Clinical trial NCT01260181
Conditions: Non-Squamous Non-Small Cell Lung Cancer
Sponsor: Hoffmann-La Roche
Start date: 2011-03-31; Completion date: 2017-09-29
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This single arm, open-label study will evaluate the efficacy and safety of erlotinib (Tarceva) in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.

Detailed description:

Arms: arm 1: Participants will receive erlotinib 150 millgrams (mg) orally daily until disease progression.
Interventions: intervention 1: Erlotinib
Intervention descriptions: intervention 1: Erlotinib 150 mg tablet will be given orally daily.

Protocol documents:
Prot_001.pdf: 
 
Official Title: 
Phase II, open-label study of erlotinib (Tarceva®) treatment in 
patients with locally advanced or metastatic non-small cell lung 
cancer who present activating mutations in the tyrosine kinase 
domain of the epidermal growth factor receptor 
NCT Number: 
NCT01260181 
Document Date: 
Protocol Version 1.5: 12 Feb 2014 
 
 
 




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Protocol ML25434 1.5, dated  12nd February 2014 
Page 3 of 95 
PROTOCOL AMENDMENT, VERSION 1.5 
SUMMARY OF CHANGES 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM  
A Protocol Amendment Acceptance Form has been added.   
GLOBAL CHANGES Main changes included: 
- 
Introduction of an interim analysis  
- 
Clearer description of some of the study efficacy variables 
- 
Update the safety information concerning: 
o Adverse events and Laboratory abnormalities 
o Handling of safety parameters 
 
PROTOCOL SYNOPSIS  
The protocol synopsis has been updated to reflect the changes to the protocol, 
where applicable, namely: 
- the response duration efficacy assessment  
- the inclusion of the intent-to-treat population analyses 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
The list of abbreviations and definitions of terms has been updated to reflect the 
changes to the protocol, where applicable. 
 
SECTION 2.2: Secondary Objectives 
To evaluate progression-free survival (PFS), defined as the time from baseline visit 
to the date of first occurrence of disease progression or death due to any cause. 
To evaluate the EGFR mutation frequency, in the study population. 
To evaluate the Overall Survival defined as the time from baseline visit to the date 
of death due to any cause. 
To evaluate the erlotinib safety profile (Tarceva®; 150 mg). 
To evaluate response duration (RD) defined as the time of initial response (CR/PR whichever is first 
recorded) until documented disease progression. 


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Protocol ML25434 1.5, dated  12nd February 2014 
Page 11 of 95 
 
 
SECTION 8.2.7: Interim Analysis  
One interim analysis is planned for the study with a cut-off date on 30th September 2013. 
This interim analysis will include an epidemiological, efficacy and safety characterization of 
erlotinib in 1st line EGFR Mut+ mNSCLC Portuguese population. 
 
Interim analysis will include the following descriptive analyses: 
Characterization - demographics, medical history, Eastern cooperative oncology group 
performance status, clinical response (RECIST criteria). 
Efficacy – Best Overall response, progression free survival, overall survival and epidermal 
growth factor receptor. Additionally, PFS will be obtained for Exon 19 and Exon 20 (if 
applicable). 
Safety – Drug compliance, adverse events (incidence of AE and SAE, incidence of AE and 
SAE with remote, possible or probable relationship with study drug, description of AE and 
SAE, SAE with remote, possible or probable relationship with study drug) and subsequent 
therapy for NSCLC. 
Analysis will be conducted according to the definitions described in section 8.1 and 
considering the populations described in section 8.2.1. 
 
TABLE 6: Categories of protocol deviations  
Table 6 was added to specify major and minor deviations 
 
No changes were made in Figures or appendices.   


Protocol ML25434 1.5, dated  12nd February 2014 
Page 12 of 95 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
 
TITLE: 
Phase II, open-label study of erlotinib (Tarceva®) treatment 
in patients with locally advanced or metastatic non-small 
cell lung cancer who present activating mutations in the 
tyrosine kinase domain of the epidermal growth factor 
receptor 
PROTOCOL NUMBER: 
 ML25434 
VERSION NUMBER: 
1.5 
EUDRACT NUMBER: 
2010-022509-17 
IND NUMBER: 
OSI 774 
TEST PRODUCT: 
Erlotinib 
MEDICAL MONITOR: 
 
SPONSOR: 
Roche Farmacêutica Química, Lda. 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
Please return the signed original of this form as instructed by your local study monitor and 
retain a copy for your study files. 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 13 of 95 
Contents 
PROTOCOL AMENDMENT ACCEPTANCE FORM ....................................................12 
SYNOPSIS OF PROTOCOL NUMBER ML25434 .........................................................16 
SCHEDULE OF ASSESSMENTS ....................................................................................23 
GLOSSARY OF ABBREVIATIONS ...............................................................................25 
PART I: 
STUDY DESIGN AND CONDUCT ......................................................29 
1. 
BACKGROUND AND RATIONALE .....................................................................29 
1.1 
Background..............................................................................................29 
1.2 
Study drug ...............................................................................................30 
1.3 
Rationale for the Study ............................................................................30 
2. 
OBJECTIVES ...........................................................................................................33 
2.1 
Primary Objectives ..................................................................................33 
2.2 
Secondary Objectives ..............................................................................33 
3. 
STUDY DESIGN ......................................................................................................33 
3.1 
Overview of Study Design ......................................................................33 
3.2 
Centres .....................................................................................................35 
3.3 
Interim Analyses ......................................................................................35 
4. 
MATERIALS AND METHODS ..............................................................................36 
4.1 
Overview .................................................................................................36 
4.2 
Inclusion Criteria .....................................................................................36 
4.3 
Exclusion Criteria ....................................................................................37 
4.4 
Number of Subjects/ Assignment to Treatment Groups..........................38 
4.5 
Concomitant Medication and Treatment .................................................38 
4.6 
Criteria for Premature Withdrawal ..........................................................39 
4.7 
Replacement Policy (Ensuring Adequate Numbers of Evaluable 
Subjects) ..................................................................................................39 
5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES.......................................40 
5.1 
Screening Examination and Eligibility Screening Form .........................40 
5.2 
Procedures for Enrolment of Eligible Patients ........................................40 
5.3 
Clinical Assessments and Procedures .....................................................40 
5.4 
Laboratory Assessments ..........................................................................42 
5.5 
Safety Follow-Up Visit (28 days after last study drug administration) ...42 
5.6 
Survival Follow-up Phase........................................................................42 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT ....................................................42 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 14 of 95 
6.1 
Dose and Schedule of IMP and Comparator(S) ......................................42 
6.2 
Preparation and Administration of IMP and Comparator(S) ..................45 
6.3 
Formulation, Packaging and Labelling....................................................46 
6.4 
Blinding and Unblinding .........................................................................46 
6.5 
Assessment of Compliance......................................................................46 
6.6 
Destruction of the Study Drug .................................................................46 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE ......................................................47 
7.1 
Adverse Events and Laboratory Abnormalities ......................................47 
7.1.1 Severity .............................................................................................................48 
7.1.2 Drug – Adverse Event relationship ..................................................................48 
7.1.3 Serious Adverse Events (Immediately Reportable to Roche) ..........................49 
7.1.4 Progression of Underlying Malignancy ...........................................................49 
7.1.5  Treatment and Follow-Up of AEs ...................................................................50 
7.1.6 Laboratory Test Abnormalities ........................................................................51 
7.2 
Handling of Safety Parameters ................................................................52 
7.2.1 Reporting of Adverse Events  ..........................................................................52 
7.2.2 Reporting of Serious Adverse Events (immediately reportable) ......................52 
7.2.3 Emergency Medical Contacts ...........................................................................53 
7.2.4 Pregnancy .........................................................................................................53 
7.3 
Warnings and Precautions  ......................................................................54 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ......................56 
8.1 
Primary and Secondary Study Variables .................................................56 
8.1.1 Primary Variable ..............................................................................................56 
8.1.2 Secondary Variables .........................................................................................56 
8.1.3  Independent Review Committee .....................................................................56 
8.1.4 Safety ................................................................................................................56 
8.2 
Statistical and Analytical Methods ..........................................................56 
8.2.1 Statistical Model ...............................................................................................56 
8.2.2  Hypothesis Testing ..........................................................................................57 
8.2.3 Types of Analyses ............................................................................................57 
8.2.4 Safety Data Analysis ........................................................................................58 
8.2.5 Other Analyses .................................................................................................58 
8.2.6 Sample Size ......................................................................................................59 
8.2.7 Interim Analysis ...............................................................................................59 
9. 
DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE ..........59 
9.1 
Assignment of Preferred Terms and Original Terminology ....................60 
10. REFERENCES ..........................................................................................................61 
11. ETHICAL ASPECTS ................................................................................................64 
11.1 
Local Regulations/Declaration of Helsinki .............................................64 
11.2 
Informed Consent ....................................................................................64 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 15 of 95 
11.3 
Independent Ethics Committees (IEC)/Institutional Review Board 
(IRB) ........................................................................................................64 
11.4 
Financial Disclosure ................................................................................65 
12. CONDITIONS FOR MODIFYING THE PROTOCOL ...........................................65 
13. CONDITIONS FOR TERMINATING THE STUDY ..............................................65 
14. STUDY DOCUMENTATION, CRFS AND RECORD KEEPING .........................65 
14.1 
Investigator's Files / Retention of Documents .........................................65 
14.2 
Source Documents and Background Data ...............................................66 
14.3 
Audits and Inspections ............................................................................66 
14.4 
Electronic Case Report Forms .................................................................66 
15. MONITORING THE STUDY ..................................................................................67 
16. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS ...67 
17. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ............67 
18. APPENDIX 1: THE RECIST CRITERIA FOR TUMOR RESPONSE ...................69 
19. APPENDIX 2: THE ECOG PERFORMANCE SCALE ..........................................79 
20. APPENDIX 3: INFORMATION ON POTENTIAL INTERACTIONS ..................80 
21. APPENDIX 4: 7TH EDITION AJCC CANCER STAGING MANUAL - PART 
IV ...............................................................................................................................82 
 
 
 


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Protocol ML25434 1.5, dated  12nd February 2014 
Page 22 of 95 
SUMMARY OF STUDY DESIGN 
 
Continuation of Screening Assessment 
150 mg erlotinib o.d. 
Until PD, death, unacceptable toxicity 
or patient’s decision 
Patient Inclusion ≤ 21 days  
Positive EGFR classical activating 
mutations test result 
EGFR Testing 
Signature of Informed Consent 
for the Study ML25434 
Eligibility Criteria Assessment 
Negative EGFR and end of the 
study  


Protocol ML25434 1.5, dated  12nd February 2014 
Page 23 of 95 
SCHEDULE OF ASSESSMENTS 
Assessment 
Screening 
Exon 19 deletion or exon 21 substitution L858R in the TK domain of EGFR gene 
Treatment Period 
Final Visit / Withdrawal 
from Treatment 
Safety Follow-
up Visit K 
Off-study 
Visit 
Days 
Visit # (Day 1 of every 8th week 
throughout treatment period) 
End of Study Treatment 
End of study 
( 28 days after 
last study drug 
administration)  
 
 
Survival 
follow-up 
every 6th 
monthsh 
-21 
to 
-1 
Visit 1 
(Baseline) 
Visit – every 8th week, until 
PD, death, unacceptable 
toxicity or patient’s 
decision 
Visit Window 
≤ 21 days 
0 
+/- 5 days 
+/- 5 days 
+/- 5 days 
+/- 15 days 
Informed 
consent 
X 
 
 
 
 
 
EGFR Testing 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Pregnancy testa 
X 
X 
 
X 
 
Physical 
examinationb 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
ECGc 
X 
To be repeated as clinically indicated 
Demographics 
X 
 
 
 
 
Haematology 
X 
X 
X 
X 
X 
Biochemistry 
X 
X 
X 
X 
X 
Coagulation 
Xj 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
Tumour 
assessmentd 
 
X 
X 
X 
 
Adverse eventse 
X 
X 
X 
X 
X  
X 
Subsequent 
therapy for 
NSCLCf 
 
 
 
 
X 
X 
Drug 
dispensing and 
accountabilityg 
 
X 
X 
Xi 
 
 
Notes: First dose of study drug to be taken as soon as positive EGFR mutations test result has been received and appropriate drug has been provided. 
a Urine or blood. 
b Including an ophthalmologic examination if clinically indicated. 
c At baseline and as clinically indicated throughout the study. 
d Tumour assessment consists at minimum of a CT scan of chest and upper abdomen (for imaging of liver and adrenal glands). Patients known to have 
bone metastasis or displaying clinical or laboratory signs (e.g. serum alkaline phosphatase (ALP) > 1.5 ULN) of bone metastasis should have an 
isotope bone scan at baseline. Brain CT scan or MRI is not mandatory but should be done if there is a clinical suspicion of cerebral metastasis. Post-
baseline assessments are to be performed within +/- 5 days for the 8 weekly assessments. If there is suspicion of disease progression based on clinical 
or laboratory findings, a tumour assessment should be performed as soon as possible, before the next scheduled evaluation. 
e Graded according to NCI CTC-AE version 4.0. During screening period only SAEs caused by a protocol-mandated intervention will be collected 
(e.g., SAEs related to invasive procedures such as biopsies, medication washout, or no treatment run-in). During the study, and until Safety Follow-up 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 24 of 95 
visit all SAEs and AEs of special interest will be collected and reported. After Safety Follow up visit all SAEs and AEs of special interest related with 
the study drug, will be collected and reported.  
f Subsequent therapy for all patients. 
g For details on drug dispensing and accountability see Section 6. of the Protocol. 
h or as appropriate. 
i Drug returning and final accountability. 
j To be obtained in the 7 days before study treatment initiation for the patients taking anti-coagulants. 
K To be performed 28 days after the last study drug administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 25 of 95 
GLOSSARY OF ABBREVIATIONS 
 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANOVA 
Analysis of variance 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
b.i.d. 
Twice Daily 
BP 
Blood pressure 
CALGB 
Cancer and Leukaemia Group B 
CEA 
Carcinoembryonic Antigen 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CPU 
Clinical Pharmacology Unit 
CR 
Complete Response 
CRF 
Case Report Form[s] 
CT 
Computer Tomography 
CNS 
Central Nervous System 
CVAD 
Central Venous Access Device 
CXR 
Chest X-Ray 
DLT 
Dose Limiting Toxicity 
EC50 
Plasma concentration associated with half-maximal effect 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EEG 
Electroencephalogram 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 26 of 95 
EGF 
Epidermal Growth Factor 
EGFR 
Epidermal Growth Factor Receptor 
EMA 
European Medicines Agency 
ESF 
eligibility screening form 
EU 
European Union 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in situ hybridization 
GABA 
Gamma-amino butyric acid 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
H0 
Null hypothesis 
H1 
Alternative hypothesis 
NSABP 
National Surgical Adjuvant Breast Project 
HPLC 
High performance liquid chromatography 
ICH 
International Conference on Harmonization 
IHC 
IMP 
Immunohistochemistry 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
intent to treat 
iv 
Intravenous 
keo 
LDH 
Equilibration rate constant 
Lactate dehydrogenase 
MRI 
Magnetic Resonance Image 
MTD 
Maximum Tolerated Dose  
NCCN 
National Comprehensive Cancer Network 
NCDB 
National Cancer Data Base 
NCI 
National Cancer Institute 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 27 of 95 
NCI-CTC 
National Cancer Institute-Common Toxicity Criteria 
NCI-CTCAE 
National Cancer Institute-Common Toxicity Criteria for 
Adverse Events 
NCIC-CTG 
NSCLC 
National Cancer Institute of Canada Clinical Trials Group 
Non small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease or Pharmacodynamic 
PFS 
Progression free survival 
PE 
PR 
Pharmacoeconomic 
Partial response 
PS 
Performance Status 
PK 
Pharmacokinetic 
p.o. 
“per os” (oral administration) 
pr 
Pulse rate 
PR 
Partial Response 
q.d. 
Once daily administration 
Q12H 
Every 12 hours 
Q3W 
Every 3 weeks 
q.w. 
RD 
Once a week 
Response duration 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RIA 
radio immunoassay 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
T1/2 
half-life  
t.b.d. 
TK 
to be determined 
Tyrosine Kinase 
TNM 
Stage Classification (Tumour/Nodes/Metastasis) 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 28 of 95 
TMAX 
time to maximum plasma concentration  
TTP 
Time to Tumor Progression 
ULN 
Upper Limit of Normal 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 29 of 95 
PART I: 
STUDY DESIGN AND CONDUCT 
 
1. BACKGROUND AND RATIONALE 
This Protocol describes an open-label study, to evaluate the anti-tumoral activity of erlotinib 
(Tarceva®) through objective response rate (ORR) in patients with non-small-cell lung 
cancer (NSCLC) in locally advanced or metastatic stages who have not received previous 
chemotherapy for their disease and who present activating mutations in the tyrosine kinase 
(TK) domain of the epidermal growth factor receptor (EGFR).  
 
1.1  Background 
Non-small cell lung cancer is the most common cause of cancer death worldwide1. In the 
EU the crude incidence of lung Cancer is 52.5 patients per 100,000 individuals each year 
with a mortality rate of 48.7 per 100,000/year. Mortality and incidence rates are very 
similar, due to low survival of these patients2. In the developed world lung cancer remains 
the commonest reason of cancer death in both men and women, although mortality rates for 
men are dropping3. Among men the incidence and mortality rates are 82.5 and 77.0 per 
100,000/year, respectively, and for women these rates are 23.9 and 22.3 per 100,000/year, 
respectively. 
 
Non-small cell lung cancer (NSCLC) comprises 80% of reported lung cancer cases and the 
majority of its new cases are diagnosed in an advanced stage4,5 once it represents a disease 
for which there is no established screening. Survival statistics are among the worst for any 
malignancies, and have not improved in the last years6. Indeed, nowadays the median 
survival for lung cancer is 6–12 months from the time of diagnosis with an overall 5-year 
survival of 5–10%. 
 
Nowadays surgery (lobectomy/pneumonectomy plus mediastinal lymph node dissection) 
offers the best chance of cure in lung cancer, especially for NSCLC cases. However, only a 
small part of patients are suitable for curative resection and the majority must rely on non-
surgical and adjuvant therapies. For most patients resection was technically unsuitable 
because of obvious dissemination of disease. Therefore, chemotherapy with palliate purpose 
to prolong patients’ life for few months has been increasingly proved by clinical studies. 
A common first-line therapy for advanced cases of NSCLC in patients with good 
performance status (PS) is based on combinations of platinum. Despite the first-line 
chemotherapy is appropriate, most patients experience disease progression. With regard to 
second-line systemic treatment (docetaxel, pemetrexed, erlotinib) this may improve the 
symptoms related to disease and survival of patients. Second-line therapy is administered 
for disease progression, recurrence, or intolerable adverse effects following administration 
of initial chemotherapy7. 
In first line, doublet chemotherapy has been found to be superior to single-agent 
chemotherapy8. Platinum-based chemotherapy combined with vinorelbine, gemcitabine or a 
taxane prolongs survival, improves quality of life and controls symptoms in patients with 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 30 of 95 
good performance status. Non-platinum combination chemotherapy can be considered in 
patients who are not fit to receive platinum agents. 
In Second line, in a phase III study, Shepherd and colleagues proved the efficacy of erlotinib 
against placebo in increasing the survival and reduced symptoms9. Erlotinib response rates 
are higher in non-smokers, women, adenocarcinomas, Asians and patients with EGFR 
mutations. Several studies show that erlotinib prolongs survival in patients with advanced 
NSCLC after the failure of first line or second line chemotherapy.  
In a phase II clinical trial, 57 patients with refractory NSCLC received erlotinib 
monotherapy and showed a response rate of 12.3% and a median survival of 8.4 months10.  
Based on these results and for a different pharmacological profile, erlotinib was approved by 
the FDA for the treatment of second and third line NSCLC. Some studies have also shown 
that mutations in the EGFR gene are associated with response to EGFR TKI11. 
 
1.2  Study drug  
Erlotinib (OSI-774; Tarceva®) 
 
Erlotinib is an orally active and potent inhibitor of tyrosine kinase, which acts on the 
epidermal growth factor receptor (EGFR) developed for the treatment of solid tumours 
including NSCLC12. The recommended daily dose of erlotinib is 150 mg13.  
Erlotinib acts via direct and reversible inhibition of the human EGFR tyrosine kinase, with 
an IC50 of 2 nM (0.786 ng/mL) in an in vitro enzyme assay, and reduces receptor 
autophosphorylation in intact tumour cells with an IC50 of 20 nM (7.86 ng/mL).  
At nanomolar concentrations, erlotinib blocks Epidermal Growth Factor (EGF)-dependent 
cellular proliferation and inhibits cell cycle progression in the G1 phase. Selectivity testing 
against a panel of isolated tyrosine kinase demonstrated that erlotinib is selective for the 
EGFR. 
The most frequently-reported adverse events (AEs) associated with single-agent erlotinib 
are rash (dermatosis), diarrhoea, nausea, fatigue, stomatitis, vomiting, and headache. On the 
other hand, skin rash was identified as a key indicator of erlotinib trough plasma 
concentrations14. These results support those from previous studies on EGFR inhibitors, 
which have revealed a similar association between drug steady-state plasma concentrations 
and the intensity of rash and diarrhoea15,16. Laboratory abnormalities, primarily involving 
changes in liver function tests (elevation of alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and/or bilirubin) are less frequently observed with single-agent 
erlotinib. These abnormalities occur occasionally in patients treated with erlotinib in 
combination with either gemcitabine, or carboplatin and paclitaxel. Caution should be used 
when administering Tarceva to patients with hepatic impairment. Dose reduction or 
interruption of Tarceva should be considered if severe adverse reactions occur13,17.  
An indication of completed and ongoing clinical studies on erlotinib in NSCLC can be 
found in the Investigator’s Brochure. 
 
