered. Platinum containing chemotherapy has become the cornerstone
of treatment for these patients and is associated with modest prolongation of life span and
improvement of quality of life (QoL). Approximately 25-30% of patients will show a major
response and 40% will have disease stabilization for some time. However, inevitably these
patients will experience tumor progression and qualify for second line treatments.
Based on data from phase III trials showing superior survival with chemotherapy as
compared to best supportive care (BSC), equal therapeutic efficacy of evaluated drugs, and
no benefit of drug combinations as compared to monotherapy, single agent chemotherapy is
the standard of care for patients with relapsed NSCLC following platinum based, first line
chemotherapy(1). Several agents are now approved for use as second line treatment in
advanced NSCLC.
The first agent to enter the second line arena was docetaxel. A phase III trial led by
Canadian investigators randomized 104 patients with relapsed advanced NSCLC to either
docetaxel or BSC. A survival advantage for the docetaxel treated patients was observed (7.0
months vs 4.6 months, p = 0.010, log-rank test). Also, progression free survival was
superior in the docetaxel arm. In addition, QoL measures all favored treatment with
docetaxel. An analysis per histology was not provided (2).
Next, erlotinib was found to produce superior patient outcomes as compared to BSC in the
same patient population in 2nd or 3rd line of treatment in the BR21 study (3). Here, 731
patients were randomized in a 2:1 fashion to treatment with erlotinib or placebo. Both
overall survival (OS) and progression free survival (PFS) were significantly longer in the
active treatment arm (6.7 vs 4.7 months and 2.2 vs 1.8 months, respectively). Although
subgroup analysis favored patients with adenocarcinoma or those who never smoked, the
treatment effects did extend to patients having squamous cell carcinoma.
Currently there are no accepted baseline criteria to allow choosing between docetaxel or
erlotinib, except for the presence of an activating epidermal growth factor receptor (EGFR)
mutation, provided patients did not receive an EGFR-tyrosine kinase inhibitor (TKI) as first
line therapy. In fact, the INTEREST trial that randomized NSCLC patients with all
histologies between gefitinib and docetaxel in the second line setting, showed no difference
in PFS and OS in the EGFR wild-type (WT) population. In a subgroup analysis, patients


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
8/38
with squamous cell carcinomas did not present any difference in PFS or OS between both
treatment groups.
One way to move forward is to select patients for treatment based upon (predictive)
biomarkers. The prime example of a predictive biomarker is the presence of an activating
EGFR mutation, as patients with this genetic aberration respond dramatically to EGFR-
TKIs. Unfortunately, the incidence of activating EGFR mutations in patients with squamous
cell lung cancer is very low, rendering this biomarker of little use for most of these patients.
Recently, a blood-based proteomic test, VeriStrat®, that appears to be both predictive and
prognostic for outcome in patients with NSCLC, has become available. VeriStrat was
developed and validated in a multi-institutional study of advanced NSCLC patients treated
with gefitinib (4). The VeriStrat algorithm was developed using a training set of pre-
treatment serum samples from patients who experienced either long term stable disease or
early progression on gefitinib therapy. Mass spectra from these patients’ serum samples
were used to define eight mass spectrometry (MS) features (i.e. peaks), differentiating these
two outcome groups. An algorithm utilizing these features and based on a k-nearest
neighbors (KNN) classification scheme was created and its parameters were optimized
using additional spectra from the training set. VeriStrat assigns each sample a “good” (VSG)
or “poor” (VSP) label. In approximately 2% of cases, an unequivocal label cannot be
assigned and an indeterminate classification is reported. The test was validated in a blinded
fashion in two independent cohorts of patients who were treated with gefitinib or erlotinib.
These studies confirmed that patients classified as VSG had better PFS and OS outcome
than patients classified as VSP (hazard ratio [HR] of death=0.47, p=0.0094 in one cohort;
HR=0.33 and p=0.0007 in the other). VeriStrat demonstrated outstanding reproducibility,
confirmed in the comparative analysis between data obtained on identical samples in two
different institutions (Vanderbilt University and University of Colorado, USA). The overall
concordance of the classification results was 97% (4). Retrospective analysis of VeriStrat
performed on available serum samples of patients from the randomized NCIC CTG BR.21
trial of erlotinib versus placebo confirmed the above results for the treatment arms(5). In
this last study it was found that patients with the VSG classification had a significantly
longer overall survival under erlotinib as compared to placebo (10.5 vs 6.6 months). VSG
patients showed a better OS than VSP patients in the group treated with erlotinib (10.5 vs
4.0 months), independent of EGFR mutation status. There was a significant prognostic
component indicating that VeriStrat measures an innate property of the disease. Further, the
BR.21 sub-study showed a strong, statistically significant correlation of VeriStrat
classification with objective response rate (ORR) and disease control rate (DCR) in
evaluable patients in the erlotinib arm (Fisher exact test 2-sided p=0.0022 for ORR and
p<0.001 for DCR).
In the initial evaluation of VeriStrat it was found that patients with relapsed squamous cell
lung carcinoma and designated to the VSG population had an unexpectedly favorable
outcome following treatment with gefitinib. The test does not seem to discriminate between
patients who receive cytotoxic chemotherapy, including standard treatment with standard
doses of docetaxel (Biodesix, data on file), as both VeriStrat groups presented similar
survival outcomes for chemotherapy.
Thus, one rational approach for using the VeriStrat test is a trial design where patients with
relapsed squamous cell lung cancer in both strata (VSG and VSP) are randomized between
an EGFR-TKI and chemotherapy. As both erlotinib and docetaxel are currently approved
for this indication, these drugs will be used in the proposed trial.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
9/38
The VeriStrat signature is expected to be able to predict the benefit of treatment with
erlotinib vs docetaxel as measured by a significant improvement in median PFS for VSG
patients with squamous cell advanced NSCLC, when treated with an EGFR-TKI, and
without significant improvement in VSP patients who receive the same treatment.
Objectives:
1. Explore the predictive ability of the VeriStrat signature, by testing for interaction
between treatment arms (Arm A: erlotinib vs Arm B: docetaxel) and VeriStrat status
(VSG vs VSP) using as outcome progression free survival.
2. Explore whether treatment with erlotinib provides progression free survival benefit
as compared to docetaxel in the VSG group.
3. Compare progression free survival in the two treatment arms (Arm A: erlotinib vs
Arm B: docetaxel) in the VSP group.
4. Explore the prognostic ability of the VeriStrat signature by testing for an overall
difference in progression free survival between the two VeriStrat groups (in case of
no significant interaction).
5. Explore the predictive ability of the VeriStrat signature using the secondary
measures of clinical efficacy including overall survival, objective response rate, and
disease control rate.
6. Compare overall survival, objective response rate and disease control rate between
treatment groups separately in the VSG and VSP groups.
7. Explore the prognostic ability of the VeriStrat signature by testing for an overall
difference in overall survival, objective response rate and disease control rate
between the two VeriStrat groups (in case of no significant interaction).
8. Assess the safety and the tolerability of the two treatments separately in each
VeriStrat group and overall.
Endpoints:
1. Primary endpoint: Progression free Survival
2. Secondary endpoints:
a.
Overall Survival
b.
Toxicities of treatment
c.
Objective Response
d.
Disease control
Patient selection criteria:
Patients are eligible only if they meet all of the following criteria within 14 days prior to
registration, except where otherwise noted:
1. Histologically or cytologically confirmed locally advanced stage IIIB, not amenable
to radical radiotherapy, or metastatic stage IV non-small cell lung cancer (NSCLC)
of predominant squamous subtype, according to the 7th edition of the TNM
classification, including M1a (separate tumor nodule in a contralateral lobe, tumor
with pleural nodules or malignant pleural or pericardial effusion) and/or M1b
(distant metastasis).