1.3  Rationale for the Study  
Advanced NSCLC remains largely fatal, with the positive impact of chemotherapy limited 
by intrinsic and acquired resistance, manifested clinically by early progression and transient 
responses. Current chemotherapy regimens have limited efficacy with a magnitude of 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 31 of 95 
survival benefit that is still modest, and lead to significant toxicity, with many patients 
unable to tolerate this kind of treatment, even in the first-line setting. There is, therefore, a 
great need to provide patients with less toxic agents such as the novel targeted therapies, 
with the potential to improve the efficacy and maintain a good quality of life with little 
associated toxicity. 
In order to improve upon the doublet chemotherapy platform for NSCLC, the targeted drugs 
were next tested in the frontline setting in large, randomized, phase III trials in unselected 
population were added TKIs to chemotherapy (trials with erlotinib TRIBUTE18 and 
TALENT19). Those trials failed to demonstrate either an improved response or a survival 
benefit from the combination of a TKI with chemotherapy in unselected population with 
advanced NSCLC. Despite the failure of the first-line trials, additional phase III trials were 
completed to confirm the previously observed activity in refractory NSCLC. The BR.21 trial 
randomized patients previously treated with chemotherapy to erlotinib or placebo, and 
showed a significant improvement in response rate (9% vs 1%) and overall survival (OS; 6.7 
vs 4.7 months; P<0.001) with erlotinib. 
Subsequently, a number of trials have confirmed the benefit of erlotinib in unselected 
patients with NSCLC. As example, in the SATURN study erlotinib has proven results as 
first-line maintenance therapy following non-progression of disease after first-line therapy20. 
The SATURN trial investigated erlotinib maintenance therapy in patients with advanced 
NSCLC who did not progress during first-line chemotherapy. This randomized, global, 
phase III study was the first to include prospective molecular marker analyses for erlotinib, 
with mandatory sample collection.  
Nowadays it is accepted the important role of erlotinib in NSCLC tumors with EGFR 
mutations after at least one prior chemotherapy regimen (SATURN study)21.Therefore it is 
important to define the impact that treatment with erlotinib may have in the first line setting. 
There is some clinical trial evidence that EGFR TKIs are efficacious as first-line therapy in 
EGFR mutation positive patients with advanced NSCLC: IPASS is a phase III trial looking 
at gefitinib as a first-line treatment in non-small cell lung cancer in 1217 patients (261 
EGFR mutation positive). Exploratory analysis of response rates in patients with EGFR 
mutations have shown a response rate of 71.2% in patients with EGFR mutations treated 
with gefitinib versus a response rate of 1.1% in patients without EGFR mutations treated 
with gefitinib22. 
Therefore, erlotinib is currently being assessed as first-line treatment in advanced NSCLC in 
prospective, randomized, registration trials. There is however, already evidence that 
erlotinib works in first-line treatment with relevant results found for the evaluation of PFS. 
Paz-Ares23performed a pooled analysis of clinical outcomes in patients with EGFR 
mutations, treated with either an EGFR TKI or chemotherapy and demonstrated clinical 
efficacy of erlotinib (and gefitinib) monotherapy in 1st line NSCLC. 
 
Table 1 - Summary of data included in pooled analysis 
 
Erlotinib 
Gefitinib 
Chemotherapy 
Patients treated in any line, n 
365 
1069 
375 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 32 of 95 
Patients treated in first-line 
setting, %  
57 
57 
95 
 
Table 2 - Pooled analysis of outcomes according to line of therapy 
 
Pooled median PFS, months (95% accuracy interval) 
 
Erlotinib 
Gefitinib 
Chemotherapy 
Any line 
13.2 
9.8 
5.9 
 
(12.0-14.7) 
(9.2-10.4) 
(5.3-6.5) 
First-line 
12.5 
9.9 
6.0 
 
(10.0-16.0) 
(9.0-10.9) 
(5.4-6.7) 
 
The results of this pooled analysis are consistent with those from other studies looking at 
EGFR TKIs as first-line therapy in patients with EGFR mutations such as the IPASS study 
of first-line gefitinib versus carboplatin/paclitaxel in Asian patients with adenocarcinoma 
who were never- or light ex-smokers where the median PFS was found to be  9.5 months 
with gefitinib and 6.3 months with chemotherapy; and the Spanish Lung Cancer Group 
study of erlotinib in patients with EGFR mutations showed a medium PFS of 14.0 months 
and an ORR (complete and partial response) of 70.6%24.These results highlight the idea that 
EGFR mutants lung cancer is a distinct class of NSCLC. 
 
A recent phase III study (OPTIMAL) of first line treatment with erlotinib compared to 
platinum-based chemotherapy (gemcitabine/carboplatine), in Asian population with NSCLC 
with EGFR mutation has shown a median PFS of 13.1 months in the erlotinib arm with 
HR=0.16 (95% CI; 0.10-0.26) versus 4.6 months in the chemotherapy arm. It has also 
shown an ORR of 82.9% in the erlotinib arm versus 36% in the chemotherapy arm 
(p<0.0001)25. Erlotinib should therefore be considered in preference to first line 
chemotherapy in patients with this distinct disease. 
 
Considering the potential benefit for patients in initiating erlotinib earlier in their treatment 
it becomes crucial to evaluate its anti-tumoral activity through a more sensitive and accurate 
endpoint such as objective response rate during first-line treatment in Caucasian 
populations. 
 
In this trial erlotinib will be given in first-line treatment for advanced NSCLC with EGFR 
mutation positive. 
Although this trial is a non-randomized phase II trial, Erlotinib is currently used in clinical 
practice to treat NSCLC26. Any patient with locally advanced or metastatic non-small cell 
lung cancer disease found to have an EGFR exon 19 deletion or exon 21 mutations will be 
offered first-line treatment with erlotinib having ORR as primary efficacy endpoint. 
 
EGFR mutations rates in Portugal 
Previous studies with gefitinib have shown the incidence of mutations to be around 8% in 
unselected patients, whereas studies conducted in Asia show mutation rates of 19-60% In 
the Spanish Lung Cancer Group study of erlotinib that included only Spanish patients with 
EGFR mutations the EGFR mutation rate was 16.6%. In this trial, the population was 
mainly female, non-smokers and adenocarcinoma. The EGFR mutation’s rate amongst 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 33 of 95 
NSCLC patients, in Portugal is currently unknown so that the health burden and economic 
implications of treatments directed specifically at patients with this characteristic cannot be 
accurately assessed. 
Therefore one of the objectives of the current study is to assess the EGFR mutation rate in 
Portugal NSCLC population. This will be done by testing Portuguese patients newly 
diagnosed with recurrent or metastatic NSCLC for the EGFR mutations.  
 
2. OBJECTIVES  
2.1  Primary Objectives 
To evaluate the anti-tumoral activity of erlotinib (Tarceva®; 150 mg) through objective 
response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) in locally 
advanced or metastatic stages who have not received previous chemotherapy for their 
disease and who present activating mutations in the tyrosine kinase (TK) domain of the 
epidermal growth factor receptor (EGFR). 
 
2.2  Secondary Objectives  
To evaluate progression-free survival (PFS), defined as the time from baseline visit to the 
date of first occurrence of disease progression or death due to any cause. 
To evaluate the EGFR mutation frequency, in the study population. 
To evaluate the Overall Survival defined as the time from baseline visit to the date of death 
due to any cause. 
To evaluate the erlotinib safety profile (Tarceva®; 150 mg). 
To evaluate response duration (RD) defined as the time of initial response (CR/PR 
whichever is first recorded) until documented disease progression. 
 
3. STUDY DESIGN 
3.1  Overview of Study Design 
This is a local open-label, multi-centre Phase II study of the anti-tumoral activity of erlotinib 
(Tarceva®; 150 mg) evaluated by objective response rate (ORR) in patients with NSCLC in 
locally advanced or metastatic stages who have not received previous chemotherapy for 
their disease and who present activating mutations in the TK domain of the EGFR. 
Summary of the study design is shown in Figure 1. 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 34 of 95 
 
Figure 1 - Summary of study design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continuation of Screening Assessment 
150 mg erlotinib o.d. 
Until PD, death, unacceptable toxicity 
or patient’s decision 
Patient Inclusion ≤ 21 days  
Positive EGFR classical activating 
mutations test result 
EGFR Testing 
Signature of Informed Consent 
for the Study ML25434 
Eligibility Criteria Assessment 
Negative EGFR and end of the 
study  


Protocol ML25434 1.5, dated  12nd February 2014 
Page 35 of 95 
 
Rationale for Study Design  
In this trial erlotinib is given in first-line treatment for advanced NSCLC. 
 
Although this trial is non-randomized phase II trial, as Erlotinib is currently used in clinical 
practice to treat NSCL it closely reflects clinical practice. 
 
Any patient with locally advanced or metastatic non-small cell lung cancer disease found to 
have an EGFR Exon 19 deletion or exon 21 substitution L858R in the TK domain of EGFR 
gene will be offered first-line treatment with erlotinib. 
 
The primary efficacy variable will be ORR. 
 
 
Rationale for Dose Selection 
The recommended daily dose of erlotinib was established at 150 mg, to be continued daily 
until disease progression.  
All enrolled patients will receive recommended dose of erlotinib (150 mg/day).No dose 
escalation is permitted. Erlotinib dose will be reduced for toxicities as detailed in Section 
6.1 . Patients will be treated until progression of disease or unacceptable toxicity. 
 
End of Study  
This study is event-driven, with a recruitment period that will last until the end of March 
2012 or until the number of patients aimed for the protocol (30) is achieved, whatever 
occurs first. Patients are to be treated until disease progression, unacceptable toxicity or 
patient request for discontinuation. 
The study will end when the last patient has stopped erlotinib therapy and completed their 
last safety follow-up visit (28 days after last study drug administration). For all patients who 
have discontinued study drug treatment and are alive, information on survival will be 
collected. 
 
3.2  Centres 
This study will comprise approximately 9 centres, in Portugal. 
 
3.3  Interim Analyses 
One interim analysis is planned for the study. This interim analysis will include an 
epidemiological, efficacy and safety characterization of erlotinib in 1st line EGFR Mut+ 
mNSCLC Portuguese population.  The rationale for this interim analysis is to analyse the 
preliminary clinical benefits on this population and compare it with the available data in 
publications held in the caucasian international population.  
Additionally, the interim analysis will evaluate the EGFR mutation rate; describe the 
enrolled population related to the gender, histology type, smoking habit and the incidence of 
EGFR mutation per sub-group; as well as the safety evaluations in terms of events, 
frequency and severity. 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 36 of 95 
4. Materials and methods 
Under no circumstances subjects who are enrolled in this study are not permitted to be re- 
enrolled for a second course of treatment with erlotinib in this study. 
4.1  Overview 
The target population of this study are patients with histologically or cytologically 
confirmed locally advanced or metastatic NSCLC who have not received previous 
chemotherapy for their disease and who present activating mutations in the TK domain of 
the EGFR. 
4.2  Inclusion Criteria 
A subject may be included if the answer to all of the following statements is "yes". 
1. Patients able and willing to give written informed consent. Consent must be 
obtained prior to any study-specific procedure. 
2.  
a) Histologically or cytologically documented inoperable, locally advanced or 
metastatic NSCLC disease; 
 
b) Patient that presents activating mutations (exon 19 deletion and/or  exon 21 
substitution L858R ) in the tyrosine kinase domain of EGFR ; 
 
3. Measurable disease, according to RECIST - Response Evaluation Criteria in 
Solid Tumours). 
 
4. Male or female patients aged ≥ 18 years. 
 
5. Life expectancy ≥ 12 weeks. 
 
6. Adequate haematological and coagulation function as assessed by the 
investigator. 
 
7. Adequate liver and renal function as assessed by the investigator. 
 
8. Female patients must be postmenopausal (24 months of amenorrhea), surgically 
sterile or they must agree to use a physical method of contraception. Male 
patients must be surgically sterile or agree to use a barrier method of 
contraception. Male and female patients must use effective contraception during 
the study and for a period of 90 days following the last administration of 
erlotinib. Acceptable methods of contraception include an established hormonal 
therapy or intrauterine device for females, and the use of a barrier contraceptive 
(i.e. diaphragm or condoms) with spermicidal. 
 
9. If applicable, patients with asymptomatic and stable cerebral metastases 
receiving medical treatment will be eligible for the study. Those patients may 
have received radiation therapy for their cerebral metastases before the initiation 
of systemic treatment for non-small-cell lung cancer. 


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Protocol ML25434 1.5, dated  12nd February 2014 
Page 39 of 95 
Caution should be exercised when erlotinib is co-administered with CYP3A4 inhibitors and 
inducers. As grapefruit juice has the potential to inhibit CYP3A4 activity, patients should 
not eat grapefruit or drink grapefruit juice during the study. 
 
4.6  Criteria for Premature Withdrawal 
Subjects have the right to withdraw from the study at any time for any reason. 
In the case that the subject decides to prematurely discontinue study treatment [“refuses 
treatment”], he/she should be asked if he/she can still be contacted for further information. 
The outcome of that discussion should be documented in both the medical records and in the 
eCRF. If lost to follow-up, the investigator should contact the subject or a responsible 
relative by telephone followed by registered mail or through a personal visit to establish as 
completely as possible the reason for the withdrawal. A complete final evaluation at the 
time of the subject’s withdrawal should be made with an explanation of why the subject is 
withdrawing from the study.  
When applicable, subjects should be informed of circumstances under which their 
participation may be terminated by the investigator without the subject’s consent.  The 
investigator may withdraw subjects from the study in the event of intercurrent illness, 
adverse events, treatment failure after a prescribed procedure, lack of compliance with the 
study and/or study procedures (e.g., dosing instructions, study visits), cure or any reason 
where it is felt by the investigator that it is in the best interest of the subject to be terminated 
from the study.  Any administrative or other reasons for withdrawal must be documented 
and explained to the subject. 
If the reason for removal of a subject from the study is an Adverse Event, the Adverse Event  
will be recorded on the eCRF. The subject should be followed until the Adverse Event has 
resolved, if possible. 
An excessive rate of withdrawals can render the study non-interpretable; therefore, 
unnecessary withdrawal of subjects should be avoided.  Should a subject decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
 
4.7  Replacement Policy (Ensuring Adequate Numbers of Evaluable 
Subjects) 
 
For Patients 
No subject prematurely discontinued from the study, for any reason, after receiving at least a 
single dose of treatment, will be replaced. 
 
For Centres 
A centre may be replaced for the following administrative reasons:   
Excessively slow recruitment. 
Poor protocol adherence. 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 40 of 95 
5. SCHEDULE OF ASSESSMENTS AND PROCEDURES 
The complete schedule of assessments is tabled in the synopsis of protocol (see Schedule of 
Assessments, page 10). 
 
5.1  Screening Examination and Eligibility Screening Form 
All subjects must provide written informed consent before any study specific assessments or 
procedures are performed.  
A screening examination should be performed 21 days before study enrolment.  Patients 
who fulfil all the inclusion and none of the exclusion criteria will be accepted into the study. 
An Eligibility Screening Form (ESF) documenting the investigator’s assessment of each 
screened subject with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator.  
A screen failure log must be maintained by the investigator. 
 
5.2  Procedures for Enrolment of Eligible Patients 
Once a patient has fulfilled the entry criteria, will be enrolled in the study, beginning with 
the EGFR mutation testing at the Central Laboratory 
 by Sequential Technique. 
A surgical fragment or biopsy formalin-fixed, paraffin-embedded or a tumour material 
obtained through aspiration cytology fixed and paraffin-embedded in a cell-block, must be 
sent to the Central Laboratory 
. If activating mutations (exons 19 and 21 
mutations) in the TK domain of EGFR gene are identified, patients are eligible to participate 
in the study. Although, for methodological issues, mutations will be identified from the exon 
18 to 21, but only patients with Exon 19 deletion or exon 21 substitution L858R in the TK 
domain of EGFR gene will be enrolled in this trial. 
 
5.3  Clinical Assessments and Procedures 
Testing for EGFR mutation will be performed only at Screening. All of the other clinical 
and safety assessments will be performed at Screening, Baseline and on Day 1 of every 8th 
week until PD, death, or unacceptable toxicity, as indicated in the Schedule of Assessments. 
For all patients who have discontinued study drug treatment and are alive, information on 
further therapy for NSCLC and survival will be collected. 
 
Tumor Response Criteria 
Tumor response will be evaluated according to the RECIST criteria (Eisenhauer et al., 2009) 
(see Appendix 1). 
In this study, tumour response will be measured using computer tomography (CT) or 
magnetic resonance image (MRI) scans of the chest and upper abdomen, for imaging of 
liver and adrenal glands. Patients known to have bone metastasis or displaying clinical or 
laboratory signs (e.g. serum alkaline phosphatase (ALP) > 1.5 ULN) of bone metastasis 
should have an isotope bone scan at baseline. In cases where there are suspected brain 
metastases, CT scanning of the brain will be performed.  


Protocol ML25434 1.5, dated  12nd February 2014 
Page 41 of 95 
Post-baseline assessments are to be performed within +/- 5 days for the 8 weekly 
assessments. If there is suspicion of disease progression based on clinical or laboratory 
findings, a tumour assessment should be performed as soon as possible, before the next 
scheduled evaluation. 
Consistency of consecutive CT-scans, X-rays or MRIs should be ensured during all 
assessments for each patient, with the same technique being used for evaluating lesions 
throughout the treatment period. The use of spiral CT or MRI is required for baseline lesions 
of < 20 millimetres (mm) and must be documented in medical records and used consistently 
throughout the study. The use of oral and IV contrast etc. should, as long as it is clinically 
possible, be kept consistent. Tumor measurements should be made by the same 
investigator/radiologist for each patient during the study to the extent that this is feasible.  
  
Scheduling of tumour assessments 
In this study, assessment of tumour progression during treatment with erlotinib will be 
performed every 8th week during the study visits and on the End of Study visit (as given in 
the Schedule of Assessments). Baseline tumour assessment must be performed within 21 
days before first dose of study drug treatment. Post-baseline assessments are to be 
performed +/- 5 days for the 8 weekly assessments. If there is suspicion of disease 
progression based on clinical or laboratory findings before the next scheduled assessment, 
an unscheduled assessment should be performed. 
If a subject inadvertently misses a prescribed tumour evaluation or a technical error prevents 
the evaluation, the subject may continue treatment until the next scheduled assessment, 
unless signs of clinical progression are present. 
 
ECOG Performance Status 
Performance Status (PS) will be measured using the ECOG performance scale (see 
Appendix 2), at screening, baseline, at each study visit on Day 1 of every 8th week of 
treatment period, and at the safety follow-up visit (28 days after the last study drug 
administration).  
It is recommended, where possible, that a subject’s PS will be assessed by the same person 
throughout the study.  
 
Clinical Safety Assessments 
The NCI CTC-AE version 4.0 will be used to evaluate the clinical safety parameters of the 
study drug. Patients will be assessed for adverse events at each clinical visit from screening 
onwards and as necessary throughout the study. 
A complete medical history (including demographics) will be performed at screening and a 
physical examination will be performed at each visit, as indicated in the Schedule of 
Assessments. 
Safety assessments will consist of monitoring and recording all AEs and serious adverse 
events (SAEs); regular monitoring of haematology, biochemical analyses results and 
physical examinations. Electrocardiogram (ECG) recordings will be performed as part of the 
screening (baseline) assessments and if clinically indicated throughout the study. 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 42 of 95 
5.4  Laboratory Assessments 
Normal ranges for the study laboratory parameters must be supplied to Roche before the 
study starts.  
 
Efficacy Laboratory Assessments 
Laboratory parameters will not be considered for the purpose of efficacy assessment. 
 
Safety Laboratory Assessments 
All safety laboratory assessments will be performed at local laboratories. 
The following will be completed according to the Schedule of Assessments: 
Blood tests with counts of the three series (leukocytes with neutrophils, haemoglobin, and 
platelets). This information will be obtained in the 21 days before initiation of treatment. 
Biochemistry: LDH, alkaline phosphatase, ASAT, ALAT, total bilirubin, serum creatinine, 
creatinine clearance (if indicated), calcium, electrolytes, glucose and urea. This information 
will be obtained in the 21 days before initiation of treatment. 
Prothrombin time, INR and aPTT. This information will be obtained in the 7 days before 
initiation of treatment. 
Pregnancy test (urine or blood) in women of childbearing age, to be performed at screening 
and in the 1st day of study treatment (baseline), before the intake of study medication and at 
the end of study treatment. 
 
5.5  Safety Follow-Up Visit (28 days after last study drug administration) 
Patients who discontinued therapy due to disease progression, unacceptable toxicity or 
patient’s decision, should have a safety follow-up completed 28 days after last dose of  
study treatment. This assessment should include physical examination, ECOG performance 
status, haematology, biochemistry, concomitant medications, adverse events and subsequent 
therapy for NSCLC.  
 
5.6  Survival Follow-up Phase  
After the final visit has been completed the patient should be followed every 6 months (± 15 
days), or as appropriate evaluated by the investigator, for collection of subsequent therapies 
and survival status.  
 
6. INVESTIGATIONAL MEDICINAL PRODUCT 
6.1  Dose and Schedule of IMP and Comparator(S) 
Erlotinib will be administered as single daily oral dose of 150 mg, until disease progression 
or unacceptable toxicity. No dose escalation of erlotinib is permitted. Dose reduction will be 
allowed according to protocol (Section 6.1.). 
 
Dose Modifications, Interruptions and Delays  
Reduction of dosing for adverse events may take place at any time during the study. 
Diarrhoea and skin rash are the major side effects associated with erlotinib. Other known 
side effects, include dry skin, fatigue, pruritus, nausea, vomiting, anorexia, abdominal pain, 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 43 of 95 
gastrointestinal perforation, dry mouth, dry eye, and headache. Dose reductions can be made 
according to the system exhibiting the greatest degree of toxicity. All toxicities will be 
graded according to the NCI CTC-AE version 4.0. 
In the event of toxicity (e.g., diarrhoea, rash) that is not controlled by optimal supportive 
care, or not tolerated due to any reason, regardless of severity, the daily dose of erlotinib 
will be decreased to 100 mg/day.  
Within 2 weeks following a dose reduction, erlotinib related toxicity must improve by at 
least one NCI-CTC grade and be NCI-CTC Grade 2 or better (any ocular toxicity must 
improve to NCI-CTC Grade 1), or a further dose reduction to 50 mg/day  will be required.  
 
Table 3 - Dose Level Reductions 
Starting Dose 
First reduction 
Second reduction 
150 mg/day 
100 mg/day 
50 mg/day 
 
Patients who cannot tolerate a dose reduction to 50 mg/day will be permanently 
discontinued from the study. 
Dosing may be interrupted for a maximum of 2 weeks if clinically indicated and if the 
toxicity is not controlled by optimal supportive medication. 
Once a patient has had a dose reduction for toxicity, the dose will not be re-escalated except 
in the case of erlotinib related rash. In the event of a rash, dose can be re-escalated when 
rash is NCI-CTC Grade 2. 
 