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
10/38
2. Progressive disease upon or after previous chemotherapy including at least one line
of platinum-based chemotherapy.
3. Measurable or evaluable disease according to RECIST v1.1 (Appendix 2).
4. ECOG PS 0-2.
5. Age ≥18 years.
6. Adequate organ function, including:
Adequate bone marrow reserve: ANC > 1.5 x 109/L, platelets > 100 x 109/L.
Hepatic: bilirubin <1.5 x ULN; AP, ALT < 3.0 x ULN; AP, ALT <5 x ULN
is acceptable in case of liver metastasis.
Renal: calculated creatinine clearance > 40 ml/min based on the Cockroft and
Gault formula.
7. Signed and dated informed consent form.
8. Male and female patients with reproductive potential must use an approved
contraceptive method, during the trial and 12 months thereafter. Female patients
with reproductive potential must have a negative pregnancy test within 7 days prior
to study registration.
9. Estimated life expectancy >12 weeks.
10. Patient compliance and geographical proximity that allow adequate follow-up.
Patients will be excluded if they meet any of the following criteria:
1. Evidence of other medical condition which would impair the ability of the patient to
participate in the trial or might preclude therapy with trial drugs (e.g. unstable or
uncompensated respiratory, cardiac, hepatic or renal disease, active infection,
uncontrolled diabetes mellitus).
2. Previous treatment with any EGFR-TKI or docetaxel.
3. Documented brain metastases unless the patient has completed local therapy for
central nervous system metastases and has been off corticosteroids for at least 14
days prior to study registration.
4. Documented presence of activating EGFR mutations, if the patient was tested for
EGFR mutations.
5. Previous malignancy within the past 5 years with the exception of adequately treated
cervical carcinoma in situ, breast cancer in situ or localized non-melanoma skin
cancer.
6. Psychiatric disorder precluding understanding of information on trial related topics,
giving informed consent, or interfering with compliance for oral drug intake.
7. Concurrent treatment with experimental drugs or other anti-cancer therapy treatment
in a clinical trial within 21 days prior to study registration.
8. Known hypersensitivity to trial drugs or hypersensitivity to any other component of
the trial drugs or any concomitant drugs contraindicated.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
11/38
Trial design and treatments administered:
Patients in both VeriStrat strata, i.e., VSG and VSP, will be randomized to receive erlotinib
or docetaxel. The investigative site and their personnel will be blinded to the result of the
VeriStrat test.
Arm A: erlotinib 150 mg/day p.o. continuously with 21 days cycle
Arm B: docetaxel 75 mg/m2 as an IV infusion Day 1 every 21 days
Dose adjustments: Dose adjustments for assigned treatment may be made according to
Sections 10.2 and 10.5, and the judgment of the treating physician.
Duration of treatment: Treatment with erlotinib or docetaxel will be continued until
progressive disease (PD) occurs, documented by clinical or radiographic progression. In
case of unacceptable toxicity patients will be withdrawn from protocol therapy although
study follow-up will continue for collection of progression and survival data as described in
Section 10.6.
Concomitant treatments: The protocol
allows
patients
to
receive the
following
concomitant treatments:
1. Antiemetic therapy at the investigator’s discretion.
2. Full supportive-care therapies during the study according to local standards of care.
3. Palliative radiation therapy.
Restricted treatments: Any disease progression requiring other forms of specific anti-
tumor therapy will be cause for early discontinuation of study therapy, but patients will
continue to be followed for progression and survival. No other anticancer therapy,
immunotherapy, hormonal cancer therapy, curative radiation, or experimental medications
will be permitted while the patients are on trial treatment.
Recruitment period: 18 months
Sample Size: 500


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
12/38
2.
Trial Design and Schedule
2.1.
Graphical trial design
Stage IIIB (non
amenable to radical
radiotherapy) or
stage IV squamous
NSCLC
VeriStrat
Analysis
Strata I &
II
VeriStrat
Good & PS
level
Strata III
& IV
VeriStrat
Poor & PS
level
RANDOMIZATION 1:1
Regimen B
Docetaxel in standard dose.
Until progression (clinical or
radiological) or unacceptable toxicity
Regimen A
Erlotinib in standard dose.
Until progression (clinical or
radiological) or unacceptable toxicity
Stratification Factors

Performance Status
(ECOG PS 0-1 vs 2)

VeriStrat Status
(VSG vs VSP)
R E G I S T R A T I O N


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
13/38
2.2.
Trial schedule of events
Screening
Treatment period5
At
PD
End of
treatment
Follow-
up
Timepoint
Up to 14 days before
Registration (except
where noted)
Cycle 1
day 1
Cycle 2
day 1
Cycle 3
day 1
Even cycle
4/6/8…
day 1
Odd cycle
5/7/9…
day 1
30-45 days
after last
dose
every 3
months
Informed consent
X
VeriStrat blood sample
X
Demographics
X
Medical history
X
Concomitant medication
X
Physical examination / PS
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
Complete blood count + diff.
X
X
X
X
X
X
X
Blood chemistry
X
X
X
X
X
X
X
Pregnancy test
X1
Tumor assessment2
X3
X
X
X
X
Adverse events
X
X
X
X
X
X
X4
Survival6
X
1.
Female patients with childbearing potential must have a negative serum or urin pregnancy test within 7 days prior to study registration. Non-childbearing
potential is defined as surgically sterile or post-menopausal (defined as ≥24 months since last menses).
2.
Thoraco-abdominal CT scan; brain imaging (CT scan or MRI) if clinical suspicion of brain metastasis. To be done within 2 weeks prior to registration
and within 5 days prior to cycles 3, 5, 7, …
3.
May be performed within 4 weeks prior to treatment start, regardless of registration date.
4.
For patients who cease study treatment for reasons other than progression, tumor assessment should be performed 30 (to 45) days after stop of study
treatment and every 6 weeks until documented progression.
5.
Treatment must start within 7 days after randomization.
6.
Survival status may be collected by patient visit or documented phone call.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
14/38
3.
List of abbreviations
ALT
alanine transaminase
ANC
absolute neutrophil count
AP
alkaline phosphatase
AST
aspartate transaminase
BSC
best supportive care
DCR
disease control rate
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
EGFR
epidermal growth factor receptor
GCP
Good Clinical Practice
HR
hazard ratio
ICH
International Conference on Harmonization
LLN
lower limit of normal lab value
KNN
k-nearest neighbor’s classification scheme
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PFS
progression free survival
PS
performance status
RDE
remote data entry
RECIST
Response Evaluation Criteria In Solid Tumors
TKI
tyrosine kinase inhibitor
QoL
Quality of Life
ULN
upper limit of normal lab value
VSG
VeriStrat Good
VSP
VeriStrat Poor
WT
wild type


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
15/38
4.
Background and Rationale
4.1.
Non-small cell lung cancer
In the Western world lung cancer remains the first cause of cancer related deaths in men and
is surpassing the deaths due to breast cancer in women. About 20% of NSCLC patients
present with localized disease amenable to therapy with curative intent, while the remaining
patients suffer from advanced disease for which treatment with palliative intent is delivered.
Platinum containing chemotherapy has become the cornerstone of treatment for these
patients; it is associated with modest prolongation of life span and improvement of QoL.
Approximately 25-30% of patients will show a major response and 40% will have disease
stabilization for some time. However, inevitably these patients will experience tumor
progression and qualify for second line treatments.
4.2.
Treatment of non-small cell lung cancer
Based on data from phase III trials showing superior survival with chemotherapy as
compared to best supportive care, equal therapeutic efficacy between evaluated drugs, and
no benefit of drug combinations as compared to monotherapy, single agent chemotherapy is
the standard of care for patients with relapsed NSCLC following platinum based, first line
chemotherapy (1). Several agents are now approved for use as second line treatment in
advanced NSCLC.
The first agent to enter the second line arena was docetaxel. A phase III trial led by
Canadian investigators randomized 104 patients with relapsed advanced NSCLC to either
docetaxel or BSC. A survival advantage for the docetaxel treated patients was observed (7.0
months vs 4.6 months, p = 0.010, log-rank test). Also, progression free survival was superior
in the docetaxel arm. In addition, QoL measures all favored treatment with docetaxel. An
analysis per histology was not provided (2).
Next, erlotinib was found to produce superior patient outcomes as compared to BSC in the
same patient population in 2nd or 3rd line of treatment in the BR21 study (3). Here, 731
patients were randomized in a 2:1 fashion to treatment with erlotinib or placebo. Both OS
and PFS were significantly longer in the active treatment arm (6.7 vs 4.7 months and 2.2 vs
1.8 months respectively). Although subgroup analysis favored patients with adenocarcinoma
or those who never smoked, the treatment effects did extend to patients having squamous
cell carcinoma.
Currently there are no accepted baseline criteria that allow choosing between docetaxel or
erlotinib, except for the presence of an activating EGFR mutation, provided patients did not
receive an EGFR-TKI as first line therapy. In fact, the INTEREST trial, randomizing
NSCLC patients with all histologies between gefitinib and docetaxel in the second line
setting, showed no difference in PFS and OS in the EGFR WT population. In subgroup
analysis, patients with squamous cell carcinomas did not present any difference in PFS or
OS between both treatment groups.
One way to move forward is to select patients for treatment based upon (predictive)
biomarkers. The prime example of a predictive biomarker is the presence of an activating
EGFR mutation, as patients with this genetic aberration respond dramatically to EGFR-
TKIs. Unfortunately, the incidence of activating EGFR mutations in patients with squamous
cell lung cancer is very low, rendering this biomarker of little use for most of these patients.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
16/38
4.3.
VeriStrat Test
Recently, a blood-based proteomic test, VeriStrat, that appears to be both predictive and
prognostic for outcome in patients with NSCLC, has become available. VeriStrat was
developed and validated in a multi-institutional study of advanced NSCLC patients treated
with gefitinib (4). The VeriStrat algorithm was developed using a training set of pre-
treatment serum samples from patients who experienced either long term stable disease or
early progression on gefitinib therapy. Mass spectra from these patients’ serum samples
were used to define eight MS features (i.e. peaks), differentiating these two outcome groups.
An algorithm utilizing these features and based on a k-nearest neighbors (KNN)
classification scheme was created and its parameters were optimized using additional
spectra from the training set. VeriStrat assigns each sample a “good” (VSG) or “poor”
(VSP) label. In approximately 2% of cases, an unequivocal label cannot be assigned and an
indeterminate classification is reported. The test was validated in a blinded fashion in two
independent cohorts of patients who were treated with gefitinib or erlotinib. These studies
confirmed that patients classified as VSG had better PFS and OS outcome than patients
classified as VSP (hazard ratio (HR) of death=0.47, p=0.0094 in one cohort; HR=0.33 and
p=0.0007 in the other). VeriStrat also demonstrated outstanding reproducibility, confirmed
in the comparative analysis between data obtained on identical samples in two different
institutions (Vanderbilt University and University of Colorado, USA). The overall
concordance of the classification results was 97% (4). Retrospective analysis of VeriStrat
performed on available serum samples of patients from the randomized NCIC CTG BR.21
trial of erlotinib versus placebo confirmed the above results for the treatment arms (5). In
this last study it was found that patients with the VSG classification had a significantly
longer overall survival under erlotinib as compared to placebo (10.5 vs 6.6 months). VSG
patients showed a better survival than VSP patients in the group treated with erlotinib (10.5
vs 4.0 months), independent of EGFR mutation status. There was a significant prognostic
component indicating that VeriStrat measures an innate property of the disease. Further, the
BR.21 sub-study showed a strong statistically significant correlation of VeriStrat
classification with ORR and DCR in evaluable patients in the erlotinib arm (Fisher’s exact
test 2-sided p=0.0022 for ORR and p=<0.001 for DCR).
In the initial evaluation of VeriStrat it was found that patients with relapsed squamous cell
lung carcinoma and designated to the VSG population had an unexpectedly favorable
outcome following treatment with gefitinib. The test does not seem to discriminate between
patients who receive cytotoxic chemotherapy, including standard treatment with standard
doses of docetaxel (Biodesix, data on file), as both VeriStrat groups present similar outcome
under chemotherapy.
Thus, one rational approach using the VeriStrat test is a trial design where patients with
relapsed squamous cell lung cancer in both strata (VSG and VSP) are randomized between
an EGFR-TKI and chemotherapy. As both erlotinib and docetaxel are currently approved
for this indication, these drugs will be used in the proposed trial.
4.4.
Hypothesis for a prospective evaluation
The VeriStrat signature will be able to predict the benefit of treatment with erlotinib vs
docetaxel measured by a significant improvement in median PFS for VSG patients with
squamous cell advanced NSCLC when treated with an EGFR-TKI, and without significant
improvement in VSP patients who receive the same treatment.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
17/38
5.
Objectives and endpoints
5.1.
Primary objective
Explore the predictive ability of the VeriStrat signature, by testing for interaction between
treatment arms (Arm A: erlotinib vs Arm B: docetaxel) and VeriStrat status (Good vs Poor)
using progression free survival as outcome.
5.2.
Secondary objectives
5.2.1.
Explore whether treatment with erlotinib provides progression free survival benefit
as compared to docetaxel in the VSG group.
5.2.2.
Compare progression free survival in the two treatment arms (Arm A: erlotinib vs
Arm B: docetaxel) in the VSP group.
5.2.3.
Explore the prognostic ability of the VeriStrat signature by testing for an overall
difference in progression free survival between the two VeriStrat groups (in case of
no significant interaction).
5.2.4.
Explore the predictive ability of the VeriStrat signature using the secondary
measures of clinical efficacy including overall survival, objective response rate,
and disease control rate.
5.2.5.
Compare overall survival, objective response rate and disease control rate between
treatment groups separately in the VSG and VSP groups.
5.2.6.
Explore the prognostic ability of the VeriStrat signature by testing for an overall
difference in overall survival, objective response rate and disease control rate
between the two VeriStrat groups (in case of no significant interaction).
5.2.7.
Assess the safety and the tolerability of the two treatments separately in each
VeriStrat group and overall.
5.3.
Primary endpoint
Progression free Survival. For definition, see Section 13.1.
5.4.
Secondary endpoints
5.4.1.
Overall Survival
5.4.2.
Toxicities of treatment
5.4.3.
Objective Response
5.4.4.
Disease Control
For definitions, see section 13.
6.
Trial design, duration and termination
The study is designed as a phase III trial to explore the differential activity of erlotinib vs
docetaxel in VSG vs VSP squamous cell NSCLC patients who relapsed after first line
platinum based chemotherapy. The primary endpoint of the study is PFS. Patients in both
VeriStrat strata, i.e. VSG and VSP, will be randomized to receive erlotinib or docetaxel, and
treatment must start within 7 days after randomization. The investigator will be blinded to
the result of the VeriStrat test.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
18/38
Patient accrual is expected to be completed within 18 months after first patient
randomization. The combined run in period, treatment and follow-up for PFS is expected to
extend the study duration to a total of 24 months (i.e., 6 months after the last patient is
randomized). All patients will be followed for survival status every 12 weeks thereafter,
until death, or up to 24 months after the last patient is randomized, at which time the study
will formally end.
The preparation of the study report is scheduled for 26 months after the first patient is
enrolled.
7.
Patient selection
Patients should only be selected and consented for screening if they fulfill the inclusion and
exclusion criteria in Sections 7.1 and 7.2, within 14 days prior to registration, except where
otherwise noted.
Written informed consent needs to be obtained prior to undertaking any study-specific
procedure, including blood collection for VeriStrat testing.
7.1.
Inclusion criteria
7.1.1.
Histologically or cytologically confirmed locally advanced stage IIIB, not
amenable to radical radiotherapy, or metastatic stage IV non-small cell lung cancer
(NSCLC) of predominant squamous subtype, according to the 7th edition of the
TNM classification, including M1a (separate tumor nodule in a contralateral lobe,
tumor with pleural nodules or malignant pleural or pericardial effusion) and/or
M1b (distant metastasis).
7.1.2.
Progressive disease upon or after previous chemotherapy including at least one line
of platinum-based chemotherapy.

Adjuvant platinum-based chemotherapy can be considered as platinum-based
chemotherapy line if administration ended in the 6 months before registration.

Platinum-based chemotherapy combined with definitive radiotherapy can be
considered as platinum-based chemotherapy line if administration ended in the
6 months before registration.
7.1.3.
Measurable or evaluable disease according to RECIST v1.1 (Appendix 2).
7.1.4.
ECOG performance status 0-2.
7.1.5.
Age ≥18 years.
7.1.6.
Adequate organ function, including:

Adequate bone marrow reserve: ANC > 1.5 x 109/L, platelets > 100 x 109/L.

Hepatic: bilirubin <1.5 x ULN; AP, ALT < 3.0 x ULN; AP, ALT <5 x ULN is
acceptable in case of liver metastasis.