Supportive Care Guidelines 
 
Diarrhoea: 
Diarrhoea has been commonly observed (~ 50% patients) and is usually transient in nature. 
Previous trials have shown that the frequency and severity of diarrhoea rarely hindered 
administration of erlotinib and could be managed with loperamide. The recommended dose 
is loperamide 4 mg at first onset, followed by 2 mg every 2 – 4 hours until diarrhoea-free for 
12 hours. Patients with diarrhoea should have regular monitoring of their electrolytes and be 
adequately rehydrated (see table 2 below). Prophylactic use of anti-diarrhoea treatments is 
not advised. 
 
 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 44 of 95 
 
Table 4 - Guidelines for management of erlotinib-related toxic effects: 
Toxicity 
Grade 
Guideline for management 
Dose modification 
of erlotinib* 
Keratitis 
2 
Interrupt the treatment. 
Ophthalmologic assessment. 
Hold until recovery, 
and then restart at 
reduced dose. 
Continue regular 
ophthalmological 
assessments while 
on treatment. 
≥ 3 
Discontinue treatment and 
seek ophthalmological advice 
 
Diarrhoea 
1  
Consider Loperamide (4 mg at 
first onset, followed by 2 mg 
every 2 – 4 hours until 
diarrhoea free for 12 hours) 
and appropriate rehydration. 
None 
2 
Loperamide (4 mg at first 
onset, followed by 2 mg every 
2 – 4 hours until diarrhoea 
free for 12 hours) and 
appropriate rehydration. 
Interrupt 
 
3 
Interrupt and give appropriate 
rehydration, monitor 
electrolyte balance and renal 
function until resolution to 
Grade ≤ 1; restart at reduced 
dose.  
Interrupt 
4 
Discontinue treatment 
 
Rash 
1 
No intervention 
None 
2 
Any of the following: 
minocyclinea, topical 
tetracycline or clindamycin, 
topical silver sulfadiazine, 
diphenhydramine, oral 
prednisone (short course) 
None** 
3 
Hold until recovery 
to ≤ grade 2, and 
then restart the dose. 
4 
Discontinue treatment 
 
Other toxicity 
≥ 2 
prolonged 
clinically 
significant 
toxicity 
Treatment as appropriate 
Hold until recovery 
to ≤ grade 1, and 
then restart at 
reduced dose. 
* If no recovery after 14 days of holding drug, patients should be discontinued from the study 
** If dose has been previously held for grade 2 rash or diarrhoea, and grade 2 symptoms recur, or if the patient finds the 
symptoms unacceptable, hold dose until recovery to ≤ grade 1 and then reduce the dose. 
a Recommended dose: 200 mg p.o. b.i.d. (loading dose), followed by 100 mg p.o. b.i.d. for 7-10 days. 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 45 of 95 
 
Rash: 
 
Skin rash or dermatosis (Grade 1 – 2) has been observed during the first several days of 
treatment with erlotinib in more than 50% and has been observed to diminish in severity 
despite continued treatment in many patients. In some patients, particularly when a 
superimposed infection is suspected, this rash appeared to improve with topical and oral 
antibiotics. In general, rash manifests as a mild or moderate erythematosus and 
papulopustular rash, which may occur, or worsen, in sun exposed areas. For patients who 
are exposed to sun, protective clothing, and/or use of sun screen (e.g. mineral-containing) 
may be advisable. In patients with severe rash, treatment may need to be discontinued or the 
dose reduced (see table 4 below). 
In the event of a rash, dose can be re-escalated when rash is ≤ grade 2. Within 2 weeks 
following a dose reduction, erlotinib related toxicity must improve by at least one NCI-CTC 
grade and be NCI-CTC Grade 2, or further dose reduction by one level will be required. 
Dosing may be interrupted for a maximum of 2 weeks if clinically indicated and if the 
toxicity is not controlled by optimal supportive medication. Once a patient has had a dose 
reduction for toxicity, the dose will not be re-escalated except in the case of erlotinib related 
rash. 
 
Stevens-Johnson syndrome 
 
Very rare cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis have 
been reported, which in some cases were fatal - see section 4.8 of SPC (30). Erlotinib 
treatment should be interrupted or discontinued if the patient develops severe bullous, 
blistering or exfoliating conditions. 
 
Interstitial Lung Disease (ILD) 
 
In patients who develop acute onset of new and/or progressive unexplained pulmonary 
symptoms such as dyspnoea, cough and fever, erlotinib therapy should be interrupted 
pending diagnostic evaluation. If ILD is diagnosed, Erlotinib should be discontinued and 
appropriate treatment initiated as necessary - see section 4.8 of the SPC (30). If ILD is 
excluded, re-medication is considered at the same dose.  
 
Missed doses: 
Doses should be taken at the same time each day. If the patient vomits after ingesting the 
tablets, the dose will be replaced only if the tablets can actually be seen and counted. A 
missed dose normally taken in the morning can be taken any time during the same day. 
Patients will be asked to report any missed doses to study site personnel. 
 
6.2  Preparation and Administration of IMP and Comparator(S) 
Erlotinib will be administered with up to 200 ml of water, preferably in the morning. The 
study drug should be taken at least 1 hour before or 2 hours after ingestion of food or any 
other medication. No food, grapefruit juice, vitamins, iron supplements, or non-prescription 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 46 of 95 
medications should be consumed between two hours before and one hour after ingestion of 
erlotinib. 
 
6.3  Formulation, Packaging and Labelling 
Erlotinib will be supplied as 150 mg, 100 mg and 25 mg round, biconvex tablets with 
straight sides. Tablet strength is expressed in terms of erlotinib free base. All tablets have a 
white film coat (Opadry White®). The tablets will be provided in blister cards. 
The study drug must be stored according to the details on the product label. The study drug 
should be stored at room temperature (15-30oC /59-86oF) and should not be used past the 
expiry date. 
 
6.4  Blinding and Unblinding 
Not applicable, study is on open label, single arm trial. 
  
6.5  Assessment of Compliance 
Subject compliance will be assessed by maintaining adequate study drug dispensing records. 
The investigator is responsible for ensuring that dosing is administered in compliance with 
the protocol. Delegation of this task must be clearly documented and approved by the 
investigator. 
Patients will be asked to return all used and unused blister cards and boxes at every study 
visit and at the end of the treatment as a measure of compliance. 
Accurate records must be kept for each study drug provided by the sponsor. These records 
must contain the following information: 
Documentation of drug shipments received from the sponsor (date received and quantity). 
Disposition of unused study drug not dispensed to patient. 
 
A Drug Dispensing Log must be kept current and should contain the following information:  
The identification of the patient to whom the study medication was dispensed. 
The date(s) and quantity of the study medication dispensed to the patient. 
The date(s) and quantity of the study medication returned by the patient. 
 
This inventory must be available for inspection by the Monitor. All supplies, including 
partially used or empty blister cards, boxes and copies of the dispensing and inventory logs, 
must be returned to the Roche Monitor at the end of the study, unless alternate destruction 
has been authorized by Roche, or required by local or institutional regulations (see Section 
6.6). 
 
6.6  Destruction of the Study Drug  
Local or institutional regulations may require immediate destruction of used investigational 
medicinal product (IMP) for safety reasons e.g., cytotoxicity.  In these cases, it may be 
acceptable for investigational site staff to destroy dispensed IMP before a monitoring 
inspection provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, returned 


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Protocol ML25434 1.5, dated  12nd February 2014 
Page 54 of 95 
7.3 Warnings and Precautions  
 
Interstitial Lung Disease (ILD)-Like Events 
Cases of interstitial lung disease (ILD)-like events, including fatalities, have been reported 
uncommonly in patients receiving erlotinib for treatment of NSCLC, pancreatic cancer or 
other advanced solid tumours. In pivotal study BR 21, in NSCLC, the incidence of serious 
ILD-like events was 0.8% in each of the placebo and erlotinib arms. In the pancreatic cancer 
study in combination with gemcitabine, the incidence of ILD-like events was 2.5% in the 
erlotinib plus gemcitabine group versus 0.4% in the placebo plus gemcitabine treated group. 
The overall incidence in patients treated with erlotinib from all studies (including 
uncontrolled studies and studies with concurrent chemotherapy) is approximately 0.6%. 
Some examples of reported diagnoses in patients suspected of having ILD-like events 
include pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial 
pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute 
respiratory distress syndrome, lung infiltration and alveolitis. These ILD-like events started 
from a few days to several months after initiating erlotinib therapy. Most of the cases were 
associated with confounding or contributing factors such as concomitant or prior 
chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung 
disease, or pulmonary infections. 
In patients who develop acute onset of new and/or progressive unexplained pulmonary 
symptoms, such as dyspnoea, cough and fever, erlotinib therapy should be interrupted 
pending diagnostic evaluation. If ILD is diagnosed, erlotinib should be discontinued and 
appropriate treatment initiated as necessary. 
 
Diarrhoea, Dehydration, Electrolyte Imbalance and Renal Failure 
Diarrhoea has occurred in patients on erlotinib, and moderate or severe diarrhoea should be 
treated with loperamide. In some cases, dose reduction may be necessary. In the event of 
severe or persistent diarrhoea, nausea, anorexia, or vomiting associated with dehydration, 
erlotinib therapy should be interrupted and appropriate measures should be taken to treat the 
dehydration. There have been rare reports of hypokalaemia and renal failure (including 
fatalities). Some reports of renal failure were secondary to severe dehydration due to 
diarrhoea, vomiting and/or anorexia while others were confounded by concomitant 
chemotherapy. In more severe or persistent cases of diarrhoea, or cases leading to 
dehydration, particularly in groups of patients with aggravating risk factors (concomitant 
medications, symptoms or diseases or other predisposing conditions including advanced 
age), erlotinib therapy should be interrupted and appropriate measures should be taken to 
intensively rehydrate the patients intravenously. In addition, renal function and serum 
electrolytes including potassium should be monitored in patients at risk of dehydration. 
 
 
Hepatitis, Hepatic Failure 
Rare cases of hepatic failure (including fatalities) have been reported during use of erlotinib. 
Confounding factors have included pre-existing liver disease or concomitant hepatotoxic 
medications. Therefore, in such patients, periodic liver function testing should be 
considered. Erlotinib dosing should be interrupted if changes in liver function are severe. 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 55 of 95 
Gastrointestinal perforation 
Patients receiving erlotinib are at increased risk of developing gastrointestinal perforation, 
which was observed uncommonly (including some cases with a fatal outcome). Patients 
receiving concomitant anti-angiogenic agents, corticosteroids, non-steroidal anti-
inflammatory drugs (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). 
 
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. 
 
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, which are also risk factors for 
corneal perforation/ulceration. Erlotinib therapy should be interrupted or discontinued if 
patients present with acute/worsening ocular disorders such as eye pain. 
 
Co-administration with medicinal products that alter the pH of the upper Gastro-
Intestinal (GI) tractErlotinib is characterised by a decrease in solubility at pH above 5. 
Medicinal products that alter the pH of the upper Gastro-Intestinal (GI) tract, like proton 
pump inhibitors, H2 antagonists and antacids, may alter the solubility of erlotinib and hence 
its bioavailability. Increasing the dose of Tarceva when co-administered with such agents is 
not likely to compensate for the loss of exposure. Combination of erlotinib with proton 
pump inhibitors should be avoided. The effects of concomitant administration of erlotinib 
with H2 antagonists and antacids are unknown; however, reduced bioavailability is likely. 
Therefore, concomitant administration of these combinations should be avoided. If the use 
of antacids is considered necessary during treatment with Tarceva, they should be taken at 
least 4 hours before or 2 hours after the daily dose of Tarceva. 
 
Lactose Intolerance 
The tablets contain lactose and should not be administered to patients with rare hereditary 
problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose 
malabsorption. 
 
Toxicity Due to Drug-Drug Interactions 
Erlotinib has a potential for clinically significant drug-drug interactions (See Appendix 4). 
 


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Protocol ML25434 1.5, dated  12nd February 2014 
Page 57 of 95 
8.2.1.2.Secondary Variables 
PFS will be summarized as median time and will be estimated trough Kaplan-Meier method. 
95% confidence interval will be estimated for median time to PFS. 
 
Overall survival variable will be summarized as median time to OS and will be estimated 
trough Kaplan-Meier method. 95% confidence interval will be estimated for median time to 
OS. 
 
The presence of EGFR mutation in the study population will be presented as relative 
frequency presented as a percentage (%).  A 95% confidence interval will be estimated for 
this value using binomial distribution.  
 
Response duration variable will be summarized as median time to response duration and 
will be estimated trough Kaplan-Meier method. 95% confidence interval will be estimated 
for median time to response duration. 
 
8.2.1.3. Exploratory Analysis 
 
PFS will be summarized by exon 19 and 21 as median time and will be estimated trough 
Kaplan-Meier method. 
 
8.2.2  Hypothesis Testing 
Not applicable. 
 
8.2.3 Types of Analyses 
8.2.3.1.Efficacy Analysis 
Efficacy analysis will be based on the intent-to-treat and per-protocol population. The ITT 
analysis will be considered as the primary analysis. 
 
 
8.2.3.1.1.Intent to treat population: 
Intention to treat population will be defined as all subjects who are enrolled to the treatment 
phase of the study, regardless if they completed treatment. 
 
8.2.3.1.2.Per-protocol population: 
Per protocol population will include all subjects enrolled in the treatment phase of the study 
without major protocol violations. The protocol violations and corresponding impact are 
listed below. 
 
 
 




Protocol ML25434 1.5, dated  12nd February 2014 
Page 59 of 95 
8.2.6 Sample Size 
The sample size was calculated based on the primary variable of the study, objective 
response rate. Since this proportion is unknown an exploratory sample size of 30 patients 
was considered to evaluate primary endpoint. This sample size will allow estimating ORR 
with a margin of error of approximately ±17.5%, for a 95% confidence interval. 
Furthermore, approximately 2000 new cases of stage IIIB and IV NSCLC are diagnosed per 
year in Portugal1 and, based on published data, expected prevalence of EGFR mutation is 
approximately 10%. With a 95% confidence interval, it was calculated that at least 420 
patients will have to be enrolled to be tested to achieve 30 positive cases for the exploratory 
sample size analysis. 
 
8.2.7 Interim Analysis 
One interim analysis is planned for the study with a cut-off date on 30th September 2013. 
This interim analysis will include an epidemiological, efficacy and safety characterization of 
erlotinib in 1st line EGFR Mut+ mNSCLC Portuguese population. 
Interim analysis will include the following descriptive analyses: 
Characterization - demographics, medical history, Eastern cooperative oncology group 
performance status, clinical response (RECIST criteria). 
Efficacy – Best Overall response, progression free survival, overall survival and epidermal 
growth factor receptor. Additionally, PFS will be obtained for Exon 19 and Exon 20 (if 
applicable). 
Safety – Drug compliance, adverse events (incidence of AE and SAE, incidence of AE and 
SAE with remote, possible or probable relationship with study drug, description of AE and 
SAE, SAE with remote, possible or probable relationship with study drug) and subsequent 
therapy for NSCLC. 
Analysis will be conducted according to the definitions described in section 8.1 and 
considering the populations described in section 8.2.1.. 
 
 
9. DATA COLLECTION, MANAGEMENT AND QUALITY 
ASSURANCE 
 
The overall procedures for quality assurance of clinical study data are described in the 
Standard Operational Procedures. 
Data for this study will be recorded via an Electronic Data Capture system EDC using 
electronic Case Report Forms (eCRF). It will be transcribed by the site from the paper 
source documents onto the eCRF. In no case the eCRF is considered as source data for 
this trial.  
Accurate and reliable data collection will be assured by verification and cross–check of the 
eCRFs against the investigator’s records by the study monitor (source document 
verification), and the maintenance of a drug–dispensing log by the investigator. 
A comprehensive validation check program utilizing front-end checks in the eCRF and 
back-end checks in the Roche data base will verify the data and discrepancies will be 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 60 of 95 
generated accordingly. These are transferred electronically to the eCRF at the site for 
resolution by the investigator. 
Throughout the study the SMT will review data according to the SMT Data Review Plan as 
described in the Data Quality Plan. 
In order to facilitate analysis of the biological samples collected in this study, the treatment 
code will be released to the responsible analytical person when the samples have been 
received at the analytical site and are ready for assay. The result of the analysis must not be 
released with individual identification of the subject until the database is closed. 
 
9.1  Assignment of Preferred Terms and Original Terminology 
For classification purposes, preferred terms will be assigned by the sponsor to the original 
terms entered on the eCRF, using the most up-to-date version of the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology for adverse events and diseases and the 
International Non-proprietary Name Drug Terms and Procedures Dictionary for treatments 
and surgical and medical procedures. 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 61 of 95 
 
10. 
REFERENCES 
                                                 
 
1 Parkin DM, Bray F, Ferlay J, Pisani P. “Global cancer statistics, 2002.” CA Cancer J. Clin 
2005; 55: 74-108. 
 
2 D’Addario G, Felip E. “Non-small-cell lung cancer: ESMO clinical recommendations for 
diagnosis, treatment and follow-up.” Ann Oncol 2008; 19(Suppl 2): ii39-ii40. 
 
3 Spiro SG, Porter JC. “Lung cancer – where are we today? Current advances in staging and 
nonsurgical treatment.” Am J Respir Crit Care Med 2002; 166: 1166-1196. 
 
4 Cartman ML, Hatfield AC, Muers MF, Peake MD, Haward RA, Forman,D. “Lung cancer: 
district active treatment rates affect survival.” J Epidemiol Community Health 2002; 56: 
424-429. 
 
5 Haura EB. “Treatment of advanced non-small-cell lung cancer: a review of current 
randomized clinical trials and an examination of emerging therapies.” Cancer Control 2001; 
8: 326-336. 
 
6 Office for National Statistics. Report: Cancer survival in England and Wales, 1991–98. 
Health Statistics Quarterly. 2000; 6: 71–80. 
 
7 Ramsey SD, Martins RG, Blough KD, Tock LS, Lubeck D, Reyes CM. “Second-line and 
Third-line Chemotherapy for Lung Cancer: Use and Cost.” Am J Manag Care 2008; 14: 
297-306. 
 
8 Delbaldo C, Michiels S, Syz N, Soria JC, Le Chevalier T, Pignon JP. “Benefits of adding a 
drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung 
cancer: a meta-analysis.” JAMA 2004; 292: 470-484. 
 
9 Shepherd FA, Pereira JR, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. “Erlotinib 
in previously treated non-small-cell lung cancer.” N Engl J Med 2005; 353: 123-32. 
 
10 Pérez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, et al. 
“Determinants of tumor response and survival with erlotinib in patients with non-small-cell 
lung cancer.” J Clin Oncol 2004; 22: 3238-47. 
 
11 Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Branngan BW, et al. 
“Activating mutations in the epidermal growth factor receptor underlying responsiveness of 
non-small-cell lung cancer to gefitinib.” N Engl J Med 2004; 350: 2129-39.  
 
12 Moyer JD, Barbacci EG,  Iwata KK, Arnold L, Boman B,  Cnnningham A, et al. 
“Induction of Apoptosis and Cell Cycle Arrest by CP-358,774, an Inhibitor of Epidermal 


Protocol ML25434 1.5, dated  12nd February 2014 
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Growth Factor Receptor Tyrosine Kinase.” CANCER RESEARCH 1997 Nov; 57: 4838-
4848. 
 
13 OSI Pharmaceuticals, Genentech Inc, and F.Hoffmann-La Roche. Clinical investigator's 
brochure, 14th Edition, 5th March 2010. 
 
14 Rudin CM, Liu W, Desai A, Karrison T, Jiang X, Janisch L, et al. “Pharmacogenomic and 
Pharmacokinetic Determinants of Erlotinib Toxicity.” J Clin Oncol 2008 Mar; 26:.1119-
1127. 
 
15Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD, Morse D, et al. “United 
States Food and Drug Administration Drug Approval Summary: Gefitinib (ZD1839; Iressa) 
Tablets.” Clin Cancer Res 2004 Feb 15; 10: 1212–1218. 
 
16Li J, Karlsson MO, Brahmer J, Spitz A, Zhao M, Hidalgo M, Baker SD. “CYP3A 
phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors.” J 
Natl Cancer Inst 2006 Dec 6: Vol. 98: 1714-1723. 
 
17 Tarceva® Summary of Product Characteristics, 1st July 2010. 
 
18 Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, 
Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA; TRIBUTE Investigator Group. 
TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin 
and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 
Sep 1;23(25):5892-9. 
 
19 Gatzemeier U, Pluzanska A, Szczesna A et al. Results of a phase III trial of erlotinib 
(OSI-774) combined with cisplatin and GC chemotherapy in advanced non-small cell lung 
cancer (NSCLC). J Clin Oncol 2004;22(suppl 14):619s. 
 
20 Capuzzo F, Ciuleanu T, Stelmakh L, Szczesna A, et al. “Erlotinib as maintenance 
treatment in advanced non-small-cell lung cancer: a multicentre randomized placebo-
controled phase 3 study.” The Lancet Oncology, 2010; 11, Nº 6:521-529. 
 
21 Cappuzzo F, Coudert BP, Wierzbicki R, Wu YL, Gonzalez EE, Davidson N, et al. 
“Efficacy and safety of erlotinib as first-line maintenance in NSCLC following non-
progression with chemotherapy: results from the phase III SATURN study.” J Thorac Oncol 
2009; 4(Supple 1): S289. 
 
22 Mok TS, Wu YL, Thongprasert S, Yang CH, et al. Gefitinib or carboplatin-paclitaxel in 
pulmonary adenocarcinoma. N Engl J Med 2009;361(10):947-57. 
 
23 Paz-Ares L, Soulières D, Melezínek I, Moecks J, et al. “Clinical outcomes in non-small-
cell lung cancer patients with EGFR mutations: pooled analysis.” J Cell Mol Med 201014, 
Nº1-2: 51-59 


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24 Rosell R, Moran T, Queralt C, Porta R, Spanish Lung Cancer Group, et al. Screening for 
epidermal growth factor receptor mutations in lung cancer. N Engl J Med 
2009;361(10):958-67. 
 
25 Zhou C, Wu Y-L, Chen G, Feng J, Liu X, Wang C, Zhang S, Wang J, Zhou S, Ren S, on 
behalf of the OPTIMAL investigators, et al. Efficacy results from the randomised phase III 
OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (cbdca) 
plus gemcitabine (gem), in chinese advanced non-small-cell lung cancer (nsclc) patients 
(pts) with EGFR activating mutations. Ann Oncol 2010;21(Suppl 8):viii1-viii12. ESMO 
2010 late-breaking abstracts. 
 
26 Neal JW, Lecia VS. “First-line use of EGFR tyrosine kinase inhibitors in patients with 
NSCLC containing EGFR mutations.” Clin Adv Hematol Oncol 2010; 8: 119-26. 
 