Renal: calculated creatinine clearance > 40 ml/min based on the Cockroft and
Gault formula.
7.1.7.
Signed and dated informed consent form.
7.1.8.
Male and female patients with reproductive potential must use an approved
contraceptive method, if appropriate. Female patients with reproductive potential


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
19/38
must have a negative serum or urin pregnancy test within 7 days prior to study
registration. Non-reproductive potential for females is defined as surgically sterile
or post-menopausal defined as ≥24 months since last menses. Male patients are
considered to have reproductive potential unless they are surgically sterile. Not
eligible: Women who are in the period of lactation.
7.1.9.
Estimated life expectancy >12 weeks.
7.1.10. Patient compliance and geographical proximity that allow adequate follow-up.
7.2.
Exclusion criteria
7.2.1.
Evidence of other medical conditions which would impair the ability of the patient
to participate in the trial or might preclude therapy with trial drugs (e.g. unstable or
uncompensated respiratory, cardiac, hepatic or renal disease, active infection,
uncontrolled diabetes mellitus).
7.2.2.
Previous treatment with any EGFR-TKI or docetaxel.
7.2.3.
Documented brain metastases unless the patient has completed local therapy for
central nervous system metastases and has been off corticosteroids for at least 14
days prior to registration.
7.2.4.
Documented presence of activating EGFR mutations, if patient was tested for
EGFR mutations.
7.2.5.
Previous malignancy within 5 years with the exception of adequately treated
cervical carcinoma in situ, breast cancer in situ or localized non-melanoma skin
cancer.
7.2.6.
Psychiatric disorder precluding understanding of information on trial related topics,
giving informed consent, or interfering with compliance for oral drug intake.
7.2.7.
Concurrent treatment with experimental drugs or other anti-cancer therapy
treatment in a clinical trial within 21 days prior to registration.
7.2.8.
Known hypersensitivity to trial drugs or hypersensitivity to any other component of
the trial drugs or any concomitant drugs contraindicated.
8.
Patient Randomization
8.1.
Randomization principles
This trial will use the web-based randomization and RDE (Remote Data Entry) system
called ETOPdata. Each participating center will access the system directly. Specific details
for randomization of patients are described in the “EMPHASIS-lung Procedures Manual”
which will be available on the ETOP website (www.etop-eu.org).
Block stratified randomization balanced by center using a minimization algorithm (6) will
be used in the study. Patients will be stratified based on VeriStrat status (VSG vs VSP) and
Performance Status (0-1 vs 2).


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
20/38
8.2.
Randomization steps
Complete the following steps to randomize a patient on this trial. Please consult the
EMPHASIS-lung Procedures Manual for detailed instructions.
Note that written informed consent needs to be obtained prior to undertaking any study-
specific procedures, including blood collection for VeriStrat testing.
8.2.1.
Screening: Verify eligibility and register the patient in the RDE facility by
completing the Identification Tab and the Eligibility Tab.
8.2.2.
VeriStrat Collection, Shipment, and Testing

Collect blood from patient and process to generate serum.

Spot serum onto the Serum Collection Card and label card with ETOPdata
assigned Patient ID.

Send serum sample card to Biodesix Inc.

Biodesix will enter results into RDE (results will not be visible to the
investigative staff). Upon generation of VeriStrat results, the RDE will send an
automatic confirmation email to the site.
8.2.3.
Randomization: After receipt of the VeriStrat confirmation, the investigator will
randomize the patient through the RDE according to the instructions in the
EMPHASIS-lung Procedures Manual as well as the ETOPdata User Manual. The
assigned treatment information will be displayed on the RDE screen and sent to the
investigator by email.
9.
Central VeriStrat testing
As described in Section 8.1.2, a serum sample from each patient must be collected prior to
randomization, and must be sent to Biodesix, the central laboratory for VeriStrat testing.
The results of the VeriStrat test will be used only for the purposes of randomization. The
investigative site and their personnel will be blinded to the result of the VeriStrat test.
9.1.
Collection of the serum sample for VeriStrat
Upon activation, the center will receive EMPHASIS-lung VeriStrat kits containing blood
collection materials, including the Serum Collection Card, labels, and shipping materials.
After obtaining signed informed consent from the patient, 3.5ml of venous blood will be
collected into the SST tube provided. Serum will be processed and shipped according to the
instructions in the kit (see the EMPHASIS-lung Procedures Manual for more information).
9.2.
Shipping of samples to central laboratory
Within 24 hours of collection, the serum sample will be shipped to Biodesix Inc. following
the kit instructions and the EMPHASIS-lung Procedures Manual, and using the pre-printed
airbills provided.
9.3.
Central laboratory evaluation
Within 72 hours of receipt of the serum sample, the central laboratory will record the result
of the VeriStrat test in the RDE system. As soon as the result is in the system, the site will


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
21/38
be notified and the patient is ready to be randomized, see the EMPHASIS-lung Procedures
Manual for details.
9.4.
Indeterminate VeriStrat result
In approximately 2% of the cases the VeriStrat Test result will be indeterminate, and the
patient cannot be allocated into either the VSG or the VSP group. These patients will also be
randomized and followed according to protocol. They will not contribute in the interaction
analysis but their outcome will be reported.
9.5.
VeriStrat test not feasible
In the rare case that a sample cannot be analyzed by Biodesix, the enrolling site will be
informed immediately by email and asked to redraw a new blood sample from the patient
for retesting. If the new sample cannot be analyzed, the patient is considered ineligible and
will not be randomized. No further information has to be entered into the ETOPdata System
for these patients.
10.
Trial treatments
Erlotinib and docetaxel are the drugs used in this trial. Both drugs are standard of care in
second line treatment of NSCLC and will be locally sourced and paid.
Drug therapy is to begin within 7 days after randomization.
10.1.
Sequence of treatments
Patients in both VeriStrat strata, i.e. VSG and VSP, will be randomized to receive erlotinib
or docetaxel. The investigative site and their personnel will be blinded to the result of the
VeriStrat test.
Arm A: erlotinib 150 mg/day p.o. continuously with 21 days cycle.
Arm B: docetaxel 75 mg/m2 as an IV infusion Day 1 every 21 days.
10.2.
Dosage, administration and schedule
10.2.1.
Docetaxel dose / route / regimen
Docetaxel is given 75 mg/m2 as an IV infusion Day 1 every 21 days.
All patients should be premedicated with oral corticosteroids such as dexamethasone 16 mg
per day (e.g., 8 mg BID) for 3 days starting 1 day prior to docetaxel administration in order
to reduce the incidence and severity of fluid retention as well as the severity of
hypersensitivity reactions.
In case of relevant toxicity, dose reductions are recommended to improve the tolerance
according to Section 10.5.
10.2.2.
Erlotinib dose / route / regimen
Erlotinib is started at a fixed oral dose of 150 mg per day.
Tablets should be taken at a fixed time each day and at least 1 hour before, or 2 hours after
the ingestion of food.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
22/38
No routine premedication (e.g. to prevent skin toxicity) is recommended for erlotinib.
Systemic or local tetracyclines, systemic or local corticosteroids and loperamide in case of
diarrhea are strongly recommended if significant toxicity occurs.
Smokers have reduced plasma levels and should be counseled for smoking reduction or
cessation, the dose of 150 mg must never be increased.
In case of relevant toxicity, dose reductions are recommended to improve the tolerance
according to Section 10.5.
10.3.
Precautions
Male and female patients with reproductive potential must use an approved contraceptive
method, if applicable during the trial treatment and 12 months thereafter.
Female patients are considered to have reproductive potential unless they are surgically
sterile or are post-menopausal and have not had menses for ≥24 months. Male patients are
considered to have reproductive potential unless they are surgically sterile.
10.4.
Concomitant treatment
The following treatments are allowed during the treatment phase of the trial:
1. Antiemetic therapy at the investigator’s discretion.
2. Full supportive-care therapies during the trial according to local standards of care.
3. Palliative radiation therapy for irradiating areas of metastasis that cannot be
managed adequately using systemic or local analgesics.
The following concurrent treatments are NOT allowed in either arm:
Other anticancer therapy, immunotherapy, hormonal cancer therapy, curative radiation, or
experimental medications are NOT allowed while the patient is on trial treatment.
Medications, herbal extracts or food which can interact with erlotinib (CYP3A4
inducers/inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir,
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice) are NOT allowed
while a patient randomized to erlotinib is on trial treatment.
10.5.
Treatment delay and dose modification for toxicity
Treatment with erlotinib or docetaxel will be continued until progression has been
documented by RECIST V1.1 (see appendix 2).
In case of toxicity, treatment interruptions should be used according to the following
sections. Docetaxel treatment delay or erlotinib dose interruptions are allowed as required,
for a maximum of 21 days per occasion. In case of unacceptable toxicity patients should be
withdrawn from trial treatment.
10.5.1.
Docetaxel
Patients who experience any of the following toxicities while on docetaxel should have
treatment withheld until resolution of the toxicity to grade ≤1 and then resumed at a dose of
55 mg/m2.

febrile neutropenia

neutrophils <500 cells/mm3 for > one week


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
23/38

other grade 3/4 non-hematological toxicities (except alopecia and fatigue).
Upon second occurrence of grade 3/4 non-hematological toxicities, docetaxel should be
permanently discontinued.
Patients who develop ≥grade 3 peripheral neuropathy should have docetaxel treatment
discontinued permanently.
10.5.2.
Erlotinib
Patients who experience any of the following toxicities while on erlotinib should have
treatment withheld until resolution of the toxicity to grade <1 and then resumed at a dose of
100mg/day.

Grade 4 acneiform rash

Grade 3/4 diarrhea despite maximal supportive care

Grade 3/4 creatinine elevation

Grade 3/4 elevations of hepatic tests (AP, ALT, bilirubin)

Any other grade 3/4 toxicities (except alopecia and fatigue)
Upon second occurrence of aforementioned toxicities, erlotinib should be permanently
discontinued.
In patients who develop an acute onset of new or progressive pulmonary symptoms, such as
dyspnea, cough or fever, treatment with erlotinib should be interrupted pending diagnostic
evaluation.
Erlotinib must be permanently discontinued in case of:

Clinically diagnosed interstitial Lung Disease (ILD)

Hepatic failure

Gastrointestinal perforation
10.6.
Treatment duration
Patients remain on trial treatment until one of the following events:

Documented progression according to RECIST v1.1 (Appendix 2).

Unacceptable toxicity

Any interruption of erlotinib of more than 3 weeks or treatment delay for
docetaxel of more than 3 weeks.

Medical condition that prevents further treatment

Significant protocol violation

Patient withdraws consent

Patient becomes pregnant
If study drug has been stopped for any reason, the patient enters the follow-up phase of the
trial. Regardless of whether or not the patient continues to receive trial treatment, the
“on treatment” schedule of evaluations must be followed until disease progression has
been confirmed. Patients who discontinue trial treatment should be assessed by the


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
24/38
investigator who must document the case on the appropriate case report form (CRF).
Remaining erlotinib tablets should be returned to the investigative site by the patient to
enable the staff to assess compliance.
11.
Safety
11.1.
Docetaxel
11.1.1.
Known adverse reactions
Very common (> 10%):

Allergy/immunology: Fever, chills, bronchospasm, anaphylactoid type
reactions, hypersensitivity reactions

Blood/bone marrow: Neutropenia, anemia, thrombocytopenia

Constitutional Symptoms: Anorexia, asthenia, fever

Dermatology/skin: Alopecia, erythema, nail disorders

Gastrointestinal: Stomatitis, diarrhea, nausea, vomiting

Infection: Infections, pharyngitis, rhinorrhea

Lymphatics: Peripheral edema, fluid retention

Neurology: Neuropathy, insomnia

Ocular/visual: Conjunctivitis, hyperlacrimation

Pain: Myalgia, Headache

Pulmonary: Dyspnea

Syndromes: Flu-like syndrome
Common (1-10%):

Cardiac general: Hypotension, tachycardia

Dermatology/skin: Dry skin, injection site reaction

Gastrointestinal: Constipation, abdominal pain, oesophagitis, dysphagia,
odynophagia

Hemorrhage/bleeding: Epistaxis

Infection: Oral thrush, febrile neutropenia

Metabolic/Laboratory: Elevated bilirubin, AP, AST, ALT

Neurology: Depression, loss of taste

Ocular/visual: Conjunctivitis

Pain: Arthralgia
11.1.2.
Warnings and precautions
Surveillance during 1st and 2nd treatment of docetaxel:


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
25/38
In case a docetaxel hypersensitivity reaction occurs despite premedication, it is very likely
to occur within a few minutes from start of the first or of the second infusion of docetaxel.
Therefore, during the 1st and the 2nd infusion, a careful evaluation of general sense of well-
being should be performed. Whenever possible, monitoring of blood pressure and heart rate
has to be performed by a physician or nurse for at least the first 10 minutes, so that
immediate intervention could occur in response to symptoms of an untoward reaction.
Facilities and equipment for resuscitation should be immediately available: antihistamine,
corticosteroids, aminophylline and epinephrine.
11.1.3.
Contraindications
Docetaxel is contraindicated in patients who have a history of severe hypersensitivity
reactions to docetaxel or to other drugs formulated with polysorbate 80. Docetaxel should
not be used in patients with neutrophil counts of <1500 cells/mm3.
11.2.
Erlotinib
11.2.1.
Known adverse reactions
The most common adverse reactions (>20%) in patients with non-small cell lung cancer are
rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, infection and vomiting.
11.2.2.
Interstitial Lung Disease (ILD)
There have been infrequent reports of serious ILD-like events (including fatalities) in
patients receiving erlotinib for the treatment of NSCLC, pancreatic cancer, or other
advanced solid tumors. In the single-agent study in patients with NSCLC, Study BR.21, the
incidence of serious ILD-like events (0.8%) was the same in the placebo and erlotinib
groups. No imbalance was noted in the incidence of serious ILD-like events in the 2 large
first-line NSCLC studies (Studies OSI2298g and BO16411), which utilized a standard
platinum-based regimen with or without erlotinib. In the combination study with
gemcitabine in patients with pancreatic cancer, Study PA.3, the incidence of ILD-like events
was 2.5% versus 0.4% in the erlotinib plus gemcitabine versus the placebo plus gemcitabine
groups, respectively. The overall incidence of ILD-like events in approximately 32,000
erlotinib-treated patients from all studies (including uncontrolled studies and studies with
concurrent chemotherapy) was approximately 1.1%. When cases from a postmarketing
surveillance study from Japan are excluded (N = 5860; 3.4% incidence), the incidence from
rest of world was approximately 0.6%. Some examples of reported diagnoses included
pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia,
interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory
distress syndrome, alveolitis, and lung infiltration. Most of the cases were associated with
confounding or contributing factors such as concomitant/prior chemotherapy, prior
radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary
infections.
In the event of acute onset of new or progressive, unexplained pulmonary symptoms such as
dyspnea, cough, and fever, erlotinib therapy should be interrupted pending diagnostic
evaluation. If ILD is diagnosed, erlotinib should be discontinued and appropriate treatment
instituted as necessary, including corticosteroids.
11.2.3.
Diarrhea
Diarrhea (sometimes severe) has occurred in patients receiving erlotinib and was usually
managed by loperamide; however, reduction in the dose of erlotinib was occasionally
necessary. In the event of severe or persistent diarrhea, nausea, anorexia, or vomiting


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
26/38
associated with dehydration, erlotinib therapy should be interrupted and appropriate
measures should be taken to intensively treat the dehydration. Since there have been rare
reports of hypokalemia and/or acute renal failure (including fatalities), secondary to severe
dehydration, renal function and serum electrolytes (including potassium) should be
monitored in this setting.
11.2.4.
Gastrointestinal Perforation
Patients receiving erlotinib are at increased risk of developing gastrointestinal perforation
(including fatalities), which was observed uncommonly. Patients receiving concomitant
anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who
have prior history of peptic ulceration or diverticular disease are at increased risk. Erlotinib
should be permanently discontinued in patients who develop gastrointestinal perforation.
11.2.5.
Renal Failure
Rare cases of acute renal failure or renal insufficiency have been reported (including
fatalities). Many of these cases have been associated with significant dehydration due to
diarrhea, vomiting, and/or anorexia. Other possible contributing factors have included
concomitant medications and/or chemotherapy, pre-existing renal disease, or other medical
conditions associated with renal disease. Periodic monitoring of renal function in patients
with these risk factors is recommended.
11.2.6.
Myocardial Infarction/Cerebral Vascular Accident
In the pancreatic cancer Study PA.3, small numerical imbalances in the incidence of stroke
and myocardial infarction (including fatalities) were noted in patients receiving erlotinib in
combination with gemcitabine. A causal relationship to erlotinib has not been established.
11.2.7.
Hepatotoxicity
Liver function abnormalities, including elevated serum ALT, AST, and/or bilirubin, have
been observed infrequently with single-agent erlotinib and occasionally with erlotinib in
combination with concomitant chemotherapy, e.g. gemcitabine. Rare cases of hepatic failure
(including fatalities) have been reported during postmarketing use of erlotinib. Confounding
factors for severe hepatic dysfunction have included pre-existing liver disease such as
cirrhosis, viral hepatitis, hepatocellular carcinoma, hepatic metastases, or concomitant
treatment with potentially hepatotoxic drugs. Periodic monitoring of liver function is
recommended. Erlotinib dosing should be interrupted if changes in liver function are severe.
11.2.8.
Patients with Hepatic Impairment
In a pharmacokinetic study (Study OSI-774-104) in patients with moderate hepatic
impairment (Child-Pugh B) associated with significant liver tumor burden, 10 of 15 patients
died on treatment or within 30 days of the last erlotinib dose. One patient died from
hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the
remaining 8 patients died from progressive disease. Six of the 10 patients who died had
baseline total bilirubin > 3 x ULN suggesting severe hepatic impairment. None of the deaths
were considered to be related to erlotinib treatment by the investigators. However, treatment
with erlotinib should be used with extra caution in patients with total bilirubin > 3 x ULN.
Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh B or C) should be
closely monitored during therapy with erlotinib. Erlotinib dosing should be interrupted or
discontinued if changes in liver function are severe such as doubling of total bilirubin and/or
tripling of transaminases in the setting of pretreatment values outside normal range.
11.2.9.
Thrombotic
Microangiopathy/Microangiopathic
Hemolytic
Anemia
with