Protocol ML25434 1.5, dated  12nd February 2014 
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PART II: 
ETHICS AND GENERAL STUDY ADMINISTRATION 
11. 
Ethical Aspects 
11.1 
Local Regulations/Declaration of Helsinki 
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 subject. For studies conducted in the EU/EEA countries, the investigator 
will ensure compliance with the EU Clinical Trial Directive [2001/20/EC]. 
In other countries where “Guideline for Good Clinical Practice” exists Roche and the 
investigators will strictly ensure adherence to the stated provisions. 
11.2 
Informed Consent  
It is the responsibility of the investigator, or a person designated by the investigator [if 
acceptable by local regulations], to obtain signed informed consent from each subject 
prior to participating in this study after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study.  
The investigator or designee must also explain that the subjects are completely free to refuse 
to enter the study or to withdraw from it at any time, for any reason.   
The electronic Case Report Forms (eCRFs) for this study contain a section for documenting 
subject informed consent, and this must be completed appropriately. If new safety 
information results in significant changes in the risk/benefit assessment, the consent form 
should be reviewed and updated if necessary. All subjects (including those already being 
treated) should be informed of the new information, given a copy of the revised form and 
give their consent to continue in the study. 
For the subject not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative.  In the case where both the subject and 
his/her legally acceptable representative are unable to read, an impartial witness should be 
present during the entire informed consent discussion.  After the subject and representative 
have orally consented to participation in the trial, the witness’ signature on the form will 
attest that the information in the consent form was accurately explained and understood.  
 
11.3 
Independent Ethics Committees (IEC)/Institutional Review Board 
(IRB)  
The sponsor will submit to the Competent Authority (CA) and IEC, the protocol and any 
accompanying material provided to the patient. The accompanying material may include 
patient information sheets, descriptions of the study used to obtain informed consent and 
terms of any compensation given to the patient as well as advertisements for the trial. 
An approval letter or certificate (specifying the protocol number and title) from the IEC/IRB 
must be obtained before study initiation by the investigator specifying the date on which the 
committee met and granted the approval.  This applies whenever subsequent 
amendments/modifications are made to the protocol. 
Any modifications made to the protocol, informed consent or material provided to the 
patient after receipt of the IEC/IRB approval must also be submitted by the Sponsor in the 


Protocol ML25434 1.5, dated  12nd February 2014 
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European economic Area (EEA) member states in accordance with local procedures and 
regulatory requirements. 
When no local review board exists, the investigator is expected to submit the protocol to a 
regional committee.  If no regional committee exists, Roche will assist the investigator in 
submitting the protocol to the European Ethics Review Committee. 
Roche shall also submit an Annual Safety Report once a year to the IEC and Competent 
Authorities (CAs) according to local regulatory requirements and timelines of each country 
participating in the study.  
11.4 
Financial Disclosure 
The investigator(s) will provide the Sponsor with sufficient accurate financial information 
(PD35) to allow the Sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities.  The investigator is 
responsible to promptly update any information provided to the Sponsor if relevant changes 
occur in the course of the investigation and for 1 year following the completion of the study 
(last patient, last visit). 
 
12. 
Conditions For Modifying The Protocol 
Requests from investigators to modify the protocol to ongoing studies will be considered 
only by consultation between an appropriate representative of the sponsor and the 
investigator (investigator representative(s) in the case of a multicenter trial). Protocol 
modifications must be prepared by a representative of the sponsor and initially reviewed and 
approved by the Country Medical Manager and Biostatistician. 
All protocol modifications must be submitted to the appropriate IEC or IRB for information 
and approval in accordance with local requirements, and to Regulatory Agencies if required. 
Approval must be obtained before any changes can be implemented, except for changes 
necessary to eliminate an immediate hazard to trial patients, or when the change(s) involves 
only logistical or administrative aspects of the trial (e.g. change in monitor(s), change of 
telephone number(s). 
13. 
Conditions For Terminating The Study 
In terminating the study, Roche and the investigator will assure that adequate consideration 
is given to the protection of the patient’s interests. The appropriate IRB/IEC and Regulatory 
Agencies should be informed accordingly. 
14. 
Study Documentation, CRFs And Record Keeping 
14.1 
Investigator's Files / Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into two different separate categories: 1) Investigator's Study 
File, and 2) subject clinical source documents. 
The Investigator's Study File will contain the protocol/amendments, CRF/DCS and schedule 
of assessments, Independent Ethics Committee/Institutional Review Board and 
governmental approval with correspondence, sample informed consent, drug records, staff 
curriculum vitae and authorization forms and other appropriate documents/correspondence, 


Protocol ML25434 1.5, dated  12nd February 2014 
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etc. In addition at the end of the study the investigator will receive the subject data, which 
includes an audit trail containing a complete record of all changes to data, query resolution 
correspondence and reasons for changes, in human readable format on CD which also has to 
be kept with the Investigator’s Study File. 
Subject clinical source documents [usually defined by the project in advance to record key 
efficacy/safety parameters independent of the CRFs] would include subject hospital/clinic 
records, physician's and nurse's notes, appointment book, original laboratory reports, ECG, 
EEG, X-ray, pathology and special assessment reports, signed informed consent forms, 
consultant letters, and subject screening and enrolment logs. The Investigator must keep the 
two categories of documents as described above (including the archival CD) on file for at 
least 15 years after completion or discontinuation of the study. After that period of time the 
documents may be destroyed, subject to local regulations. 
Should the Investigator wish to assign the study records to another party or move them to 
another location, Roche must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site for 
any or all of the documents, special arrangements must be made between the Investigator 
and Roche to store these in a sealed container[s] outside of the site so that they can be 
returned sealed to the Investigator in case of a regulatory audit. Where source documents are 
required for the continued care of the subject, appropriate copies should be made for storing 
outside of the site. 
ICH GCP guidelines require that Investigators maintain information in the study subject’s 
records which corroborate data collected on the eCRF(s).  Completed eCRF will be 
forwarded to Roche. 
14.2 
Source Documents and Background Data 
The investigator shall supply the sponsor on request with any required background data 
from the study documentation or clinic records. This is particularly important when errors in 
data transcription are suspected. In case of special problems and/or governmental queries or 
requests for audit inspections, it is also necessary to have access to the complete study 
records, provided that subject confidentiality is protected. 
14.3 
Audits and Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development Quality 
Assurance Unit or its designees or to health authority inspectors after appropriate 
notification, always through the investigator supervision. The verification of the eCRF data 
must be by inspection of source documents, again under investigator’s supervision. 
14.4 
Electronic Case Report Forms  
Data for this study will be captured via an Electronic Data Capture (EDC) system by using 
eCRFs on a laptop. The data is entered on to the laptop using the off-line mode. An audit 
trail will maintain a record of initial entries and changes made; reasons for change; time and 
date of entry; and user name of person authorizing entry or change. The investigator will 
connect and enter data on a regular basis. 
For each patient enrolled, an eCRF must be completed and electronically signed by the 
principal investigator or authorized delegate from the study staff. This also applies to 
records for those patients who fail to complete the study (even during a pre-randomization 
screening period if an eCRF was initiated). If a patient withdraws from the study, the reason 


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must be noted on the eCRF. If a patient is withdrawn from the study because of a treatment-
limiting AE, thorough efforts should be made to clearly document the outcome. 
The investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the sponsor in the eCRFs and in all required reports. 
15. 
MONITORING THE STUDY 
It is understood that the responsible Roche monitor (or designee) will contact and visit the 
investigator regularly and will be allowed, on request and always through the investigator 
supervision, to inspect the various records of the trial (eCRF and other pertinent data) 
provided that patient confidentiality is maintained in accord with local requirements. 
It will be the monitor's responsibility to inspect the eCRF at regular intervals throughout the 
study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them. The monitor must verify that the patient 
received the study drug assigned by the randomization centre. The monitor should have 
access to laboratory test reports and other patient records needed to verify the entries on the 
eCRF. The investigator (or deputy) agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
16. 
CONFIDENTIALITY OF TRIAL DOCUMENTS 
AND SUBJECT RECORDS 
The investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On eCRFs or other documents submitted 
to the sponsor, patients should not be identified by their names, but by an identification 
code. The investigator should keep a patient enrolment log showing codes, names and 
addresses. 
The investigator should maintain documents not for submission to Roche, e.g., Roche 
already maintains rigorous confidentiality standards for clinical studies by “coding” (i.e. 
assigning a unique patient identity (ID) number at the investigator site) all patients enrolled 
in Roche clinical studies. This means that patient names are not included in data sets that are 
transmitted to any Roche location. 
17. 
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS 
Roche will comply with the requirements for publication of study results. 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission. This allows the sponsor to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the 
investigator. Country-specific analyses will be allowed upon approval by Roche 
Headquarters. 
In accordance with standard editorial and ethical practice, Roche will generally support 
publication of multicenter trials only in their entirety and not as individual centre data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
Data derived from RCR specimen analysis on individual subjects will not be provided to 
study investigators, except where explicitly stipulated in a study protocol (e.g. if the result is 
an enrolment criterion). Exceptions may be granted (e.g. if biomarker data would be linked 


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to safety issues). The aggregate results of any research conducted using RCR specimens will 
be available in accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements and / or know- how originating from 
the use of the RCR will become and remain the exclusive and unburdened property of 
Roche, except where agreed otherwise.  
 


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18. 
Appendix 1: The RECIST Criteria for Tumor 
Response 
Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 
Quick Reference (http://ctep.cancer.gov/guidelines/recist.html) 
 
Measurability of tumour at baseline 
1. Definitions 
At baseline, tumour lesions/lymph nodes will be categorized measurable or non-measurable 
as follows: 
1.1. Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm calliper measurement by clinical exam (lesions which cannot be accurately 
measured with callipers should be recorded as non-measurable). 
•   20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be P15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
1.2. Non-measurable 
 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with P10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, and inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses /abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
 
1.3. Special considerations regarding lesion measurability 
 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic lesions: 


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• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
2. Specifications by methods of measurements 
 
2.1. Measurement of lesions 
All measurements should be recorded in metric notation, using callipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the treatment 
start and never more than 4 weeks before the beginning of the treatment. 
 
2.2. Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and P10mm diameter as assessed using callipers (e.g. skin nodules). For the case 
of skin lesions, documentation by colour photography including a ruler to estimate the size 
of the lesion is suggested. As noted above, when lesions can be evaluated by both clinical 
exam and imaging, imaging evaluation should be undertaken since it is more objective and 
may also be reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumour evaluation 
is not advised. However, they can be useful to confirm complete pathological response 


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when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumour response. 
If markers are initially above the upper normal limit, however, they must normalize for a 
patient to be considered in complete response. Because tumour markers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease 
specific basis. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumour types such as 
germ cell tumours, where known residual benign tumours can remain). When effusions are 
known to be a potential adverse effect of treatment (e.g. with certain taxane compounds or 
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment can be considered if the measurable 
tumour has met criteria for response or stable disease in order to differentiate between 
response (or stable disease) and progressive disease. 
 
Tumor response evaluation 
1. Assessment of overall tumour burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumour burden at baseline and use this as a comparator for subsequent measurements. Only 
patients with measurable disease at baseline should be included in protocols where objective 
tumour response is the primary endpoint. Measurable disease is defined by the presence of 
at least one measurable lesion. In studies where the primary endpoint is tumour progression 
(either time to progression or proportion with progression at a fixed date), the protocol must 
specify if entry is restricted to those with measurable disease or whether patients having 
non-measurable disease only are also eligible. 
2. Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where patients have only one or two organ sites involved a 
maximum of two and four lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the 
next largest lesion which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumour. Pathological nodes which are defined 
as measurable and may be identified as target lesions must meet the criterion of a short axis 
of P15mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumour. Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, saggital or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm·30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm 


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should be recorded as the node measurement. All other pathological nodes (those with short 
axis P10mm but <15 mm) should be considered non-target lesions. Nodes that have a short 
axis <10 mm are considered non-pathological and should not be recorded or followed. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterise any objective 
tumour regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are 
not required and these lesions should be followed as ‘present’, ‘absent’, or in rare cases 
‘unequivocal progression’. In addition, it is possible to record multiple non-target lesions 
involving the same organ as a single item on the case record form (e.g. ‘multiple enlarged 
pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
3. Response criteria 
This section provides the definitions of the criteria used to determine objective tumour 
response for target lesions. 
3.1. Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression). 
Stable Disease (SD): Neither sufficient shrinking to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
3.2. Special notes on the assessment of target lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10mm. Case report forms or other data collection methods may therefore be 
designed to have target nodal lesions recorded in a separate section where, in order to 
qualify for CR, each node must achieve a short axis <10 mm. For PR, SD and PD, the actual 
short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan 
that the radiologist may not feel comfortable assigning an exact measure and may report 
themas being ‘too small to measure’. When this occurs it is important that a value be 
recorded on the case report form. If it is the opinion of the radiologist that the lesion has 


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likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned (Note: It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this circumstance as 
well). This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness). The measurement of these lesions is potentially 
non-reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error. To reiterate, however, if the radiologist is able 
to provide an actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesion. If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the ‘coalesced lesion’. 
3.3. Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumour response 
for the group of non-target lesions. 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumour marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: 
the appearance of one or more new lesions is also considered progression). 
3.4. Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient has, also, measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumour burden has increased sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to quality for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
When the patient has only non-measurable disease: This circumstance arises in some phase 
III trials when it is not a criterion of study entry to have measurable disease. The same 
general concepts apply here as noted above, however, in this instance there is no measurable 
disease assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease burden 
based on the change in non-measurable disease is comparable in magnitude to the increase 
that would be required to declare PD for measurable disease: i.e. an increase in tumour 


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burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to 
widespread, or may be described in protocols as ‘sufficient to require a change in therapy’. 
If ‘unequivocal progression’ is seen, the patient should be considered to have had overall 
PD at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so, therefore 
the increase must be substantial. 
3.5. New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumour (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the patient’s baseline lesions show partial or complete response. 
For example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ 
cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of 
this is the patient who has visceral disease at baseline and while on study has a CT or MRI 
brain ordered which reveals metastases. The patient’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. If a new lesion is 
equivocal, for example because of its small size, continued therapy and follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a 
new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
a.) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b.) No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, 
this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET 
scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
4. Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. On occasion 
a response may not be documented until after the end of therapy so protocols should be clear 
if post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 


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response designation. The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. Furthermore, depending on the nature of the study and the 
protocol requirements, it may also require confirmatory measurement. Specifically, in non-
randomized trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the ‘best overall response’. This is described further below. 
4.1. Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 
1 on the next page provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be 
used. 
 
 


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4.2. Missing assessments and invaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will 
have achieved PD status, regardless of the contribution of the missing lesion. 
4.3. Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response IS 
NOT required: Best response in these trials is defined as the best response across all time 
points (for example, a patient who has SD at first assessment, PR at second assessment, and 
PD on last assessment has a best overall response of PR). When SD is believed to be best 
response, it must also meet the protocol specified minimum time from baseline. If the 
minimum time is not met when SD is otherwise the best time point response, the patient’s 
best response depends on the subsequent assessments. For example, a patient who has SD at 
first assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD. The same patient lost to follow-up after the first SD assessment would be 
considered invaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met 
at a subsequent time point as specified in the protocol (generally 4 weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 3. 
 
 
4.4. Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes. As noted earlier, this means 
that patients with CR may not have a total sum of ‘zero’ on the electronic case report form 
(eCRF). 


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In trials where confirmation of response is required, repeated ‘NE’ time point assessments 
may complicate best response determination. The analysis plan for the trial must address 
how missing data/assessments will be addressed in determination of response and 
progression. For example, in most trials it is reasonable to consider a patient with time point 
responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy. The objective 
response status of such patients is to be determined by evaluation of target and non-target 
disease as shown in Tables 1–3. 
Conditions that define early progression, early death and inability to evaluate are study 
specific and should be clearly described in each protocol (depending on treatment duration, 
treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
assigning a status of complete response. FDG-PET may be used to upgrade a response to a 
CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should 
be prospectively described in the protocol and supported by disease specific medical 
literature for the indication. However, it must be acknowledged that both approaches may 
lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
4.5. Frequency of tumour re-evaluation 
Frequency of tumour re-evaluation while on treatment should be protocol specific and 
adapted to the type and schedule of treatment. However, in the context of phase II studies 
where the beneficial effect of therapy is not known, follow-up every 6–8 weeks (timed to 
coincide with the end of a cycle) is reasonable. Smaller or greater time intervals than these 
could be justified in specific regimens or circumstances. The protocol should specify which 
organ sites are to be evaluated at baseline (usually those most likely to be involved with 
metastatic disease for the tumour type under study) and how often evaluations are repeated. 
Normally, all target and non-target sites are evaluated at each assessment. In selected 
circumstances certain non-target organs may be evaluated less frequently. For example, 
bone scans may need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
After the end of the treatment, the need for repetitive tumour evaluations depends on 
whether the trial has as a goal the response rate or the time to an event (progression/death). 
If ‘time to an event’ (e.g. time to progression, disease-free survival and progression-free 
survival) is the main endpoint of the study, then routine scheduled re-evaluation of protocol 
specified sites of disease is warranted. In randomized comparative trials in particular, the 
scheduled assessments should be performed as identified on a calendar schedule (for 
example: every 6–8 weeks on treatment or every 3–4 months after treatment) and should not 


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be affected by delays in therapy, drug holidays or any other events that might lead to 
imbalance in a treatment arm in the timing of disease assessment..6. Confirmatory 
measurement/duration of response 
 
4.6.1. Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and 
CR is required to ensure responses identified are not the result of measurement error. This 
will also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials. However, in all other 
circumstances, i.e. in randomized trials (phase II or III) or studies where stable disease or 
progression are the primary endpoints, confirmation of response is not required since it will 
not add value to the interpretation of trial results. However, elimination of the requirement 
for response confirmation may increase the importance of central review to protect against 
bias, in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general not less than 6–8 weeks) that is defined in the study 
protocol. 
4.6.2. Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first 
met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively documented. 
4.6.3. Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest 
sum on study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and 
diseases. If the proportion of patients achieving stable disease for a minimum period of time 
is an endpoint of importance in a particular trial, the protocol should specify the minimal 
time interval required between two measurements for determination of stable disease. 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 79 of 95 
19. 
Appendix 2: The ECOG Performance Scale 
 
The Eastern Cooperative Oncology Group Performance Status Assessment 
(Oken et al., 1982) 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
 


Protocol ML25434 1.5, dated  12nd February 2014 
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20. 
Appendix 3: Information on Potential Interactions 
 
Erlotinib is metabolized in the liver by the hepatic cytochromes in humans, primarily 
CYP3A4 and to a lesser extent by CYP1A2, and the pulmonary isoform CYP1A1. Potential 
interactions may occur with drugs which are metabolized by, or are inhibitors or inducers of, 
these enzymes. 
Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib 
plasma concentrations. Inhibition of CYP3A4 metabolism by ketoconazole (200 mg p.o. 
BID for 5 days) resulted in increased exposure to erlotinib (86% in median erlotinib 
exposure (AUC)) and a 69% increase in Cmax when compared to erlotinib alone. When 
erlotinib was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and 
CYP1A2, the erlotinib exposure (AUC) and maximum concentration (Cmax) increased by 
39% and 17%, respectively. Therefore caution should be used when administering erlotinib 
with potent CYP3A4 or combined CYP3A4/CYP1A2 inhibitors. In these situations, the dose 
of erlotinib should be reduced if toxicity is observed. 
Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly 
decrease erlotinib plasma concentrations. Induction of CYP3A4 metabolism by rifampicin 
(600 mg p.o. QD for 7 days) resulted in a 69% decrease in the median erlotinib AUC, 
following a 150 mg dose of erlotinib as compared to erlotinib alone. 
Pre-treatment and co-administration of rifampicin with a single 450 mg dose of erlotinib 
resulted in a mean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg erlotinib 
dose in the absence of rifampicin treatment. Alternative treatments lacking potent CYP3A4 
inducing activity should be considered when possible. For patients who require concomitant 
treatment with erlotinib and a potent CYP3A4 inducer such as rifampicin an increase in 
dose to 300 mg should be considered while their safety is closely monitored, and if well 
tolerated for more than 2 weeks, further increase to 450 mg could be considered with close 
safety monitoring. Higher doses have not been studied in this setting. 
Pre-treatment or co-administration of erlotinib did not alter the clearance of the prototypical 
CYP3A4 substrates midazolam and erythromycin. Significant interactions with the 
clearance of other CYP3A4 substrates are therefore unlikely. Oral availability of midazolam 
did appear to decrease by up to 24%, which was however not attributed to effects on 
CYP3A4 activity. 
The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. 
Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and hence 
its bioavailability. Co-administration of erlotinib with omeprazole, a proton pump inhibitor, 
decreased the erlotinib exposure (AUC) and Cmax by 46% and 61%, respectively. There was 
no change to Tmax or half-life. Concomitant administration of erlotinib with 300 mg 
ranitidine, an H2-receptor antagonist, decreased erlotinib exposure (AUC) and Cmax by 33% 
and 54%, respectively. Therefore, co-administration of drugs reducing gastric acid 
production with erlotinib should be avoided where possible. Increasing the dose of erlotinib 
when co-administered with such agents is not likely to compensate for this loss of exposure. 
However when erlotinib was dosed in a staggered manner, 2 hours before or 10 hours after 
ranitidine 150 mg b.i.d., erlotinib exposure (AUC) and Cmax decreased only by 15% and 
17%, respectively. If patients need to be treated with such drugs, then an H2-receptor 


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Protocol ML25434 1.5, dated  12nd February 2014 
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21. 
Appendix 4: 7th Edition AJCC Cancer Staging 
Manual - Part IV  
 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, 
Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh 
Edition (2010) published by Springer Science and Business  Media LLC, www.springer.com.” 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 83 of 95 
 
 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 84 of 95 
 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is 
the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business  Media LLC, www.springer.com.” 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 85 of 95 
 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 86 of 95 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original source for 
this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and 
Business  Media LLC, www springer com.” 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 87 of 95 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 88 of 95 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 89 of 95 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 90 of 95 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 91 of 95 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 
 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 92 of 95 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 
 
 


Protocol ML25434 1.5, dated  12nd February 2014 
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“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 
 
 


Protocol ML25434 1.5, dated  12nd February 2014 
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“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 
 
 
 
 


Protocol ML25434 1.5, dated  12nd February 2014 
Page 95 of 95 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 
 
 
 
“Used with the permission of the American Join Committee on Cancer (AJCC), Chicago, Illinois. The original 
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer 
Science and Business  Media LLC, www springer com.” 
 