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
27/38
Thrombocytopenia/Hemolytic Uremic Syndrome
Isolated reports of microangiopathic haemolytic anemia with thrombocytopenia and
hemolytic uremia syndrome (HUS) have been received. All patients received erlotinib and
gemcitabine concurrently. A causal relationship to erlotinib has not been established.
11.2.10.
Bullous and Exfoliative Skin Disorders
Bullous, blistering and exfoliative skin conditions have been reported, including very rare
cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some
cases were fatal. Erlotinib treatment should be interrupted or discontinued if the patient
develops severe bullous, blistering, or exfoliating conditions.
11.2.11.
Ocular Disorders
Very rare cases of corneal perforation or ulceration have been reported during use of
erlotinib. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis
sicca or keratitis have been observed with erlotinib treatment and may be potential risk
factors. Erlotinib therapy should be interrupted or discontinued if patients present with
acute/worsening ocular disorders such as eye pain.
Infrequent occurrences of keratitis have been observed during erlotinib treatment. Isolated
reports of uveitis and orbital cellulitis have been reported in patients receiving erlotinib
therapy.
Patients who develop irregular or excessive eyelash growth should be monitored for eye
symptoms such as eye pain. Careful removal of in-growing/abnormal/elongated eyelashes
should be considered if increased growth leads to scratching and/or irritation of the cornea.
Patients with a prior history of ocular disorders or additional identifiable risk factors should
be closely monitored by a physician.
12.
Adverse events and reporting
12.1.
Adverse event reporting
The main criterion for tolerability is the occurrence of toxicities and adverse events. The
severity and causality will be classified according to the NCI CTCAE Version 4. The
CTCAE is available for downloading on the internet, see Appendix 3
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html).
An adverse event (AE) is defined as any untoward medical occurrence that occurs from the
first dose of study medication until 30 days after the final dose, regardless of whether it is
considered related to a medication.
In addition, any known untoward event that occurs subsequent to the adverse event
reporting period that the investigator assesses as possibly related to the protocol treatment
should be considered an adverse event.
Symptoms of the targeted cancer (if applicable) should not be reported as adverse events.
The adverse event severity grade provides a qualitative assessment of the extent or intensity
of an adverse event, as determined by the investigator or as reported by the subject. The
severity grade does not reflect the clinical seriousness of the event, only the degree or extent
of the affliction or occurrence (e.g. severe nausea, mild seizure), and does not reflect the
relationship to study drug.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
28/38
Severity grade for other adverse events not covered in the toxicity grading scale:
1 = Grade 1
Mild
2 = Grade 2
Moderate
3 = Grade 3
Severe
4 = Grade 4
Life-threatening
5 = Grade 5
Fatal
Note:
Report the highest grade observed within one period.
Baseline symptoms will be recorded on the CRF and will continue to be
followed up during treatment.
Laboratory abnormalities for non-safety parameters will be documented on the
Adverse Event Form only for grades 3 and higher.
AEs should not be reported in a narrative description.
12.2.
Definition of Serious Adverse Event (SAE)
12.2.1.
SAEs during trial treatment
An SAE is defined in general as any undesirable medical occurrence/adverse drug
experience that occurs during or within 30 days after stopping study treatment and which, at
any dose, results in any of the following:
is fatal (any cause),
life-threatening,
requires or prolongs inpatient hospitalization,
results in persistent or significant disability/incapacity,
is a congenital anomaly or birth defect,
is a secondary malignancy,
requires significant medical intervention.
Second (non-NSCLC) malignancies are always considered SAEs, no matter when they are
diagnosed. These events should be reported on the Serious Adverse Event Forms.
Other significant/important medical events which may jeopardize the patient are also
considered serious adverse events.
Serious also includes any other event that the investigator or the ETOP Safety Office judges
to be serious or which is defined as serious by the regulatory agency in the country in which
the event occurred.
An unexpected adverse event is one that is not listed as a known toxicity in the summary of
product characteristics.
A related adverse event is one for which the investigator assesses that there is a reasonable
possibility that the event is related to the drug. All adverse events judged as having a
reasonable suspected causal relationship to the trial medication qualify as adverse reactions.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
29/38
Events not considered to be serious adverse events are hospitalizations occurring under the
following circumstances:
elective surgery;
occur on an outpatient basis and do not result in admission (hospitalization <
24h);
are part of the normal treatment or monitoring of the studied treatment;
progression of disease.
12.2.2.
SAEs after end of trial treatment
During the follow-up phase (starting 30 days after end of trial treatment), the following
events have to be reported as SAE:
fatal, life-threatening and other medically significant events possibly, probably
or definitely related to late effects of trial treatment
disabling events
second primary cancer
congenital anomaly
pregnancy
In the case of pregnancy (involving a treated female or male patient) occurring during trial
treatment or within 1 year after treatment discontinuation, the investigator shall immediately
notify the ETOP Safety Office by completing the pregnancy reporting form. The
investigator shall ensure that the case is followed up to the end of the pregnancy and supply
a final report on the outcome.
12.3.
Definition of Serious Adverse Drug Reaction (SADR)
SADRs are all SAEs considered to be related (possibly, probably, definitely) to the trial
treatment.
12.4.
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR)
A SUSAR is a serious adverse reaction that is assessed as unexpected on the basis of the
applicable
Swiss
product
information
and/or
the
European
summary
of
product
characteristics.
12.5.
Reporting SAEs
Any SAE must be reported by submitting the completed SAE Initial Report Tab in the RDE
system within 24 hours.
Submission is done via the electronic data capture system, or in case of unavailability, by
sending the paper version of the SAE form by fax to the ETOP Safety Office:
+41 31 389 92 29
The SAE outcome must be reported within 14 days after onset by completing the SAE
Follow-up Report Tab. In case the SAE is reported as ongoing after 14 days, the follow-up
report has to be submitted again with the final outcome.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
30/38
The ETOP Safety Office will forward each SAE to the trial chairs and notify principal
investigators of any SADR meeting the criteria for expedited reporting (SUSAR) within the
timelines specified in GCP.
The local Ethics committee must be informed by the principal investigator about local
SAEs.
The ETOP Safety Office will inform appropriate persons about all SAEs related to trial
medication (per either investigator or ETOP Safety Office review) within 24 hours of
receipt.
The ETOP Safety Office will record the SAE and prepare a periodic summary report of all
SAEs received. Principal Investigators will receive the summary report on a regular basis.
13.
Endpoints definition
13.1.
Progression free survival
This is the primary endpoint. It is defined as the time from the date of randomization until
documented progression or death without documented progression.
13.2.
Overall survival
Defined as time from the date of randomization until death from any cause.
13.3.
Objective response
Objective response is defined as best overall response (CR or PR) across all assessment
time-points according to RECIST Criteria 1.1 (Appendix 2), during the period from
randomization to termination of trial treatment.
13.4.
Disease control
Disease control is defined as achieving objective response or stable disease for at least 6
weeks.
13.5.
Toxicities of treatment
Adverse events classified according to NCI CTCAE version 4.
14.
Trial procedures
This section gives an overview of procedures, clinical and laboratory evaluations and
follow-up investigations.
14.1.
Trial stages
The trial consists of the following stages:
Screening: the screening period must occur no longer than 14 days before
registration in the RDE system. Baseline evaluations must be done within 14
days prior to registration. Please consult the EMPHASIS-lung procedures
manual for more information.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
31/38
VeriStrat Testing: The serum for the VeriStrat testing has to be collected and
sent to Biodesix within 3 working days after registration and
before
randomization.
Treatment phase: Drug therapy is to begin within 7 days of randomization.
End of treatment will be the date of the end of treatment visit that will occur 30 -
40 days following the last dose of study drug.
Follow-up period: every 3 months following end of treatment visit until death,
patients will be followed up to document outcome. Between end of treatment
and progression, the visit schedule needs to follow the one corresponding to the
treatment phase, see section 14.6.
14.2.
Baseline evaluations (within 14 days prior to registration)
Medical history including symptoms, smoking history, medications, co-
morbidities and allergies.
Physical examination including blood pressure [mmHg], ECOG performance
status (see definition in EMPHASIS-lung procedures manual), and body weight
[kg] and height [cm].
Hematology: hemoglobin, neutrophils, platelets.
Renal function: serum creatinine and creatinine clearance calculated according
to Cockroft-Gault.
Hepatic function: ALT, AP, Bilirubin.
Serum or urin pregnancy test for women of reproductive potential, within 7 days
prior to registration.
CT scan of thorax and abdomen, within 2 weeks before registration, with i.v.
contrast (alone or in combination with PET) to determine measurable disease
according to RECIST v1.1 (at least one lesion outside of irradiated areas that can
be measured in at least one dimension as ≥10 mm, or ≥15 mm in case of lymph
nodes). In the presence of clinically suspected metastases outside of these fields,
additional imaging of the affected body part is recommended.
CT scan of brain is not mandatory and only recommended in case of clinically
suspected brain metastasis.
14.3.
Before Randomization
For VeriStrat testing collect, process and ship serum sample according instructions in the
kits and in the EMPHASIS-lung Procedures Manual.
14.4.
Routine evaluations before and during trial treatment
On day 1 of every 3-week treatment cycle:
Recording of symptoms / adverse events
Physical examination including blood pressure, performance status, and body
weight
Hematology: hemoglobin, neutrophils, platelets