 
 
 
 
 
 

SAP_000.pdf: 
 
Official Title: 
Phase II, open-label study of erlotinib (Tarceva®) treatment in 
patients with locally advanced or metastatic non-small cell lung 
cancer who present activating mutations in the tyrosine kinase 
domain of the epidermal growth factor receptor 
NCT Number: 
NCT01260181 
Document Date: 
SAP Version 1: 28 March 2014 
 
 


 
MUTAR 
Phase II, open-label study of erlotinib (Tarceva®) treatment in 
patients with locally advanced or metastatic non-small cell lung 
cancer who present activating mutations in the tyrosine kinase 
domain of the epidermal growth factor receptor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN, Version No 1  
 
PROTOCOL NUMBER:  
ML25434 
STUDY DRUG:   
 
Erlotinib 
IND NUMBER:   
 
RO0508231 
SPONSOR:  
 
 
Roche Farmacêutica Química, Lda. 
PLAN PREPARED BY:   
 
DATE:  
 
 
          28 March, 2014 
 


Statistical analysis plan 
2 | 108 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN (SAP) 
 
STUDY TITLE: Phase II, open-label study of erlotinib (tarceva®) treatment in patients with locally 
advanced or metastatic non-small cell lung cancer who present activating mutations in the tyrosine 
kinase domain of the epidermal growth factor receptor - MuTAR 
 
PROTOCOL VERSION: 1.5   
 
PROTOCOL DATE: 12Feb2014 
 
 
SAP prepared by: 
 
_____________________________________ 
 
__________/________/___________  
 
 
 
 
              
                 dd/mmm/yyyy 
Biostatistician 
 
 
 
SAP reviewed by: 
 
_____________________________________ 
 
__________/________/___________  
 
 
 
 
    
 
                 dd/mmm/yyyy 
Senior Biostatistician 
 
 
 
 
SAP reviewed and approved by: 
 
_____________________________________ 
 
__________/________/___________  
   
 
 
 
 
                 dd/mmm/yyyy 
 
Roche Farmacêutica Química, Lda. 
 


Statistical analysis plan 
3 | 108 
CONFIDENTIAL 
 
Contents: 
INDEX OF TABLES .......................................................................................................................................... 5 
INDEX OF FIGURES ........................................................................................................................................ 7 
INDEX OF LISTINGS ....................................................................................................................................... 8 
1 
BACKGROUND ...................................................................................................................................... 9 
1.1 
Background and rationale ........................................................................................................... 9 
1.1.1 
Background ............................................................................................................................. 9 
1.1.2 
Erlotinib (OSI-774; Tarceva®) ................................................................................................ 10 
2 
STUDY OBJECTIVES ............................................................................................................................. 11 
2.1 
Primary Objectives .................................................................................................................... 11 
2.2 
Secondary Objectives ................................................................................................................ 11 
3 
STUDY DESIGN .................................................................................................................................... 12 
3.1 
Protocol synopsis ...................................................................................................................... 12 
3.2 
Study population ....................................................................................................................... 13 
3.3 
Endpoints .................................................................................................................................. 15 
3.3.1 
Primary efficacy endpoint ..................................................................................................... 15 
3.3.2 
Secondary efficacy endpoints ............................................................................................... 15 
3.3.3 
Safety outcome endpoints ................................................................................................... 15 
3.4 
Analysis timing .......................................................................................................................... 16 
4 
STUDY CONDUCT ................................................................................................................................ 17 
4.1 
Randomization issues ............................................................................................................... 17 
4.2 
Data Monitoring ........................................................................................................................ 17 
5 
STATISTICAL METHODS ...................................................................................................................... 18 
5.1 
Determination of sample size ................................................................................................... 18 
5.2 
Analysis Populations ................................................................................................................. 18 
5.2.1 
Intention to treat (ITT) population ....................................................................................... 18 
5.2.2 
Per protocol (PP) population ................................................................................................ 18 
5.2.3 
Safety population ................................................................................................................. 19 
5.3 
Analysis of study conduct ......................................................................................................... 19 
5.3.1 
Patient disposition ................................................................................................................ 19 
5.3.2 
Demographics ....................................................................................................................... 19 
5.3.3 
Childbearing potential/Pregnancy test ................................................................................. 19 
5.3.4 
Medical history ..................................................................................................................... 20 
5.3.5 
ECOG performance status .................................................................................................... 20 
5.3.6 
Concomitant medications ..................................................................................................... 20 


Statistical analysis plan 
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CONFIDENTIAL 
5.3.7 
Tumour assessment .............................................................................................................. 21 
5.3.8 
Clinical response (RECIST criteria) ........................................................................................ 21 
5.3.9 
Efficacy analysis .................................................................................................................... 21 
5.3.10 
Safety analysis .................................................................................................................. 22 
5.3.11 
Subsequent therapy for NSCLC ........................................................................................ 24 
5.4 
Missing data .............................................................................................................................. 24 
5.5 
Interim Analyses ....................................................................................................................... 25 
6 
STATISTICAL TABLES ........................................................................................................................... 26 
6.1 
Patient disposition .................................................................................................................... 26 
6.2 
Demographics ........................................................................................................................... 26 
6.3 
Childbearing potential/Pregnancy test ..................................................................................... 26 
6.4 
Medical history ......................................................................................................................... 26 
6.5 
ECOG performance status ......................................................................................................... 26 
6.6 
Concomitant medications ......................................................................................................... 26 
6.7 
Tumour assessment .................................................................................................................. 27 
6.8 
Clinical response (RECIST criteria) ............................................................................................. 27 
6.9 
Efficacy analysis ........................................................................................................................ 27 
6.9.1 
Primary Efficacy analysis ....................................................................................................... 27 
6.9.2 
Secondary Efficacy analysis .................................................................................................. 27 
6.9.3 
Exploratory Efficacy analysis ................................................................................................. 28 
6.10 
Safety analysis ........................................................................................................................... 28 
6.10.1 
Drug dispensing and accountability ................................................................................. 28 
6.10.2 
Physical examination ........................................................................................................ 28 
6.10.3 
ECG ................................................................................................................................... 28 
6.10.4 
Laboratory data ................................................................................................................ 29 
6.10.5 
Adverse events ................................................................................................................. 29 
6.11 
Subsequent therapy for NSCLC ................................................................................................. 29 
6.12 
Interim Analysis......................................................................................................................... 29 
7 
REFERENCES ....................................................................................................................................... 30 
Appendix 1: Protocol Synopsis ................................................................................................................... 32 
Appendix 2: Study Flowchart ...................................................................................................................... 37 
Appendix 3: Derived Variables ................................................................................................................... 39 
Appendix 4: Handling incomplete dates..................................................................................................... 42 
Appendix 5: The RECIST Criteria for Tumor Response ............................................................................... 43 
Appendix 6: Statistical Tables ..................................................................................................................... 55 
Appendix 7: Listings .................................................................................................................................. 105 
 


Statistical analysis plan 
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INDEX OF TABLES 
Table 1 – Patients’ disposition .................................................................................................................... 55 
Table 2 – Demographics – ITT population .................................................................................................. 56 
Table 3 – Chilbearing potential / Pregnancy test – ITT population ............................................................ 57 
Table 4 – Medical history: NSCLC Diagnosis – ITT population .................................................................... 58 
Table 5 – Medical history: Co-mordidities – ITT population ...................................................................... 60 
Table 6 – Eastern cooperative oncology group performance status – ITT population .............................. 61 
Table 7 – Concomitant medication – ITT population ................................................................................. 62 
Table 8 – Tumour assessment – ITT population ......................................................................................... 63 
Table 9 – Clinical response: RECIST criteria – ITT population ..................................................................... 64 
Table 10 – Best overall response: RECIST criteria – ITT population ........................................................... 66 
Table 11 – Best overall response: RECIST criteria – PP population ............................................................ 67 
Table 12 – Progression free survival – ITT population................................................................................ 68 
Table 13 – Progression free survival – PP population ................................................................................ 69 
Table 14 – Overall survival – ITT population .............................................................................................. 70 
Table 15 – Overall survival – PP population ............................................................................................... 71 
Table 16 – Epidermal growth factor receptor – All patients ...................................................................... 72 
Table 17 – Epidermal growth factor receptor ............................................................................................ 73 
Table 18 – Response duration– ITT population .......................................................................................... 74 
Table 19 – Response duration– PP population ........................................................................................... 75 
Table 20 – Progression free survival by exon 19 and 21– ITT population .................................................. 76 
Table 21 – Progression free survival by exon 19 and 21– PP population ................................................... 77 
Table 22 – Drug dispensing and accountability – Safety population .......................................................... 78 
Table 23 – Physical examination – Safety population ................................................................................ 80 
Table 24 – Electrocardiogram – Safety population .................................................................................... 81 
Table 25 – Hematology – Safety population .............................................................................................. 82 
Table 26 – Coagulation – Safety population ............................................................................................... 84 
Table 27 – Biochemistry – Safety population ............................................................................................. 86 
Table 28 – Adverse events and serious adverse events – Safety population ............................................. 93 
Table 29 – Incidence of adverse events – Safety population ..................................................................... 94 
Table 30 – Incidence of serious adverse events – Safety population ......................................................... 95 
Table 31 – Incidence of adverse events with remote, possible or probable relationship with study drug – 
Safety population ....................................................................................................................................... 96 
Table 32 – Incidence of serious adverse events with remote, possible or probable relationship with study 
drug – Safety population ............................................................................................................................ 97 


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CONFIDENTIAL 
Table 33 – Adverse events – Safety population ......................................................................................... 98 
Table 34 – Serious adverse events – Safety population ............................................................................. 99 
Table 35 – Adverse events with remote, possible or probable relationship with study drug – Safety 
population ................................................................................................................................................ 100 
Table 36 – Serious adverse events with remote, possible or probable relationship with study drug – 
Safety population ..................................................................................................................................... 101 
Table 37 – Adverse envents of special interest: Interstitial lung disease – Safety population ................ 102 
Table 38 – Adverse envents of special interest: Stevens-Johnson syndrome – Safety population .......... 103 
Table 39 – Subsequent therapy for NSCLC – Safety population ............................................................... 104 
 
 


Statistical analysis plan 
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CONFIDENTIAL 
INDEX OF FIGURES 
Figure 1 - Summary of study design ........................................................................................................... 12 
Figure 2 – Kaplan-Meier curve for progression free survival – ITT population .......................................... 27 
Figure 3 – Kaplan-Meier curve for overall survival – ITT population .......................................................... 27 
Figure 4 – Kaplan-Meier curve for response duration – ITT population .................................................... 28 
Figure 5 – Kaplan-Meier curve for progression free survival by exon 19 and 21 – ITT population ............ 28 


Statistical analysis plan 
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CONFIDENTIAL 
INDEX OF LISTINGS 
Listing 1 – Co-morbidities – PP population ............................................................................................... 105 
Listing 2 – Abnormal findings in ECOG results – PP population ............................................................... 106 
Listing 3 – Concomitant medication – PP population ............................................................................... 107 
Listing 4 – Adverse events – Safety population ........................................................................................ 108 
 


Statistical analysis plan 
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1 BACKGROUND 
1.1 BACKGROUND AND RATIONALE 
This is an open-label study, to evaluate the anti-tumoral activity of erlotinib (Tarceva®) through objective 
response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) in locally advanced or metastatic 
stages who have not received previous chemotherapy for their disease and who present activating 
mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR). 
 
1.1.1 Background 
Non-small cell lung cancer is the most common cause of cancer death worldwide1. In the EU the crude 
incidence of lung Cancer is 52.5 patients per 100,000 individuals each year with a mortality rate of 48.7 
per 100,000/year. Mortality and incidence rates are very similar, due to low survival of these patients2. 
In the developed world lung cancer remains the commonest reason of cancer death in both men and 
women, although mortality rates for men are dropping3. Among men the incidence and mortality rates 
are 82.5 and 77.0 per 100,000/year, respectively, and for women these rates are 23.9 and 22.3 per 
100,000/year, respectively2. Non-small cell lung cancer (NSCLC) comprises 80% of reported lung cancer 
cases and the majority of its new cases are diagnosed in an advanced stage4,5, once it represents a 
disease for which there is no established screening. Survival statistics are among the worst for any 
malignancies, and have not improved in the last years6. Indeed, nowadays the median survival for lung 
cancer is 6–12 months from the time of diagnosis with an overall 5-year survival of 5–10%3. Nowadays 
surgery (lobectomy/pneumonectomy plus mediastinal lymph node dissection) offers the best chance of 
cure in lung cancer, especially for NSCLC cases2. However, only a small part of patients are suitable for 
curative resection and the majority must rely on non-surgical and adjuvant therapies3. For most patients 
resection was technically unsuitable because of obvious dissemination of disease. Therefore, 
chemotherapy with palliate purpose to prolong patients’ life for few months has been increasingly 
proved by clinical studies3. A common first-line therapy for advanced cases of NSCLC in patients with 
good performance status (PS) is based on combinations of platinum. Despite the first-line chemotherapy 
is appropriate, most patients experience disease progression. With regard to second-line systemic 
treatment (docetaxel, pemetrexed, erlotinib) this may improve the symptoms related to disease and 
survival of patients2. Second-line therapy is administered for disease progression, recurrence, or 
intolerable adverse effects following administration of initial chemotherapy7. In first line, doublet 
chemotherapy has been found to be superior to single-agent chemotherapy8. Platinum-based 
chemotherapy combined with vinorelbine, gemcitabine or a taxane prolongs survival, improves quality 
of life and controls symptoms in patients with good performance status. Non-platinum combination 


Statistical analysis plan 
10 | 108 
CONFIDENTIAL 
chemotherapy can be considered in patients who are not fit to receive platinum agents. In Second line, 
in a phase III study, Shepherd and colleagues proved the efficacy of erlotinib against placebo in 
increasing the survival and reduced symptoms9. Erlotinib response rates are higher in non-smokers, 
women, adenocarcinomas, Asians and patients with EGFR mutations2. Several studies show that 
erlotinib prolongs survival in patients with advanced NSCLC after the failure of first line or second line 
chemotherapy9. In a phase II clinical trial, 57 patients with refractory NSCLC received erlotinib 
monotherapy and showed a response rate of 12.3% and a median survival of 8.4 months10. Based on 
these results and for a different pharmacological profile, erlotinib was approved by the FDA for the 
treatment of second and third line NSCLC. Some studies have also shown that mutations in the EGFR 
gene are associated with response to EGFR TKI11. 
 
1.1.2 Erlotinib (OSI-774; Tarceva®) 
Erlotinib is an orally active and potent inhibitor of tyrosine kinase, which acts on the epidermal growth 
factor receptor (EGFR) developed for the treatment of solid tumours including NSCLC12. The 
recommended daily dose of erlotinib is 150 mg13.  
Erlotinib acts via direct and reversible inhibition of the human EGFR tyrosine kinase, with an IC50 of 2 
nM (0.786 ng/mL) in an in vitro enzyme assay, and reduces receptor autophosphorylation in intact 
tumour cells with an IC50 of 20 nM (7.86 ng/mL)13.  
At nanomolar concentrations, erlotinib blocks Epidermal Growth Factor (EGF)-dependent cellular 
proliferation and inhibits cell cycle progression in the G1 phase. Selectivity testing against a panel of 
isolated tyrosine kinase demonstrated that erlotinib is selective for the EGFR13. 
The most frequently-reported adverse events (AEs) associated with single-agent erlotinib are rash 
(dermatosis), diarrhoea, nausea, fatigue, stomatitis, vomiting, and headache13. On the other hand, skin 
rash was identified as a key indicator of erlotinib trough plasma concentrations14. These results support 
those from previous studies on EGFR inhibitors, which have revealed a similar association between drug 
steady-state plasma concentrations and the intensity of rash and diarrhoea15,16. Laboratory 
abnormalities, primarily involving changes in liver function tests (elevation of alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), and/or bilirubin) are less frequently observed with single-agent 
erlotinib. These abnormalities occur occasionally in patients treated with erlotinib in combination with 
either gemcitabine, or carboplatin and paclitaxel13. Caution should be used when administering Tarceva 
to patients with hepatic impairment. Dose reduction or interruption of Tarceva should be considered if 
severe adverse reactions occur13,17.  
An indication of completed and ongoing clinical studies on erlotinib in NSCLC can be found in the 
Investigator’s Brochure13. 


Statistical analysis plan 
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2 STUDY OBJECTIVES 
2.1 PRIMARY OBJECTIVES 
The primary objective of this study is to evaluate the anti-tumoral activity of erlotinib (Tarceva®; 150 
mg) through objective response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) in locally 
advanced or metastatic stages who have not received previous chemotherapy for their disease and who 
present activating mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor 
(EGFR). 
 
2.2 SECONDARY OBJECTIVES 
The secondary objectives of this study are: 
 
To evaluate progression-free survival (PFS);  
 
To evaluate the EGFR mutation frequency; 
 
To evaluate the overall survival (OS); 
 
To evaluate the erlotinib safety profile (Tarceva®; 150 mg); 
 
To evaluate response duration. 
 
 
 
 


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3 STUDY DESIGN 
This is a local open-label, multi-centre Phase II study of the anti-tumoral activity of erlotinib (Tarceva®; 
150 mg) evaluated by objective response rate (ORR) in patients with NSCLC in locally advanced or 
metastatic stages who have not received previous chemotherapy for their disease and who present 
activating mutations in the TK domain of the EGFR. Summary of the study design is shown in Figure 1. 
 
 
Figure 1 - Summary of study design 
 
3.1 PROTOCOL SYNOPSIS 
The protocol synopsis is in Appendix 1. For additional details, see the Study Flowchart in Appendix 2. 
 


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3.2 STUDY POPULATION 
The target populations of this study are patients with histologically or cytologically confirmed locally 
advanced or metastatic NSCLC who have not received previous chemotherapy for their disease and who 
present activating mutations in the TK domain of the EGFR. 
 
Inclusion criteria: 
A subject may be included if the answer to all of the following statements is "yes". 
1. Patients able and willing to give written informed consent. Consent must be obtained prior to 
any study-specific procedure. 
2.  
a) Histologically or cytologically documented inoperable, locally advanced or metastatic 
NSCLC disease; 
b) Patient that presents activating mutations (exon 19 deletion and/or  exon 21 
substitution L858R ) in the tyrosine kinase domain of EGFR ; 
3. Measurable disease, according to RECIST - Response Evaluation Criteria in Solid Tumours). 
4. Male or female patients aged ≥ 18 years. 
5. Life expectancy ≥ 12 weeks. 
6. Adequate haematological and coagulation function as assessed by the investigator. 
7. Adequate liver and renal function as assessed by the investigator. 
8. Female patients must be postmenopausal (24 months of amenorrhea), surgically sterile or they 
must agree to use a physical method of contraception. Male patients must be surgically sterile 
or agree to use a barrier method of contraception. Male and female patients must use effective 
contraception during the study and for a period of 90 days following the last administration of 
erlotinib. Acceptable methods of contraception include an established hormonal therapy or 
intrauterine device for females, and the use of a barrier contraceptive (i.e. diaphragm or 
condoms) with spermicidal. 
9. If applicable, patients with asymptomatic and stable cerebral metastases receiving medical 
treatment will be eligible for the study. Those patients may have received radiation therapy for 
their cerebral metastases before the initiation of systemic treatment for non-small-cell lung 
cancer. 
10. Able to comply with the required protocol and follow-up procedures. 
 
Exclusion criteria 
A subject will be excluded if the answer to any of the following statements is "yes". 


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1. Previous treatment with chemotherapy or therapy against EGFR, either with antibody or 
small molecule (tyrosine kinase inhibitor) for metastatic disease. The administration of 
neo-adjuvant or adjuvant therapy is allowed as long as it has finalized  6 months before 
entering the study. Patients can have received radiotherapy as long as the irradiated lesion 
is not the only target lesion for evaluating response and as long as radiotherapy has been 
completed before initiating the study treatment (28 days period is recommended). 
Treatment with an investigational drug agent during the four weeks before enrolment in 
the study. 
2. History of another neoplasm other than carcinoma in situ of the uterine cervix, basal cell 
skin carcinoma treated adequately, or prostate carcinoma with a good prognosis 
(Gleason  6) treated radically. History of another neoplasm treated curatively and without 
evidence of disease in the last 5 years. History of breast cancer and melanoma at any time. 
3. Patients with symptomatic cerebral metastases. 
4. Known hypersensitivity to erlotinib or any of its excipients. 
5. Any significant ophthalmologic abnormality, especially severe dry eye syndrome, 
keratoconjunctivitis sicca, Sjögren’s syndrome, severe exposure keratitis or any other 
disorder likely to increase the risk of corneal epithelial lesions. (The use of contact lenses is 
not recommended during the study. The decision to continue to wear contact lenses 
should be discussed with the patient’s treating oncologist and the ophthalmologist.) 
6. Use of coumarins (Sintrom®; Varfine®). If the patient requires anti-coagulant therapy, 
instead of coumarins, the use of a low molecular weight heparin is recommended, 
whenever clinically possible. 
7. Patients with severe hepatic and renal impairment as assessed by the investigator. 
8. Evidence of any other disease, neurological or metabolic dysfunction, physical examination 
or laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or puts the patient at high risk for 
treatment-related complications. 
9.  
a) Positive urine pregnancy test in women of childbearing potential. Female patients 
should not be pregnant or breast-feeding. 
b) Patients (male or female) with reproductive potential not willing to use effective 
method of contraception during the trial and during 90 days after the last erlotinib 
administration. Oral or injectable contraceptive agents cannot be the sole method of 
contraception. 
10. Patients with pre-existing disease of the lung parenchyma such as lung fibrosis, 
lymphangitic carcinomatosis.  


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11. Patients with known infection with HIV, HBV, HCV. Testing is not required in the absence of 
clinical signs and symptoms suggestive of these conditions. 
12. Patients those in the Investigator’s opinion are not able to accomplish protocol 
requirements. 
13. Incapacity to take oral medication or previous surgical procedures that affect absorption 
and imply the need for intravenous or parenteral feeding. 
 
3.3 ENDPOINTS 
3.3.1 Primary efficacy endpoint 
The primary efficacy endpoint is ORR defined as the proportion of patients in whom a complete 
response (CR) or partial response (PR), as per RECIST 1.1, is observed, assessed based on diagnostic 
imaging.    
 
3.3.2 Secondary efficacy endpoints 
 
Progression-free survival, defined as the time from baseline visit to the date of first occurrence 
of disease progression or death due to any cause.  
 
Overall survival defined as the time from the baseline visit (first dose of erlotinib) to the date of 
death due to any cause. 
 
Frequency of EGFR mutation.  
 
Response duration, defined as the time of initial response (CR/PR whichever is first recorded) 
until documented disease progression. 
 
3.3.3 Safety outcome endpoints 
Safety of the treatment will be evaluated by all adverse events using the National Cancer Institute 
Common Terminology Criteria for AEs (NCI CTC-AE) version 4.0. The incidence of serious adverse events 
(SAEs) and non-SAEs related to erlotinib therapy will be determined. Additional information about AEs 
of special interest (serious and non-serious) such as Stevens-Johnson syndrome and interstitial lung 
disease (ILD) will be collected. Information about laboratory exams (haematology, biochemistry and 
coagulation), ECG and physical examination will be also collected.  
 


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3.4 ANALYSIS TIMING 
One interim analysis is planned for the study with a cut-off date on 30th September 2013. This interim 
analysis will include an epidemiological, efficacy and safety characterization of erlotinib in 1st line EGFR 
Mut+ mNSCLC Portuguese population. 


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4 STUDY CONDUCT 
4.1 RANDOMIZATION ISSUES 
Not applicable, since this is a single-arm trial (all patients are assigned to treatment). For each patient 
enrolled in the study, a sequential number will be attributed (01- 30). 
 
4.2 DATA MONITORING 
See the study Trial Monitoring Plan. 
 


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5 STATISTICAL METHODS 
5.1 DETERMINATION OF SAMPLE SIZE 
The sample size was calculated based on the primary variable of the study, objective response rate. 
Since this proportion is unknown an exploratory sample size of 30 patients was considered to evaluate 
primary endpoint. This sample size will allow estimating ORR with a margin of error of approximately 
±17.5%, for a 95% confidence interval. 
Furthermore, approximately 2000 new cases of stage IIIB and IV NSCLC are diagnosed per year in 
Portugal1 and, based on published data, expected prevalence of EGFR mutation is approximately 10%. 
With a 95% confidence interval, it was calculated that at least 420 patients will have to be screened to 
achieve 30 positive cases for the exploratory sample size analysis. 
 
5.2 ANALYSIS POPULATIONS 
5.2.1 Intention to treat (ITT) population 
Intention to treat population will be defined as all subjects who are enrolled to the treatment phase of 
the study, regardless if they completed treatment. 
 
5.2.2 Per protocol (PP) population 
Per protocol population will include all subjects enrolled in the treatment phase of the study without 
major protocol violations. 
The protocol violations and corresponding impact are listed below. 
 
Category 
Impact 
Assessment not performed 
Minor/Major 
Deviations from the dosing of the IPs 
Major 
Inconsistency with inclusion/exclusion criteria 
Major 
Non-compliance with the dose reduction schedule 
Major 
Prohibited concomitant medication 
Major 
Treatment not discontinued after withdrawal criteria is met 
Major 
Visit dates not per protocol 
Minor 
 


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5.2.3 Safety population 
All patients who received at least one dose of study medication will be included in the safety population. 
 
5.3 ANALYSIS OF STUDY CONDUCT 
A descriptive analysis of all study variables will be done. For continuous variables, the mean, standard 
deviation (SD), median, maximum and minimum will be computed whereas for categorical variables the 
absolute (n) and relative frequencies (%) will be described. 
 
All analyses will be performed using SAS version 9.4 (SAS Institute Inc, Cary, USA). 
 
All derived variables to be used in the analysis are described in Appendix 3. 
 
5.3.1 Patient disposition 
The number of patients included in this study, as well as the number of screening failures will be 
described in this section. The reason for study treatment termination will be described (progression of 
disease, unacceptable toxicity and withdrawal of informed consent or death) together with reason for 
treatment discontinuation (lost to follow-up, investigator’s decision or other reason) through absolute 
(n) and relative frequencies (%). The number (n) and relative frequency (%) of each study population will 
be also summarized. 
 
5.3.2 Demographics 
The age, smoking duration and average number of cigarettes/day if smoker/ex-smoker at the screening 
visit will be described using median, mean, standard deviation, maximum and minimum. 
Gender and smoking habits (non-smoker, smoker or ex-smoker) will be described using absolute (n) and 
relative (%) frequencies. 
Demographic characteristics will be presented considering the ITT population. 
 
5.3.3 Childbearing potential/Pregnancy test 
For female patients, the childbearing potential and contraception method at the screening visit will be 
described using absolute (n) and relative (%) frequencies. If a female patient is of childbearing potential, 
the incidence of pregnancy tests performed and respective result (positive/negative) will be evaluated. 


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The number of men who uses a contraception protection, or who are surgically sterilized or naturally 
sterile or abstinent or have a partner surgically sterile will also be assessed using frequencies. 
The childbearing potential/pregnancy test information will be collected at the screening visit, baseline 
visit and at the end of study treatment.  
Results will be presented considering the ITT population. 
 
5.3.4 Medical history 
5.3.4.1 NSCLC Diagnosis 
The disease duration (in years) at the screening visit will be described using median, mean, standard 
deviation, maximum and minimum. The diagnosis technique (histology/cytology), pathology results 
(adenocarcinoma, bronchoalveolar carcinoma, large cell carcinoma, squamous cells carcinoma, mixed 
cell type or other), TNM classification (T, N and M)) and location of metastatic disease (adrenal glands, 
liver, brain, bone or other) will also be described using absolute (n) and relative (%) frequencies. 
 
5.3.4.2 Co-morbidities 
The number of patients having any co-morbidity at the screening visit will be assessed. For patients with 
co-morbidities, the frequency of patients in grade 1 to 5, or with mild, moderate, severe, life threatening 
or disabling severity or death related will be described. 
 
Results on medical history will be presented considering the ITT population. 
5.3.5 ECOG performance status 
The absolute (n) and relative (%) frequencies of patients with performance status information at each 
visit will be assessed as well as its respective result using median, mean, standard deviation, minimum 
and maximum. 
Results will be presented considering the ITT population. 
 
5.3.6 Concomitant medications 
The absolute (n) and relative (%) frequencies of patients taking any concomitant medication will be 
assessed.   
Concomitant medication will be presented considering the ITT population. 


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5.3.7 Tumour assessment 
The absolute (n) and relative (%) frequencies of patients with a pre-existing CXR, a chest and upper 
abdomen CT Scan or MRI, an isotope bone scan, a brain CT Scan or a brain MRI will be described for 
each visit. For patients with any of these exams performed, the proportion of patients with abnormal 
clinically relevant exam results will be evaluated. Tumor assessment using the RECIST criteria (Appendix 
5) will be carried at baseline, within +/- 5 days of the 8-weekly assessments and at the end of study 
treatment visit. For tumor assessments completed outside the scheduled time, results will be analyzed 
as part of the nearest scheduled visit.  
Results on tumour assessment will be presented considering the ITT population. 
 
5.3.8 Clinical response (RECIST criteria) 
At each planned time point, the overall response (complete response (CR), partial response (PR), stable 
disease (SD), or progressive disease (PD)) will be assessed for each patient, taking into account both 
target and non-target lesions, as per RECIST criteria. This will be summarized as the percentage of 
patients reaching each level of response at that time point. At the end of the study treatment, best 
overall response will be determined for all patients and presented as percentages of patients with each 
level of response. 
In addition, for each study visit the number of patients with lesions evaluated through CT Scans, MRIs or 
Spiral CT Scans will be described, as well as the percentage of patients with target and non-target lesions 
placed at the brain, liver, lymph nodes, bones, skin, peritoneum, lung or other location. 
Results on clinical response will be presented considering the ITT population. 
 
5.3.9 Efficacy analysis 
In this trial, the efficacy endpoints will be analyzed for ITT and PP population. The ITT analysis will be 
considered as the primary analysis. 
 
5.3.9.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the objective response rate (ORR) defined by the number of patients 
with complete response (CR) or partial response (PR) as the best overall response during the treatment 
period divided by the total number of patients based on diagnostic imaging according to RECIST 1.1 (see 
Appendix 5). The ninety five percent (95%) confidence interval will be estimated for the ORR. 
 


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5.3.9.2 Secondary Efficacy Endpoints 
The secondary efficacy variables include: 
- 
Progression-free survival (PFS), defined as the time from baseline visit to the date of first 
occurrence of disease progression or death for any cause while the patient was under study or 
during the prolonged follow-up period. PFS will be summarized as median time and will be 
estimated using the Kaplan-Meier method. Ninety five percent (95%) confidence interval will be 
estimated for median time to PFS. 
 
- 
Overall survival (OS), defined as the time from the first dose of erlotinib to the date of death 
due to any cause while the patient was under study or during the prolonged follow-up period. 
Overall survival variable will be summarized as median time to OS and will be estimated using 
the Kaplan-Meier method. 95% confidence interval will be estimated for median time to OS. 
The date of first dose is not captured in the study CRF. Therefore, for this endpoint it will be 
assumed that the patient will take the first dose at the day of the baseline visit. 
 
- 
Epidermal growth factor receptor (EGFR) mutation frequency. The presence of EGFR mutation 
(exon 19 deletion and/or exon 21 substitution L858R) in the study population will be presented 
as the relative frequency of those mutations among the total screened patients.  A 95% 
confidence interval will be estimated for this value using binomial distribution. 
 
- 
Response duration, defined as the time of initial response (CR/PR whichever is first recorded) 
until documented tumor progression. Response duration will be summarized as median time 
and will be estimated using the Kaplan-Meier method. Ninety five percent (95%) confidence 
interval will be estimated for median time to response duration. 
 
5.3.9.3 Exploratory Efficacy analysis 
PFS will be summarized by exon 19 and 21 as median time and will be estimated trough Kaplan-Meier 
method. 
 
5.3.10 Safety analysis 
Safety endpoints will be presented considering the safety population. 
 


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5.3.10.1 Drug dispensing and accountability 
During the treatment period, the number of patients whose study medication was dispensed will be 
evaluated together with the frequency of patients starting the study with doses of 150mg, 100mg or 
50mg,  the median (range) duration of study drug dispensability, and the mean (SD)/median (range) 
number of respective units (tablets) dispensed. Moreover, the percentage of patients who kept the 
same initial dose until the end of study treatment and who had to change dose will be calculated as well 
as the mean of the weighted average doses of each patient (the weights being the time a patient was on 
each dose). 
At the end of study treatment, the mean (SD) compliance ratio for each patient will be derived, and the 
respective percentage of compliant patients assessed. Furthermore, a patient will be deemed compliant 
if the compliance ratio is at least 80%.  
 
5.3.10.2 Physical examination 
The absolute (n) and relative (%) frequencies of patients who perform a physical examination at each 
visit will be evaluated. The frequency of abnormal results in the examination of the skin, nails, thorax, 
abdomen, extremities, head, genital, neurological, temperature or other physical examination will be 
described. 
 
5.3.10.3 ECG 
The absolute (n) and relative (%) frequencies of patients who perform an ECG at the screening visit, and 
every time that is clinically indicated will be described, as well as the frequency of abnormal clinically 
relevant ECGs results for each visit and for total study duration. 
 
5.3.10.4 Laboratory data 
Laboratory assessment will be carried out at the screening visit and all visits during the treatment 
period. For the following laboratory parameters: 
1) Hematology (hemoglobin, leucocytes, neutrophils, platelets),  
2) Coagulation (prothrombin time, activated partial thromboplastin (aPTT), international 
normalized ratio (INR – only at the screening visit) and  
3) Biochemistry (urea, glucose, AST, ALT, creatinine clearance (if indicated), serum creatinine, 
calcium, sodium, potassioum, chloride, LDH, alkaline phosphatase, total bilirubin)  
the percentage of patients with abnormal clinically relevant values will be assessed. 


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Laboratory will be summarized in shift from baseline tables. 
 
5.3.10.5 Adverse events 
Adverse event (AE) data will be presented in frequency tables (overall, by grade (1, 2, 3, 4, or 5), by 
severity (mild, moderate, severe, life threatening or disabling or death related), by relationship 
(unrelated, remote relation, possible relation or probable relation) and by action taken (dose changed, 
interrupted, withdrawal or none). In tables showing the incidence of adverse events, subjects who 
experienced the same event on more than one occasion are counted only once in the calculation of the 
event frequency.  
For selected events of particular interest, such as Stevens-Johnson syndrome and interstitial lung 
disease, summary tables will be presented for time to first onset of the event and for the total number 
of episodes. Every occurrence of an event in any subject will be counted in the total number of episodes 
but successive reports of an identical event in the same phase (treatment, follow-up) will be combined 
(concatenated) into a one episode if the end date of the earlier event was the same as the start date of 
the later event, or if the end date of the earlier event was missing.  
A listing of adverse events by patient, whose adverse events led to withdrawal of study treatment or to 
dose modification will be done. In case of deaths, a brief narrative describing each death will be done.   
All AEs and laboratory variables will be assessed according to the NCI CTC-AE version 4.0 grading system.  
 
5.3.11 Subsequent therapy for NSCLC 
In the safety follow-up and off-study visits, the frequency of patients who continue treatment for NSCLC 
with subsequent therapies will be assessed. For the patients taking subsequent therapies, the 
therapeutic line and treatment will be further described using absolute (n) and relative (%) frequencies. 
Results on subsequent therapy for NSCLC will be presented considering the safety population. 
 
5.4 MISSING DATA 
Incomplete dates will be handled as stated in Appendix 4. All other missing values will be individually 
omitted from the analyses. 
 


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5.5 INTERIM ANALYSES 
Interim analysis will include the following descriptive analyses: 
Characterization - demographics, medical history, Eastern cooperative oncology group performance 
status, clinical response (RECIST criteria). 
Efficacy – Best Overall response, progression free survival, overall survival and epidermal growth factor 
receptor. Additionally, PFS will be obtained for Exon 19 and Exon 20 (if applicable). 
Safety – Drug compliance, adverse events (incidence of AE and SAE, incidence of AE and SAE with 
remote, possible or probable relationship with study drug, description of AE and SAE, SAE with remote, 
possible or probable relationship with study drug) and subsequent therapy for NSCLC. 
Interim analysis will be conducted following the methodology/assumptions considered in section 5.3. 
 
 
 


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6  STATISTICAL TABLES 
 
6.1 PATIENT DISPOSITION 
Patient disposition will be presented as described in Table 1 of Appendix 6. 
 
6.2 DEMOGRAPHICS 
Demographic characteristics will be presented as described in Table 2 of Appendix 6. 
 
6.3 CHILDBEARING POTENTIAL/PREGNANCY TEST 
Results of the childbearing potential/pregnancy test will be presented as described in Table 3 of 
Appendix 6. 
 
6.4 MEDICAL HISTORY 
Results on medical history will be presented as described in Table 4 and Table 5 of Appendix 6. 
By-patient listing of co-morbidities will be presented in Listing 1 of Appendix 7. 
 
6.5 ECOG PERFORMANCE STATUS 
ECOG performance status data will be presented in Table 6 of Appendix 6. 
By-patient listing of ECOG results will be presented in Listing 2 of Appendix 7. 
 
6.6 CONCOMITANT MEDICATIONS 
Concomitant medications will be presented in Table 7 of Appendix 6. 
By-patient listing of concomitant medications will be presented in Listing 3 of Appendix 7. 
 


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6.7 TUMOUR ASSESSMENT 
Results of tumour assessment will be presented as described in Table 8 of Appendix 6. 
 
6.8 CLINICAL RESPONSE (RECIST CRITERIA) 
Results of the clinical response according RECIST criteria will be presented in Table 9 of Appendix 6. 
 
6.9 EFFICACY ANALYSIS 
6.9.1 Primary Efficacy analysis 
Results of the primary efficacy analysis will be presented for ITT population in Table 10 of Appendix 6 
and PP population in Table 11 of Appendix 6. 
 
6.9.2 Secondary Efficacy analysis 
Results of the secondary efficacy analysis will be presented in, Table 12 to Table 19 of Appendix 6 and in 
Figure 2 to Figure 4. 
 
 
 
[Insert figure] 
 
 
Figure 2 – Kaplan-Meier curve for progression free survival – ITT population 
 
 
 
 
 
 
 
[Insert figure] 
 
Figure 3 – Kaplan-Meier curve for overall survival – ITT population 


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[Insert figure] 
 
 
Figure 4 – Kaplan-Meier curve for response duration – ITT population 
 
6.9.3 Exploratory Efficacy analysis 
Results of progression free survival by exon 19 and 21 will be presented in Table 20 and Table 21 of 
Appendix 6 and in Figure 5. 
 
 
[Insert figure] 
 
 
Figure 5 – Kaplan-Meier curve for progression free survival by exon 19 and 21 – ITT population 
 
6.10 SAFETY ANALYSIS 
6.10.1 Drug dispensing and accountability 
Results on the drug administration will be presented in Table 22 of Appendix 6. 
 
6.10.2 Physical examination 
Physical exam findings will be presented in Table 23 of Appendix 6. 
 
6.10.3 ECG 
Electrocardiogram findings will be presented in Table 24  of Appendix 6. 
 


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6.10.4 Laboratory data 
Hematology, coagulation, biochemistry results will be presented in Table 25, Table 26 and Table 27, 
respectively,  of Appendix 6. 
 
6.10.5 Adverse events 
Adverse events will be described in Table 28 to Table 38 of Appendix 6. 
By-patient listing with data about adverse events will be presented in Listing 4 of Appendix 7. 
 
6.11 SUBSEQUENT THERAPY FOR NSCLC 
Results on subsequent therapy for NSCLC will be present in Table 39 of Appendix 6. 
 
6.12 INTERIM ANALYSIS 
The interim analysis will include the analyses described in the following sections: 6.2 Demographics, 6.4 
Medical history, 6.5 ECOG performance status, 6.8 Clinical response (RECIST criteria), 6.9 Efficacy 
analysis, 6.10.1 Drug dispensing and accountability (only reduction in starting dose and compliance) and 
6.10.5 Adverse events (Table 29 to Table 34, Table 36 and Table 39).  


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7 REFERENCES 
 
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treatment and follow-up.” Ann Oncol 2008; 19(Suppl 2): ii39-ii40. 
 
3- Spiro SG, Porter JC. “Lung cancer – where are we today? Current advances in staging and nonsurgical 
treatment.” Am J Respir Crit Care Med 2002; 166: 1166-1196. 
 
4- Cartman ML, Hatfield AC, Muers MF, Peake MD, Haward RA, Forman,D. “Lung cancer: district active 
treatment rates affect survival.” J Epidemiol Community Health 2002; 56: 424-429. 
 
5- Haura EB. “Treatment of advanced non-small-cell lung cancer: a review of current randomized clinical 
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6- Office for National Statistics. Report: Cancer survival in England and Wales, 1991–98. Health Statistics 
Quarterly. 2000; 6: 71–80. 
 
7- Ramsey SD, Martins RG, Blough KD, Tock LS, Lubeck D, Reyes CM. “Second-line and Third-line 
Chemotherapy for Lung Cancer: Use and Cost.” Am J Manag Care 2008; 14: 297-306. 
 
8- Delbaldo C, Michiels S, Syz N, Soria JC, Le Chevalier T, Pignon JP. “Benefits of adding a drug to a single-
agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis.” JAMA 
2004; 292: 470-484. 
 
9- Shepherd FA, Pereira JR, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. “Erlotinib in previously treated 
non-small-cell lung cancer.” N Engl J Med 2005; 353: 123-32. 
 
10- Pérez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, et al. “Determinants of 
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11- Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Branngan BW, et al. “Activating 
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12- Moyer JD, Barbacci EG,  Iwata KK, Arnold L, Boman B,  Cnnningham A, et al. “Induction of Apoptosis and 
Cell Cycle Arrest by CP-358,774, an Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinase.” CANCER 
RESEARCH 1997 Nov; 57: 4838-4848. 
 
13- OSI Pharmaceuticals, Genentech Inc, and F.Hoffmann-La Roche. Clinical investigator's brochure, 14th 
Edition, 5th March 2010. 
 
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Determinants of Erlotinib Toxicity.” J Clin Oncol 2008 Mar; 26:.1119-1127. 
 
15- Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD, Morse D, et al. “United States Food and Drug 
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16- Li J, Karlsson MO, Brahmer J, Spitz A, Zhao M, Hidalgo M, Baker SD. “CYP3A phenotyping approach to 
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Appendix 1: Protocol Synopsis 
SINOPSES OF AIMS PROTOCOL NUMBER: ML25434 
TITLE  
Phase II, open-label study of erlotinib (Tarceva®) treatment 
in patients with locally advanced or metastatic non-small 
cell lung cancer who present activating mutations in the 
tyrosine kinase domain of the epidermal growth factor 
receptor. 
SPONSOR 
Roche Farmacêutica Química, Lda   CLINICAL 
PHASE 
II 
INDICATION 
Locally advanced or metastatic non-small cell lung cancer 
(NSCLC). 
OBJECTIVES 
Primary: 
Objective response rate (ORR) of erlotinib (Tarceva®; 150 
mg) in patients with locally advanced or metastatic stage 
non-small-cell lung cancer (NSCLC), who have not received 
previous chemotherapy for their disease and who present 
activating mutations in the tyrosine kinase (TK) domain of 
the epidermal growth factor receptor (EGFR). 
 
Secondary: 
 
Progression-free survival (PFS), 
 
Overall survival (OS),  
 
Safety profile, 
 
Evaluate the EGFR mutation frequency in the study 
population 
TRIAL DESIGN 
Open-label, multi-centre Phase II study. 
NUMBER OF PATIENTS 
30 patients 
TARGET POPULATION 
Patients with histologically or cytologically confirmed locally 
advanced or metastatic NSCLC who have not received 
previous chemotherapy for their disease and who present 
activating mutations in the TK domain of the EGFR. 
INCLUSION CRITERIA 
1. Patients able and willing to give written informed 
consent. Consent must be obtained prior to any 
study-specific procedure. 
2.  
a) Histologically or cytologically documented 
inoperable, locally advanced or metastatic NSCLC 
disease; 
b) Patient that presents activating mutations in the 
tyrosine kinase domain of EGFR (Exon 19 deletion  
and/or exon 21 substitution L858R ); 
3. Measurable disease, according to RECIST - 
Response Evaluation Criteria in Solid Tumours). 
4. Male or female patients aged ≥ 18 years. 
5. Life expectancy ≥ 12 weeks. 
6. Adequate haematological and coagulation function 
as assessed by the investigator. 