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
32/38
Serum creatinine
Hepatic function: ALT, AP, Bilirubin
14.5.
Tumor evaluations during treatment
These evaluations will occur prior to the start of odd cycles (3, 5, 7, 9, ..) until progression.
They should be performed within 5 days before the start of the subsequent cycle:
CT thorax and abdomen
14.6.
Evaluations in the follow-up phase before progression
Patients who discontinue treatment before progression should have the following
assessments 30-45 days after study treatment stop and every 6 weeks thereafter:
Physical examination
CT thorax and abdomen (plus further imaging, repeating former disease
evaluation imaging techniques, if applicable)
Documentation of further treatments
14.7.
Evaluations at progression
Each patient will receive trial treatment until documented progression. At progression, do
the following:
CT thorax and abdomen, document progression on the respective CRF
Documentation of further treatments
14.8.
End of treatment visit
At the end of the trial treatment and irrespective of the reason for stopping treatment, a
post treatment visit at the center is to be scheduled after 30 to 45 days following last
treatment day. The following procedures should be performed:
Recording of symptoms
Physical examination including blood pressure
Hematology: hemoglobin, neutrophils, platelets
Hepatic function: ALT, AP, Bilirubin
Serum creatinine
CT thorax and abdomen, if not done within the last 30 days
14.9.
Evaluations after progression
Patients with progression will end trial treatment and should have documented survival
every 12 weeks until death. Survival status can be collected by patient visit or documented
phone calls.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
33/38
15.
Case report forms and documentation
15.1.
Case report forms schedule
CRFs will only be available on-line at the ETOPdata Remote Data Entry (RDE) facility. No
paper forms will be used, with the exception of a paper SAE form in case of system
unavailability.
Tab in the RDE
To be completed
Identification
At screening, prior to randomization
Eligibility
At screening, prior to randomization
Baseline
At randomization
Cycle
At the end of each cycle and 30 days post trial treatment
Tumor assessment
At baseline and at start of odd cycles 3, 5, 7, ...; every 6 weeks
until progression in case of treatment discontinuation; at
progression
Adverse event
At baseline;
At the end of each cycle;
At end of treatment visit
Pregnancy
At first documentation of pregnancy;
At end of pregnancy
Serious adverse event
Within 24h of occurrence of SAE to RDE, or via fax to ETOP
safety office in case of system unavailability
Follow-up
Patients who discontinue treatment before progression: every 6
weeks;
After progression: At every follow-up visit, every 12 weeks until
death.
Consult the EMPHASIS-lung Procedures Manual as well as the ETOPdata User Manual for
detailed instructions on how to complete, save and submit the electronic CRFs.
16.
Statistical considerations
The study is designed as a phase III trial to explore the differential activity on PFS of
erlotinib vs docetaxel in VSG vs VSP squamous cell lung cancer patients who relapsed after
first line platinum based chemotherapy (7). The main endpoint of the study is PFS.
At an accrual rate of 28 patients per month and a study accrual period of 18 months, 500
patients will be randomized to the two treatment arms. An approximately equal number of
VSG and VSP patients are expected to enter the study (ratio 50/50). It is assumed that the


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
34/38
PFS Hazard Ratio of erlotinib versus docetaxel will be HR=0.675 for the VSG patients
(median PFS of 4 months for erlotinib and of 2.7 months for docetaxel), while HR=1.23 for
the VSP patients (median PFS of 2.2 and 2.7 months, respectively)
16.1.
Primary objective
Explore differential activity of treatment effect on PFS in the two VeriStrat groups by
testing for interaction between treatment arms (Arm A: erlotinib vs Arm B: docetaxel) and
VeriStrat status (Good vs Poor).
16.2.
Secondary objective

Test for significant difference in PFS (and other secondary endpoints) between
treatment arms in the VSG group.

Test for significant difference in PFS (and other secondary endpoints) between
treatment arms in the VSP group and overall (in case of no significant interaction).

Test for significant difference in PFS (and other secondary endpoints) between
VeriStrat groups (in case of no significant interaction) adjusting for treatment if
necessary.

Explore differential activity of treatment effect on the secondary endpoints in the
two VeriStrat groups by test for interaction between treatment arms and VeriStrat
status.

Assess the safety and the tolerability of the two treatments separately in each
VeriStrat group and overall.
16.3.
Sample size determination
For a sample size of 500, accrued in 18 months and an additional follow-up of 2 months,
86% power is achieved for testing at a two-sided significance level of 0.05, the null
hypothesis that the difference on median PFS when treated with erlotinib vs docetaxel is
independent of VeriStrat status, under the above stated assumptions of HR=0.675 for VSG
patients and HR=1.23 for VSP patients, assuming a hazard for censoring of 0.01 (power of
82% is achieved for a hazard for censoring of 0.05).
In the case the median PFS for erlotinib treated VeriStrat Poor patients is as high as 2.4,
(HR=1.125), with all other assumptions the same, we retain a power of 74%.
Simulations are run with the R software package and used for sample size calculations,
along with the Interaction Survival Power/Sample Size program from the Southwest
Oncology Group, SWOG (http://www.swogstat.org/stat/public/Help/survivalint.html).
Secondary objective: Test for significant difference in PFS between treatment arms in the
VSG group.
For the sample size of 250 patients accrued in 18 months in the VSG group, and with a total
study duration of 20 months (total events 204), a power of 80% is achieved to detect with a
two-sided logrank test at a significance level of 0.05, a 32.5% difference in median PFS
(HR=0.675) between the two treatment groups.
The EAST software package is used for sample size calculations in the VSG patient group
(EAST 5, Version 5.4.0.0, Cytel Inc. 2010).