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7. Adequate liver and renal function as assessed by 
the investigator. 
8. Female patients must be postmenopausal (24 
months of amenorrhea), surgically sterile or they 
must agree to use a physical method of 
contraception. Male patients must be surgically 
sterile or agree to use a barrier method of 
contraception. Male and female patients must use 
effective contraception during the study and for a 
period of 90 days following the last administration 
of erlotinib. Acceptable methods of contraception 
include an established hormonal therapy or 
intrauterine device for females, and the use of a 
barrier contraceptive (i.e. diaphragm or condoms) 
with spermicidal.  
9. If applicable, patients with asymptomatic and 
stable cerebral metastases receiving medical 
treatment will be eligible for the study. Those 
patients may have received radiation therapy for 
their cerebral metastases before the initiation of 
systemic treatment for non-small-cell lung cancer. 
 Able to comply with the required protocol and follow-up 
procedures 
EXCLUSION CRITERIA 
1. Previous treatment with chemotherapy or therapy 
against EGFR, either with antibody or small 
molecule (tyrosine kinase inhibitor) for metastatic 
disease. The administration of neo-adjuvant or 
adjuvant therapy is allowed as long as it has 
finalized  6 months before entering the study. 
Patients can have received radiotherapy as long as 
the irradiated lesion is not the only target lesion for 
evaluating response and as long as radiotherapy 
has been completed before initiating the study 
treatment (28 days period is recommended). 
Treatment with an investigational drug agent 
during the four weeks before enrolment in the 
study. 
2. History of another neoplasm other than carcinoma 
in situ of the uterine cervix, basal cell skin 
carcinoma treated adequately, or prostate 
carcinoma with a good prognosis (Gleason  6) 
treated radically. History of another neoplasm 
treated curatively and without evidence of disease 
in the last 5 years. History of breast cancer and 
melanoma at any time. 
3. Patients with symptomatic cerebral metastases. 
4. Known hypersensitivity to erlotinib or any of its 
excipients. 


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5. Any significant ophthalmologic abnormality, 
especially severe dry eye syndrome, 
keratoconjunctivitis sicca, Sjögren’s syndrome, 
severe exposure keratitis or any other disorder 
likely to increase the risk of corneal epithelial 
lesions. (The use of contact lenses is not 
recommended during the study. The decision to 
continue to wear contact lenses should be 
discussed with the patient’s treating oncologist and 
the ophthalmologist.) 
6. Use of coumarins (Sintrom®; Varfine®). If the 
patient requires anti-coagulant therapy, instead of 
coumarins, the use of a low molecular weight 
heparin is recommended, whenever clinically 
possible. 
7. Patients with severe hepatic and renal impairment 
as assessed by the investigator. 
8. Evidence of any other disease, neurological or 
metabolic dysfunction, physical examination or 
laboratory finding giving reasonable suspicion of a 
disease or condition that contraindicates the use of 
an investigational drug or puts the patient at high 
risk for treatment-related complications. 
9.  
a) Positive urine pregnancy test in women of 
childbearing potential. Female patients should not 
be pregnant or breast-feeding. 
b) Patients (male or female) with reproductive 
potential not willing to use effective method of 
contraception during the trial and during 90 days 
after the last erlotinib administration. Oral or 
injectable contraceptive agents cannot be the sole 
method of contraception.  
10. Patients with pre-existing disease of the lung 
parenchyma such as lung fibrosis, lymphangitic 
carcinomatosis.  
11. Patients with known infection with HIV, HBV, HCV. 
Testing is not required in the absence of clinical 
signs and symptoms suggestive of these conditions. 
12. Patients those in the Investigator’s opinion are not 
able to accomplish protocol requirements. 
Incapacity to take oral medication or previous surgical 
procedures that affect absorption and imply the need for 
intravenous or parenteral feeding. 
LENGTH OF STUDY 
This study is event-driven, with a recruitment period that 
will last until the end of March 2012 or until the number of 
patients aimed for the protocol (30) is achieved, whatever 
occurs first. Patients are to be treated until disease 
progression, unacceptable toxicity, death or patient request 
for discontinuation. 
END OF STUDY 
The study will end when the last patient has stopped 
erlotinib therapy and completed their last safety follow-up 
visit (28 days after last study drug administration). For all 


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patients who have discontinued study drug treatment and 
are alive, information on survival will be collected. 
INVESTIGATIONAL MEDICINAL 
PRODUCT(S) DOSE/ ROUTE/ REGIMEN 
Patients will be dosed daily with 150 mg erlotinib taken 
orally until disease progression or unacceptable toxicity. 
Dose reduction will be allowed according to protocol 
(Section 6.) 
ASSESSMENTS OF: 
- EFFICACY 
 
 
 
 
 
 
 
- SAFETY 
 
 
 
 
 
 
 
 
- EGFR Mutation analysis 
 
 
Primary Endpoint: 
 
Objective Response Rate (ORR). 
 
Secondary Endpoints: 
 
Progression Free Survival, 
 
Overall Survival (OS), 
 
Safety profile, 
 
EGFR mutation frequency. 
 
All evaluations will be performed accordingly with the 
Schedule of Assessments. If clinically indicated, more 
evaluations could be performed. All adverse events (AEs) 
will be assessed using the National Cancer Institute 
Common Terminology Criteria for AEs (NCI CTC-AE) version 
4.0. The incidence of serious adverse events (SAEs) and non-
SAEs related to erlotinib therapy will be determined. 
Additional information about AEs of special interest (serious 
and non-serious) such as Stevens-Johnson syndrome and 
interstitial lung disease (IDL)-like events will be collected. 
Information about laboratory exams (haematology, 
biochemistry and coagulation), ECG and physical 
examination will be also collected. 
 
If patients are deemed eligible to participate in the study by 
the investigator, a surgical fragment or biopsy formalin-
fixed, paraffin-embedded or a tumour material obtained 
through aspiration cytology fixed and paraffin-embedded in 
a cell-block, must be sent to the Central Laboratory 
. If activating mutations (exons 19 and/or 21 
mutations) in the TK domain of EGFR gene are identified, 
patients are eligible to participate in the study. 
STATISTICAL CONSIDERATIONS 
- STATISTICAL METHODS 
 
 
 
 
 
 
 
 
Efficacy Analyses: 
The primary and secondary efficacy analyses will be 
performed on the intent-to-treat population, defined as all 
subjects who are enrolled to the treatment phase of the 
study, regardless if they completed treatment. 
For ORR 95% confidence interval will be estimated. 
PFS and OS will be estimated and presented as median time 
to PFS and OS trough Kaplan-Meier method. 95% 
confidence intervals will be estimated for this parameters. 
EGFR expression will be presented as a percentage and 95% 
confidence intervals will be estimated for this value. 


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- SAMPLE SIZE CONSIDERATION 
 
 
Safety Analyses: 
All safety parameters will be summarized and presented in 
tables based on the safety population. 
AE data will be presented in standard frequency tables 
(overall and by intensity) by body system. All AEs and 
laboratory variables will be assessed according to the NCI 
CTC-AE version 4.0 grading system. 
 
 
The sample size was calculated based on the primary 
variable of the study, objective response rate. Since this 
proportion is unknown an exploratory sample size of 30 
patients was considered to evaluate primary endpoint. This 
sample size will allow estimating ORR with a margin of error 
of approximately ±17.5%, for a 95% confidence interval. 
 
Furthermore, approximately 2000 new cases of stage IIIB 
and IV NSCLC are diagnosed per year in Portugal1 and, 
based on published data, expected prevalence of EGFR 
mutation is approximately 10%. With a 95% confidence 
interval, it was calculated that at least 420 patients will have 
to be enrolled to be tested to achieve 30 positive cases for 
the exploratory sample size analysis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: Study Flowchart 
Assessment 
Screenin
g 
Exon 19 deletion or exon 21 substitution L858R in the TK domain of EGFR gene 
Treatment Period 
Final Visit / 
Withdrawal from 
Treatment 
Safety Follow-up 
Visit K 
Off-study 
Visit 
Days 
Visit # (Day 1 of every 8th week throughout 
treatment period) 
End of Study 
Treatment 
End of study 
( 28 days after 
last study drug 
administration)  
 
 
Survival 
follow-up 
every 6th 
monthsh 
-21 
to 
-1 
Visit 1 
(Baseline) 
Visit – every 8th week, until 
PD, death, unacceptable 
toxicity or patient’s decision 
Visit Window 
≤ 21 days 
0 
+/- 5 days 
+/- 5 days 
+/- 5 days 
+/- 15 days 
Informed 
consent 
X 
 
 
 
 
 
EGFR Testing 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Pregnancy testa 
X 
X 
 
X 
 
Physical 
examinationb 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
ECGc 
X 
To be repeated as clinically indicated 
Demographics 
X 
 
 
 
 
Haematology 
X 
X 
X 
X 
X 
Biochemistry 
X 
X 
X 
X 
X 
Coagulation 
Xj 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
Tumour 
assessmentd 
 
X 
X 
X 
 
Adverse eventse 
X 
X 
X 
X 
X  
X 
Subsequent 
therapy for 
NSCLCf 
 
 
 
 
X 
X 
Drug dispensing 
and 
accountabilityg 
 
X 
X 
Xi 
 
 
Notes: First dose of study drug to be taken as soon as positive EGFR mutations test result has been received and appropriate drug has been 
provided. 
a Urine or blood. 
b Including an ophthalmologic examination if clinically indicated. 
c At baseline and as clinically indicated throughout the study. 
d Tumour assessment consists at minimum of a CT scan of chest and upper abdomen (for imaging of liver and adrenal glands). Patients 
known to have bone metastasis or displaying clinical or laboratory signs (e.g. serum alkaline phosphatase (ALP) > 1.5 ULN) of bone 
metastasis should have an isotope bone scan at baseline. Brain CT scan or MRI is not mandatory but should be done if there is a clinical 
suspicion of cerebral metastasis. Post-baseline assessments are to be performed within +/- 5 days for the 8 weekly assessments. If there is 


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suspicion of disease progression based on clinical or laboratory findings, a tumour assessment should be performed as soon as possible, 
before the next scheduled evaluation. 
e Graded according to NCI CTC-AE version 4.0. During screening period only SAEs caused by a protocol-mandated intervention will be 
collected (e.g., SAEs related to invasive procedures such as biopsies, medication washout, or no treatment run-in). During the study, and 
until Safety Follow-up visit all SAEs and AEs of special interest will be collected and reported. After Safety Follow up visit all SAEs and AEs of 
special interest related with the study drug, will be collected and reported. 
f Subsequent therapy for all patients. 
g For details on drug dispensing and accountability see Section 6. of the Protocol. 
h or as appropriate. 
i Drug returning and final accountability. 
j To be obtained in the 7 days before study treatment initiation for the patients taking anti-coagulants. 
K To be performed 28 days after the last study drug administration. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3: Derived Variables 
The following variables will be derived: 
 
Screening visit 
Age: The difference between the screening visit date and the patient’s birth date, in whole years. 
Duration of disease: The difference between the screening visit date and the date of NSCLC diagnosis, in 
whole years. 
Smoking duration (in years): For ex-smokers is the difference between the start and stop year (in years) 
of smoking and for smokers is the difference between the start year and the screening visit year. 
Stage TNM: a categorical variable will be obtained. The following criteria will be considered: 
Occult Carcinoma – TX, N0, M0; 
Stage 0 – Tis N0 M0; 
Stage IA – T1a N0 M0; 
Stage IB – T1b N0 M0; 
Stage IIA – T2b N0 M0 or T1a N1 M0 or T1b N1M0 or T2a N1 M0; 
Stage IIB – T2b N1 M0 or T3 N0 M0; 
Stage IIIA – T1a N2 M0 or T1b N2 M0 or T2a N2 M0 or T2b N2 M0 or T3 N1 M0 or T3 N2 M0 or T4 N0 
M0 or T4 N1 M0; 
Stage IIIB – T1a N3 M0 or T1b N3 M0 or T2a N3 M0 or T2b N3 M0 or T3 N3 M0 or T4 N2 M0 or T4 N3 
M0; 
Stage IV – Any T, any N and M1a or Any T, any N and M1b. 
 
Treatment period 
Response duration: It will be measured from the time of initial response (CR/PR whichever is first 
recorded) until documented tumor progression (in weeks). 
Best overall response: a categorical variable will be obtained, defined as the best response across all 
time points, according to RECIST 1.1, until end of study treatment. The following criteria will be 
considered: 
Complete response – Patients who presented at least one complete response; 
Partial response – Patients who not presented a complete response and presented at least one 
partial response; 
Stable disease – Patients who not presented response (complete or partial) and presented at least 
one stable disease; 
Progression disease – Patients who not presented response or stable disease and presented 
progression disease; 


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Inevaluable – All assessments are inevaluable. 
Objective response: A dichotomous variable (yes/no) will be calculated. Patients who presented 
complete response or partial response as the best overall response will be classified in “yes”. Otherwise 
patients will be classified in “no”. 
Event PFS: A dichotomous variable (yes/no) will be calculated. Patients who presented progression 
disease or death for any cause will be classified in “yes”. Otherwise patients will be classified in “no”. 
Time PFS: Time between baseline visit and date of first occurrence of disease progression or death for 
any cause (in weeks) while the patient was under study or during the prolonged follow-up period. In 
patients where disease progression or death from any cause was not observed, the time will be 
censored at the date of last visit or last contact with the patient. 
Time overall survival: The time from the first dose of erlotinib (assumed to be baseline visit) to the date 
of death due to any cause (in weeks). For patients alive at the end of the follow-up period, the time was 
censored at the date of last visit or last contact with the patient. 
 
Medication and adverse events 
Duration of adverse event: The interval between the start and end or patient worsened in severity or 
death dates of the adverse event in days. 
Time to first onset (Interstitial lung disease): Time between baseline visit and first occurrence of 
Interstitial lung disease, in weeks, within patients with this adverse event. 
Time to first onset (Stevens-Johnson syndrom): Time between baseline visit and first occurrence of 
Stevens-Johnson syndrom, in weeks, within patients with this adverse event. 
Duration of study drug dispensability: The interval between the dispensed medication date at baseline 
and the returned medication date at the end of study treatment visit in weeks. 
Drug compliance: The ratio of used units (tablets) (dispensed at a visit) to number of days between 
visits. In case the prescribed dose is 50mg, the denominator of this ratio will be multiplied by two. 
Weighted average doses: the weighted average doses of each patient will be calculated according to 
the following formula 
 
(                         )  (                         )   (                       ) 
                                       
 
 
 
Study populations 
ITT: A dichotomous variable (yes/no) will be calculated. Patients who are enrolled to the treatment 
phase of the study (baseline visit) will be classified in “yes”. Otherwise patients will be classified in “no”. 


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PP: A dichotomous variable (yes/no) will be calculated. Patients who are enrolled to the treatment 
phase of the study (baseline visit) and without major protocol violations will be classified in “yes”. 
Otherwise patients will be classified in “no”. 
Safety: A dichotomous variable (yes/no) will be calculated. Patients who received at least one dose of 
study medication will be classified in “yes”. Otherwise patients will be classified in “no”. 
 
 
 
 
 
 
 


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Appendix 4: Handling incomplete dates 
 
Birth dates 
If only the year is known, the complete date will be assumed to be July 1st of the given year. If both 
month and year are known, the complete date will be assumed to be the 15th of the given month. 
 
Death dates 
If both month and year are known, the complete date will be assumed to be the 1st of the given month. 
If only the year is known, the complete date will be: 
- the date of last visit or last contact with the patient, if the year of death is equal to the year of 
last contact  
- the 1st day of the year, if the year of death is higher than the year of last contact. 
 
Adverse events 
Start date 
If only the year is known, the complete date will be assumed to be January 1st of the given year. If both 
month and year are known, the complete date will be assumed to be the 1st of the given month.  
End date 
If only the year is known, the complete date will be assumed to be December 31st of the given year. If 
both month and year are known, the complete date will be assumed to be the last day of the given 
month.  
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 5: The RECIST Criteria for 
Tumor Response 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Quick Reference (http://ctep.cancer.gov/guidelines/recist.html) 
 
Measurability of tumor at baseline 
1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as follows: 
1.1. Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must 
be P15mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
1.2.Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with 
P10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
 
1.3.Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone 
lesions. However, these techniques can be used to confirm the presence or disappearance of bone 
lesions. 


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• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CTor MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if noncystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in the 
lesion. Study protocols should detail the conditions under which such lesions would be considered 
measurable. 
 
2. Specifications by methods of measurements 
 
2.1. Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 
weeks before the beginning of the treatment. 
 
2.2. Method of assessment 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable 
by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and P10mm 
diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by 
color photography including a ruler to estimate the size of the lesion is suggested. As noted above, when 
lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be undertaken 
since it is more objective and may also be reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated 
lung. 


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CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review 
at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If markers 
are initially above the upper normal limit, however, they must normalize for a patient to be considered 
in complete response. Because tumor markers are disease specific, instructions for their measurement 
should be incorporated into protocols on a disease specific basis. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if 
required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential adverse effect 
of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in order to 
differentiate between response (or stable disease) and progressive disease. 
 
Tumor response evaluation 
1. Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor burden 
at baseline and use this as a comparator for subsequent measurements. Only patients with measurable 
disease at baseline should be included in protocols where objective tumor response is the primary 
endpoint. Measurable disease is defined by the presence of at least one measurable lesion. In studies 
where the primary endpoint is tumor progression (either time to progression or proportion with 
progression at a fixed date), the protocol must specify if entry is restricted to those with measurable 
disease or whether patients having non-measurable disease only are also eligible. 
 


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2. Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions 
total (and a maximum of two lesions per organ) representative of all involved organs should be 
identified as target lesions and will be recorded and measured at baseline (this means in instances 
where patients have only one or two organ sites involved a maximum of two and four lesions 
respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be visible by 
imaging even if not involved by tumor. Pathological nodes which are defined as measurable and may be 
identified as target lesions must meet the criterion of a short axis of P15mm by CT scan. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter 
normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane; for MRI the plane of acquisition may be axial, saggital or coronal). The smaller of 
these measures is the short axis. For example, an abdominal node which is reported as being 20 mm·30 
mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm 
should be recorded as the node measurement. All other pathological nodes (those with short axis 
P10mm but <15 mm) should be considered non-target lesions. Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. A sum of the diameters (longest 
for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the sum, then as noted above, only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterise any objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should also be recorded at baseline. Measurements are not required and these 
lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. In addition, 
it is possible to record multiple nontarget lesions involving the same organ as a single item on the case 
record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
3. Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response for 
target lesions. 
3.1. Evaluation of target lesions 


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Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
3.2. Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even if 
the nodes regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section where, 
in order to qualify for CR, each node must achieve a short axis <10 mm. For PR, SD and PD, the actual 
short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes which are recorded as 
target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report themas being ‘too small to measure’. When this occurs it is 
important that a value be recorded on the case report form. If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph 
node is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well). This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). The measurement of these lesions 
is potentially non-reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error. To reiterate, however, if the radiologist is able to provide 
an actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest diameters of 
the fragmented portions should be added together to calculate the target lesion sum. Similarly, as 


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lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion. If the lesions have truly coalesced such that they are 
no longer separable, the vector of the longest diameter in this instance should be the maximal longest 
diameter for the ‘coalesced lesion’. 
3.3. Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the group 
of non-target lesions. 
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the appearance 
of one or more new lesions is also considered progression). 
3.4. Special notes on assessment of progression of nontarget disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal progression’ on 
the basis of the non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size of one or more 
non-target lesions is usually not sufficient to quality for unequivocal progression status. The designation 
of overall progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 
When the patient has only non-measurable disease. This circumstance arises in some phase III trials 
when it is not a criterion of study entry to have measurable disease. The same general concepts apply 
here as noted above, however, in this instance there is no measurable disease assessment to factor into 
the interpretation of an increase in non-measurable disease burden. Because worsening in non-target 
disease cannot be easily quantified (by definition: if all lesions are truly non-measurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable disease is comparable in magnitude to 
the increase that would be required to declare PD for measurable disease: i.e. an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase 
diameter in a measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to 
‘large’, an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have objective 


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criteria to apply to non-measurable disease, the very nature of that disease makes it impossible to do 
so, therefore the increase must be substantial. 
3.5. New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e. not attributable to 
differences in scanning technique, change in imaging modality or findings thought to represent 
something other than tumor (for example, some ‘new’ bone lesions may be simply healing or flare of 
pre-existing lesions). This is particularly important when the patient’s baseline lesions show partial or 
complete response. For example, necrosis of a liver lesion may be reported on a CT scan report as a 
‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. An example of this is the patient who has 
visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals metastases. 
The patient’s brain metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline. If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate 
the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm: 
a.) Negative FDG-PET at baseline, with a positivel FDG-PET at follow-up is a sign of PD based on a new 
lesion. 
b.) No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
 
 
4. Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until the 
end of treatment taking into account any requirement for confirmation. On occasion a response may 
not be documented until after the end of therapy so protocols should be clear if post-treatment 


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assessments are to be considered in determination of best overall response. Protocols must specify how 
any new therapy introduced before progression will affect best response designation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and will 
also take into consideration the appearance of new lesions. Furthermore, depending on the nature of 
the study and the protocol requirements, it may also require confirmatory measurement. Specifically, in 
non-randomized trials where response is the primary endpoint, confirmation of PR or CR is needed to 
deem either one the ‘best overall response’. This is described further below. 
4.1. Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 1 on the 
next page provides a summary of the overall response status calculation at each time point for patients 
who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 


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4.2. Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) 
at that time point. If only a subset of lesion measurements are made at an assessment, usually the case 
is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point response. This 
would be most likely to happen in the case of PD. For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and at follow-up only two lesions were assessed, but those gave a sum of 
80 mm, the patient will have achieved PD status, regardless of the contribution of the missing lesion. 
 


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4.3. Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on last assessment 
has a best overall response of PR). When SD is believed to be best response, it must also meet the 
protocol specified minimum time from baseline. If the minimum time is not met when SD is otherwise 
the best time point response, the patient’s best response depends on the subsequent assessments. For 
example, a patient who has SD at first assessment, PD at second and does not meet minimum duration 
for SD, will have a best response of PD. The same patient lost to follow-up after the first SD assessment 
would be considered inevaluable. 
Best response determination in trials where confirmation of complete or partial response IS required: 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent time 
point as specified in the protocol (generally 4 weeks later). In this circumstance, the best overall 
response can be interpreted as in Table 3. 
 
4.4. Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ size (<10 
mm), they may still have a measurement reported on scans. This measurement should be recorded even 
though the nodes are normal in order not to overstate progression should it be based on increase in size 
of the nodes. As noted earlier, this means that patients with CR may not have a total sum of ‘zero’ on 
the electronic case report form (eCRF). 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in most 
trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a confirmed 
response. 