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
35/38
Intermediate evaluation of the VeriStrat actual partition observed in the trial (Poor vs Good)
will be performed after 200 patients have been randomized, with the possibility to increase
the sample size by 50 patients if needed to retain at least 80% power. In addition, the
number of patients with indeterminate VeriStrat result will be assessed and if deemed
necessary, the total sample size will be increased by this number, which is expected to be
not higher than 10 patients (2% indeterminates).
16.4.
Evaluation of primary and secondary objectives
The total study duration will be approximately 23 months: 18 months recruitment period,
and at least 2 months treatment and follow-up period for the last randomized patient. The
final evaluation will be done within 6 months after the two-month visit of the last entered
patient, approximately 26 months after the inclusion of the first patient.
The primary efficacy analysis will include all eligible patients with a VSG or VSP signature
entering the study (efficacy cohort). The significance of an interaction term included in a
Cox proportional hazards regression model for PFS, will be explored. The test will be
performed at the 0.05 significance level. The VeriStrat status indicator and a randomized
treatment indicator will be included in the model for PFS along with the interaction term.
In case the interaction term is not significant, a Cox regression analysis exploring the
treatment effect adjusted for VeriStrat status will be performed. The prognostic significance
of the VeriStrat status adjusted for treatment will also be explored in this Cox model.
Progression free survival (PFS) and overall survival (OS) will be estimated by the Kaplan
Meier method and compared between the treatments in the full cohort and in each VeriStrat
subgroup by means of the logrank test, stratified when appropriate.
The analyses will be repeated for OS, and the other secondary endpoints for the whole
cohort and the two VeriStrat subgroups separately. Clinical efficacy will be further
described by objective response rate (ORR) and disease control rate (DCR).
Safety and the tolerability of the docetaxel and erlotinib treatments will be described overall
and separately in each VeriStrat subgroup by tabulation of the CTCAE V4 grades. The
safety cohort will encompass all patients who have received at least one dose of trial
treatment.
17.
Criteria for termination of the trial
17.1.
Discontinuation of protocol treatment for individual patients
Protocol treatment should be stopped in the following situations:
Disease progression.
Occurrence
of
unacceptable
toxicities.
Stopping
protocol
treatment
is
determined by medical judgment of the treating physician.
Inter-current severe illnesses which would in the judgment of the investigator
affect assessments of the clinical status to a significant degree and require
discontinuation of protocol therapy.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
36/38
Note: Diagnosis of another neoplastic disease (second malignant tumor) does
not mandate a stop of trial therapy, patients may continue to receive
protocol treatment after appearance of a second primary tumor, stopping
protocol treatment is determined by the medical judgment of the treating
physician.
Request by the patient.
If a patient refuses to have the treatments or follow-up examinations and tests
needed to determine whether the treatment is safe and effective.
The decision for discontinuation of protocol treatment of individual patients is taken by the
treating physician based on his medical evaluation and taking into account the patient’s
individual situation.
17.2.
General criteria for termination of the trial
The trial will be stopped if early analyses of the study data show a significant harm, by
decision of ETOP or Trial Steering Committee.
18.
Ethics approval procedures and Patient Informed Consent
The Investigator will ensure that this study is conducted in full conformance with the
principles of the “Declaration of Helsinki” or with the laws and regulations of the country in
which the research is conducted, whichever affords the greater protection to the individual.
The study must fully adhere to the principles outlined in “Guideline for Good Clinical
Practice” ICH Tripartite Guideline (January 1997) or with local law if it affords greater
protection to the patient. For studies conducted in the EU/EEA countries, the Investigator
will ensure compliance with the EU Clinical Trial Directive (2001/20/EC).
18.1.
Ethical Review Board/Ethics Committee
The protocol and the use of biological samples from patients must have the approval of a
properly constituted committee or committees responsible for approving clinical studies.
The ERB/IRB written, signed approval letter/form must contain approval of the designated
investigator, the protocol (identifying protocol title and version number), and of the patient
informed consent. Documentation of Ethics Committee approval must be sent to the ETOP
Coordinating Office prior to center activation.
18.2.
Regulatory approval procedures
There will be local, regional and country specific differences in the regulations concerning
the use of biological samples for research. Each site will be expected to notify ETOP of the
local regulations and seek the relevant approvals.
If applicable, in addition to the approval of the Ethics Committee according to national
legislation, the protocol, other protocol related documents including patient information and
informed consent and other documents as required locally must be submitted to and be
approved by the health authority. Documentation of health authority approval must be sent
to the ETOP Coordinating Office prior to participating center activation.


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
37/38
18.3.
Informed consent
Informed consent for each patient will be obtained prior to initiating any trial procedures in
accordance with the “Patient Information and Informed Consent".
One signed and dated copy of the informed consent must be given to each patient and the
original copy must be retained in the investigator's trial records. The informed consent form
must be available in the case of data audits. Verification of signed informed consent and the
date signed are required for inclusion to this trial.
18.4.
Confidentiality
The samples and data collected will be coded to protect patient confidentiality. Each patient
will have a unique identifier assigned by the ETOPdata RDE facility. Sites are responsible
to keep a patient log locally in order to be able to link the unique identifier to the record of
the patient.
Biological material will be assigned the same unique identifier. No identifiable / personal
data will be stored in the trial database or the tissue repositories in the central labs.
Biological material will be transferred outside the treating institution for central testing.
Results of the assays will be coded only by the patient identifier.
18.5.
Duration of study
Data will be kept in the central database for an unlimited time. The ETOP Foundation
Council will decide about the eventual discontinuation of this study and deletion of data.
19.
Governance and administrative issues
19.1.
Steering Committee
A Steering Committee will be constituted for this trial. The Steering Committee is
responsible for maintaining the scientific integrity of the trial, for example, by
recommending changes to the protocol in light of emerging clinical or scientific data from
other trials. Membership will include the trial co-chairs, trial statistician, ETOP officials,
representatives from some participating institutions and groups, and a representative from
Biodesix.
19.2.
Publication
The results of the trial will be published according to the ETOP publication guidelines
(appendix 4).
19.3.
Clinical trial insurance
ETOP will contract the appropriate liability insurance for this trial. Patients who suffer
injuries due to the trial should report them immediately to their physician. The local
group/institution should report all alleged claims immediately to the ETOP Coordinating
Office.
20.
References


ETOP 3-12 EMPHASIS-lung
V 1.0, 30.May.2012
38/38
1. di Maio M, Chiodini P, Georgoulias V, Hatzidaki D, Takeda K, Wachters FM, Gebbia V,
Smit EF, Morabito A, Gallo C, Perrone F, Gridelli C. Meta analysis of single agent
chemotherapy compared with combination chemotherapy as second line treatment of
advance non-small cell lung cancer. ASCO and ESMO guidelines. 2009, J. Clin. Oncol, pp.
27, 1836-1843.
2. Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N,
Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J. Prospective randomized trial
of docetaxel versus best supportive care in patients with non-small-cell lung cancer
previously treated with platinum-based chemotherapy. 2000, J Clin Oncol. , pp.
18(10):2095-103.
3. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S,
Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B,
Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L. Erlotinib in previously
treated non-small-cell lung cancer. 2005, N Engl J Med., pp. 353(2):123-32.
4. Taguchi F, Solomon B, Gregorc V, et al. Mass spectrometry to classify non-small-cell
lung cancer patients for clinical outcome after treatment with epidermal growth factor
receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. 2007, J Natl
Cancer Inst, pp. 99:838-46.
5. Carbone D, Lesley Seymour, Keyue Ding et al. Serum proteomic prediction of outcomes
in advanced NSCLC patients treated with erlotinib or placebo in the NCIC CTG BR.21 trial.
2nd European Lung Cancer Conference. 2010, J Thorac Oncol , p. 5(5) S80 abstr. 203O.
6. Pocock SJ and Simon R. Sequential treatment assignment with balancing for prognostic
factors in the controlled clinical trials. 1975, Biometrics, pp. 31:103-15.
7. Sargent DJ, Conley BA, Allegra C, and Collette L.Clinical Trial Designs for Predictive
Marker Validation in Cancer Treatment Trials. 2005, J Clin Onco, pp. 23:2020-2027.
8. Yildiz PB, Shyr Y, Rahman JS, Wardwell NR, Zimmerman LJ, Shakhtour B, Gray WH,
Chen S, Li M, Roder H, Liebler DC, Bigbee WL, Siegfried JM, Weissfeld JL, Gonzalez AL,
Ninan M, Johnson DH, Carbone DP, Caprioli RM, Massion PP. Diagnostic accuracy of
MALDI mass spectrometric analysis of unfractionated serum in lung cancer. 2007, J.
Thorac. Oncol., S. 2 (10): 893-901.