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Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective response: it 
is a reason for stopping study therapy. The objective response status of such patients is to be 
determined by evaluation of target and non-target disease as shown in Tables 1–3. 
Conditions that define ‘early progression, early death and inevaluability’ are study specific and should be 
clearly described in each protocol (depending on treatment duration, treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of complete response. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by disease specific 
medical literature for the indication. However, it must be acknowledged that both approaches may lead 
to false positive CR due to limitations of FDG-PETand biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date 
when progression was suspected. 
4.5. Frequency of tumor re-evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted to the 
type and schedule of treatment. However, in the context of phase II studies where the beneficial effect 
of therapy is not known, follow-up every 6–8 weeks (timed to coincide with the end of a cycle) is 
reasonable. Smaller or greater time intervals than these could be justified in specific regimens or 
circumstances. The protocol should specify which organ sites are to be evaluated at baseline (usually 
those most likely to be involved with metastatic disease for the tumor type under study) and how often 
evaluations are repeated. Normally, all target and non-target sites are evaluated at each assessment. In 
selected circumstances certain non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected. 
After the end of the treatment, the need for repetitive tumor evaluations depends on whether the trial 
has as a goal the response rate or the time to an event (progression/death). If ‘time to an event’ (e.g. 
time to progression, disease-free survival, progression-free survival) is the main endpoint of the study, 
then routine scheduled re-evaluation of protocol specified sites of disease is warranted. In randomised 
comparative trials in particular, the scheduled assessments should be performed as identified on a 
calendar schedule (for example: every 6–8 weeks on treatment or every 3–4 months after treatment) 


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and should not be affected by delays in therapy, drug holidays or any other events that might lead to 
imbalance in a treatment arm in the timing of disease assessment. 
4.6. Confirmatory measurement/duration of response 
4.6.1. Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is required 
to ensure responses identified are not the result of measurement error. This will also permit appropriate 
interpretation of results in the context of historical data where response has traditionally required 
confirmation in such trials. However, in all other circumstances, i.e. in randomized trials (phase II or III) 
or studies where stable disease or progression are the primary endpoints, confirmation of response is 
not required since it will not add value to the interpretation of trial results. However, elimination of the 
requirement for response confirmation may increase the importance of central review to protect 
against bias, in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
4.6.2. Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded on 
study). 
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
4.6.3. Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on study 
(if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If the 
proportion of patients achieving stable disease for a minimum period of time is an endpoint of 
importance in a particular trial, the protocol should specify the minimal time interval required between 
two measurements for determination of stable disease. 
 
 
 
 
 
 
 
 


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Appendix 6: Statistical Tables 
 
Table 1 – Patients’ disposition 
 
Total 
(n=xx) 
 
 
 
Patients eligible for study treatment, n(%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Patient complete the treatment as per protocol, n(%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Reason for study treatment terminationa), n (%) 
 
 
Progression of disease 
 
 
Unacceptable toxicity 
 
 
Withdrawal of informed consent 
 
 
Death 
 
 
Total 
 
 
 
 
 
Reason for study treatment descontinuationa), n (%) 
 
 
Lost to follow-up 
 
 
Investigator’s decision 
 
 
Other 
 
 
Total 
 
 
 
 
 
Study populations, n (%) 
 
 
PP 
 
 
Safety 
 
 
 
 
 
a) Calculated for patients who received at least one treatment. 
 
 
 


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Table 2 – Demographics – ITT population 
 
Total 
(n=xx) 
 
 
 
Gender, n (%) 
 
 
Male 
 
 
Female 
 
 
Total 
 
 
 
 
 
Age (years) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Smoking habits, n (%) 
 
 
Non-smoker 
 
 
Smoker 
 
 
Ex-smoker 
 
 
Total 
 
 
 
 
 
If smoker/ex-smoker 
 
 
Smoking duration (years) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Number of cigarettes/day 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 


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Table 3 – Chilbearing potential / Pregnancy test – ITT population 
 
Total 
(n=xx) 
 
Screening visit 
Baseline 
End of study 
treatmenttreatment 
 
 
 
 
If female 
 
 
 
 
 
 
Childbearing 
potential 
and 
contraception, n (%) 
 
 
 
 
 
 
Childbearing 
potential 
without 
contraceptive protection 
 
 
 
 
 
 
Childbearing 
potential 
with 
contraceptive protection 
 
 
 
 
 
 
xxxxx 
 
 
 
 
 
 
Xxxxx 
 
 
 
 
 
 
Xxxxx  
 
 
 
 
 
 
Surgically sterilized 
 
 
 
 
 
 
Postmenopausal 
 
 
 
 
 
 
Naturally sterile 
 
 
 
 
 
 
Abstinence/partner 
surgically 
sterile 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
If female patient is of childbearing 
 
 
 
 
 
 
Pregnancy test performed, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Result of the pregnancy test, n (%) 
 
 
 
 
 
 
Positive 
 
 
 
 
 
 
Negative 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
If male 
 
 
 
 
 
 
Use 
of 
the 
appropriate 
contraception protection, n (%) 
 
 
 
 
 
 
Does not use contraceptive 
 
 
 
 
 
 
Uses contraceptive protection 
 
 
 
 
 
 
Surgically sterilized 
 
 
 
 
 
 
Naturally sterile 
 
 
 
 
 
 
Abstinence/partner surgically 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 4 – Medical history: NSCLC Diagnosis – ITT population 
 
Total 
(n=xx) 
 
 
 
Duration of disease (years) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Diagnosis technique, n (%) 
 
 
Histology - Bronchoscopy 
 
 
Histology - Other 
 
 
Cytology - Sample FNA (Fine Needle Aspirate) 
 
 
Cytology - Sputum 
 
 
Cytology - Pleural effusion 
 
 
Cytology - Other 
 
 
Total 
 
 
 
 
 
Patology results, n (%) 
 
 
Adenocarcinoma  
 
 
Bronchoalveolar carcinoma  
 
 
Large cell carcinoma  
 
 
Squamous cells carcinoma  
 
 
Mixed cell type  
 
 
Other 
 
 
 
 
 
TNM classification: T, n (%) 
 
 
X 
 
 
0  
 
 
is  
 
 
1a 
 
 
1b 
 
 
2  
 
 
3  
 
 
4  
 
 
Total 
 
 
 
 
 
TNM classification:N, n (%) 
 
 
X  
 
 
0  
 
 
1  
 
 
2a 
 
 
2b 
 
 
3 
 
 
Total 
 
 
 
 
 
TNM classification:M, n (%) 
 
 
X  
 
 
0  
 
 
1a  
 
 
1b 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 4 (Cont.) - Medical history: NSCLC Diagnosis – ITT population 
 
Total 
(n=xx) 
 
 
 
TNM classification,  n (%) 
 
 
Occult carcinama 
 
 
Stage 0 
 
 
Stage IA 
 
 
Stage IB 
 
 
Stage IIA 
 
 
Stage IIB 
 
 
Stage IIIA 
 
 
Stage IIIB 
 
 
Stage IV 
 
 
Total 
 
 
 
 
 
Metastatic disease, n (%) 
 
 
Adrenal glands 
 
 
Liver 
 
 
Brain 
 
 
Bone 
 
 
Other 
 
 
 
 
 
 
 


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Table 5 – Medical history: Co-mordidities – ITT population 
 
Total 
(n=xx) 
 
 
 
Any co-morbidity, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
If yes: 
 
 
Grade, n (%)a) 
 
 
Grade 1 
 
 
Grade 2  
 
 
Grade 3  
 
 
Grade 4 
 
 
Grade 5 
 
 
Total 
 
 
 
 
 
Severity, n (%)a) 
 
 
Mild  
 
 
Moderate  
 
 
Severe  
 
 
Life threatning or disabling  
 
 
Death related 
 
 
 
 
 
a) Percentage calculated within the total number of co-morbidities reported by ITT population (n=xxx). 
 
 
 
 


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Table 6 – Eastern cooperative oncology group performance status – ITT population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
ECOG result, n (%) 
 
 
 
 
 
 
 
 
 
 
0 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG result 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG: Eastern Cooperative Oncology Group. 
 
 
 


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Table 7 – Concomitant medication – ITT population 
 
Total 
(n=xx) 
 
 
 
Concomitant medication, n(%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
 
 
 
 


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Table 8 – Tumour assessment – ITT population 
 
Total 
(n=xx) 
 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
Exam performed, n (%) 
 
 
 
 
 
 
 
 
CXR 
 
 
 
 
 
 
 
 
Chest and upper abdomen CT 
Scan 
 
 
 
 
 
 
 
 
Isotope Bone Scan  
 
 
 
 
 
 
 
 
Brain CT Scan 
 
 
 
 
 
 
 
 
Brain MRI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CXR - result, n (%) 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest and upper abdomen CT 
Scan result, n (%) 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest and upper abdomen MRI 
result, n (%) 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Isotope Bone Scan - result, n (%) 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brain CT Scan - result, n (%) 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brain MRI - result, n (%) 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 9 – Clinical response: RECIST criteria – ITT population 
 
Total 
(n=xx) 
 
Visit xx 
End of study treatment 
 
 
 
Target lesion 
 
 
 
 
Response, n(%) 
 
 
 
 
Complete response  
 
 
 
 
Partial response  
 
 
 
 
Stable disease  
 
 
 
 
Progressive disease  
 
 
 
 
Not all evaluable 
 
 
 
 
Any 
 
 
 
 
Total 
 
 
 
 
Assessment exam, n (%) 
 
 
 
 
CT Scan 
 
 
 
 
MRI  
 
 
 
 
Spiral CT Scan 
 
 
 
 
Total 
 
 
 
 
Lesion location, n (%) 
 
 
 
 
Brain  
 
 
 
 
Liver  
 
 
 
 
Lymph nodes  
 
 
 
 
Bones  
 
 
 
 
Skin 
 
 
 
 
Peritoneum  
 
 
 
 
Lung  
 
 
 
 
Other 
 
 
 
 
Measurable lesion longest diameter (mm) 
 
 
 
 
N 
 
 
 
 
Mean 
 
 
 
 
Median 
 
 
 
 
Standard Deviation 
 
 
 
 
Minimum 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
Non-target lesion 
 
 
 
 
Response, n(%) 
 
 
 
 
Complete response  
 
 
 
 
Non-CR  
 
 
 
 
Non-PD  
 
 
 
 
Progressive disease  
 
 
 
 
Not all evaluable 
 
 
 
 
Any 
 
 
 
 
Total 
 
 
 
 
Assessment exam, n (%) 
 
 
 
 
CT Scan 
 
 
 
 
MRI  
 
 
 
 
Spiral CT Scan 
 
 
 
 
Total 
 
 
 
 
Lesion location, n (%) 
 
 
 
 
xxxx  
 
 
 
 
xxxx 
 
 
 
 
xxxx 
 
 
 
 
Lesion assessment, n (%) 
 
 
 
 
Present  
 
 
 
 
Absent 
 
 
 
 
Unequivocal progression 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Tabel 9 (Cont.) - Clinical response: RECIST criteria – ITT population 
 
Total 
(n=xx) 
 
Visit xx 
End of study treatment 
 
 
 
New lesions, n (%) 
 
 
 
 
Yes 
 
 
 
 
No  
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
Overall response, n(%) 
 
 
 
 
Complete response  
 
 
 
 
Partial response  
 
 
 
 
Stable disease  
 
 
 
 
Progressive disease  
 
 
 
 
Inevaluable 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 10 – Best overall response: RECIST criteria – ITT population  
 
Total 
(n=xx) 
 
 
Best overall response, n(%) 
 
 
Complete response  
 
 
Partial response  
 
 
Stable disease  
 
 
Progressive disease  
 
 
Inevaluable 
 
 
Total 
 
 
 
 
 
Objective response ratea), n (%), 95% CI 
 
 
 
 
a) Objective response rate: patients with complete or partial response. 
95% CI: 95% confidence interval. 
 
 
 
 


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Table 11 – Best overall response: RECIST criteria – PP population  
 
Total 
(n=xx) 
 
 
Best overall response, n(%) 
 
 
Complete response  
 
 
Partial response  
 
 
Stable disease  
 
 
Progressive disease  
 
 
Inevaluable 
 
 
Total 
 
 
 
 
 
Objective response ratea), n (%), 95% CI 
 
 
 
 
a) Objective response rate: patients with complete or partial response. 
95% CI: 95% confidence interval. 
 
 
 


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Table 12 – Progression free survival – ITT population 
 
Statistics 
CI95% 
PFS (weeks) 
 
 
N 
 
 
Censored 
 
 
Events (disease progression or death) 
 
 
Mean 
 
 
Median 
 
 
Percentile 25% 
 
 
Percentile 75% 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
PFS: Progression free survival. 
CI95%: 95% confidence interval. 
 
 
 
 


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Table 13 – Progression free survival – PP population 
 
Statistics 
CI95% 
PFS (weeks) 
 
 
N 
 
 
Censored 
 
 
Events (disease progression or death) 
 
 
Mean 
 
 
Median 
 
 
Percentile 25% 
 
 
Percentile 75% 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
PFS: Progression free survival. 
CI95%: 95% confidence interval. 
 
 
 
 
 


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Table 14 – Overall survival – ITT population 
 
Statistics 
CI95% 
Overall survival (weeks) 
 
 
N 
 
 
Censored 
 
 
Events (death) 
 
 
Mean 
 
 
Median 
 
 
Percentile 25% 
 
 
Percentile 75% 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
CI95%: 95% confidence interval. 
 
 
 


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Table 15 – Overall survival – PP population 
 
Statistics 
CI95% 
Overall survival (weeks) 
 
 
N 
 
 
Censored 
 
 
Events (death) 
 
 
Mean 
 
 
Median 
 
 
Percentile 25% 
 
 
Percentile 75% 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
CI95%: 95% confidence interval. 
 
 
 
 
 


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Table 16 – Epidermal growth factor receptor – All patients 
 
Total 
(n=xx) 
 
 
 
EGFR test performed, n(%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
EGFR positive result, n (%), 95% CI 
 
 
Positive 
 
 
Negative 
 
 
Total 
 
 
 
 
 
Exon 19 and/or exon 21 mutations, n (%) 
 
 
Exon 19 
 
 
Exon 21 
 
 
 
 
 
Positive result: patients with Exon 19 and/or exon 21 mutations. 
 
 
 


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Table 17 – Epidermal growth factor receptor 
 
Total 
(n=xx) 
Exon 19 and/or exon 21 mutations, n (%) 
 
 
ITT Population 
 
 
Exon 19 
 
 
Exon 21 
 
 
PP Population 
 
 
Exon 19 
 
 
Exon 21 
 
 
 
 
 
Positive result: patients with Exon 19 and/or exon 21 mutations. 
 
 
 
 


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Table 18 – Response duration– ITT population 
 
Statistics 
CI95% 
Response duration (weeks) 
 
 
N 
 
 
Censored 
 
 
Events (death) 
 
 
Mean 
 
 
Median 
 
 
Percentile 25% 
 
 
Percentile 75% 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
CI95%: 95% confidence interval. 
 
 
 


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Table 19 – Response duration– PP population 
 
Statistics 
CI95% 
Response duration (weeks) 
 
 
N 
 
 
Censored 
 
 
Events (death) 
 
 
Mean 
 
 
Median 
 
 
Percentile 25% 
 
 
Percentile 75% 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
CI95%: 95% confidence interval. 
 
 
 


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Table 20 – Progression free survival by exon 19 and 21– ITT population 
 
Exon 19 
Exon 21 
 
Statistics 
CI95% 
Statistics 
CI95% 
PFS (weeks) 
 
 
 
 
N 
 
 
 
 
Censored 
 
 
 
 
Events (disease progression or 
 
 
 
 
Mean 
 
 
 
 
Median 
 
 
 
 
Percentile 25% 
 
 
 
 
Percentile 75% 
 
 
 
 
Minimum 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
PFS: Progression free survival. 
CI95%: 95% confidence interval. 
 
 
 


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Table 21 – Progression free survival by exon 19 and 21– PP population 
 
Exon 19 
Exon 21 
 
Statistics 
CI95% 
Statistics 
CI95% 
PFS (weeks) 
 
 
 
 
N 
 
 
 
 
Censored 
 
 
 
 
Events (disease progression or 
 
 
 
 
Mean 
 
 
 
 
Median 
 
 
 
 
Percentile 25% 
 
 
 
 
Percentile 75% 
 
 
 
 
Minimum 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
PFS: Progression free survival. 
CI95%: 95% confidence interval. 
 
 


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Table 22 – Drug dispensing and accountability – Safety population 
 
Total 
(n=xx) 
 
 
 
Starting dose of study drug, n (%) 
 
 
150 mg 
 
 
100 mg 
 
 
50 mg 
 
 
Total 
 
 
 
 
 
Reduction in starting dose, n (%) 
 
 
Yes 
 
 
No  
 
 
Total 
 
 
 
 
 
Dose per day (mg) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Cumulative dose (mg) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Duration of study drug dispensability (weeks) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Study drug dispensed (tablets) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Study drug used (tablets) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Study drug unused (tablets) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
 
 
 


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Table 22 (Cont.) – Drug dispensing and accountability – Safety population 
 
Total 
(n=xx) 
 
 
 
 
 
 
Study drug missing (tablets) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Drug compliance (%) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Patient compliant, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 23 – Physical examination – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
Physical examination 
rerformed, n (%) 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin examination, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nails examination, n(%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thorax examination, n(%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdomen examination, n(%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extremities examination, n(%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Head examination, n(%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genital examination, n(%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurologic examination, n(%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature examination, n(%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
physical 
examination, 
n(%) 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
81 | 108 
CONFIDENTIAL 
Table 24 – Electrocardiogram – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
ECG performed, n (%) 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG result, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal  
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG: Electrocardiogram. 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
82 | 108 
CONFIDENTIAL 
Table 25 – Hematology – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
Hemoglobin, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leucocytes, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
83 | 108 
CONFIDENTIAL 
Table 25 (Cont.) – Hematology – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
Neutrophils, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelets, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
84 | 108 
CONFIDENTIAL 
Table 26 – Coagulation – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
Prothrombin time, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APTT, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
85 | 108 
CONFIDENTIAL 
Table 26 (Cont.) – Coagulation – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
INR, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
86 | 108 
CONFIDENTIAL 
Table 27 – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
Urea, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucose, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
87 | 108 
CONFIDENTIAL 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
AST, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
88 | 108 
CONFIDENTIAL 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
Creatinine clearance, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum creatinine, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
89 | 108 
CONFIDENTIAL 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
Calcium, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sodium, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
90 | 108 
CONFIDENTIAL 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
Potassium, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chloride, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
91 | 108 
CONFIDENTIAL 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
LDH, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alkaline phosphatase, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
92 | 108 
CONFIDENTIAL 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
Screening 
Baseline 
Visit xx 
End of study 
treatment 
End of study  
 
 
 
 
 
 
Total bilirubin, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
 
 
 
 
 
 
 
 
 
 
Abnormal, clinically relevant 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Baseline versus current visit 
 
 
 
 
 
 
 
 
 
 
Normal - Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Normal - Abnormal, clinically 
relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- 
Abnormal, 
clinically 
irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically irrelevant 
- Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Normal 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically relevant 
- 
- 
- 
- 
 
 
 
 
 
 
Abnormal, clinically relevant - 
Abnormal, clinically irrelevant 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
93 | 108 
CONFIDENTIAL 
Table 28 – Adverse events and serious adverse events – Safety population 
 
Total  
(n=xx) 
Patients with at least one adverse event, n (%)a) 
 
No  
 
 
Yes  
 
 
Total 
 
 
 
 
 
Patients with at least one serious adverse event, n (%)a) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Patients with at least one adverse event of special interest, n (%)a) 
 
 
Stevens-Johnson Syndrom 
 
 
Interstitial Lung Disease 
 
 
 
 
 
Grade of adverse events, n (%)b) 
 
 
Grade 1  
 
 
Grade 2  
 
 
Grade 3  
 
 
Grade 4  
 
 
Grade 5  
 
 
Total 
 
 
 
 
 
Severity of adverse events, n (%)b) 
 
 
Mild 
 
 
Moderate 
 
 
Severe 
 
 
Life threatning or disabling 
 
 
Death related 
 
 
Total 
 
 
 
 
 
Relationship of study drug, n (%)b) 
 
 
Unrelated  
 
 
Remote relation 
 
 
Possible relation 
 
 
Probable relation 
 
 
Total 
 
 
 
 
 
Action taken for adverse event, n (%)b) 
 
 
Dose increased 
 
 
Dose not changed  
 
 
Dose reduced 
 
 
Drug interrupted 
 
 
Drug withdrawn  
 
 
Not applicable 
 
 
Unknown 
 
 
 
 
 
Serious adverse events, n (%)b) 
 
 
Yes 
 
 
No 
 
 
 
 
 
Outcome, n (%)b) 
 
 
Not recovered / Not resolve 
 
 
Recovering / Resolving 
 
 
Recovered / Resolved 
 
 
Recovered / Resolved with sequelae 
 
 
Fatal 
 
 
Unknown 
 
 
 
 
a) Percentage calculated within the total number of patients of safety population (n=xx). 
b) Percentage calculated within the total number of adverse events reported by safety population (n=xxx). 
 
 


Statistical analysis plan 
94 | 108 
CONFIDENTIAL 
Table 29 – Incidence of adverse events – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of adverse events, n (%) 
 
Body system 1 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Body system 2 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 


Statistical analysis plan 
95 | 108 
CONFIDENTIAL 
Table 30 – Incidence of serious adverse events – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of serious adverse events, n (%) 
 
Body system 1 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Body system 2 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 


Statistical analysis plan 
96 | 108 
CONFIDENTIAL 
Table 31 – Incidence of adverse events with remote, possible or probable relationship with 
study drug – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of adverse events with remote, possible or probable 
relationship with study drug, n (%) 
 
Body system 1 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Body system 2 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 
 


Statistical analysis plan 
97 | 108 
CONFIDENTIAL 
Table 32 – Incidence of serious adverse events with remote, possible or probable relationship 
with study drug – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of serious adverse events with remote, possible or 
probable relationship with study drug, n (%) 
 
Body system 1 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Body system 2 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 


Statistical analysis plan 
98 | 108 
CONFIDENTIAL 
Table 33 – Adverse events – Safety population 
 
Total  
(n=xx) 
 
 
Adverse events, n (%) 
 
Body system 1 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Body system 2 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
Percentage calculated within the total number of adverse events reported by safety population (n=xxxx). 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
99 | 108 
CONFIDENTIAL 
Table 34 – Serious adverse events – Safety population 
 
Total  
(n=xx) 
 
 
Serious adverse events, n (%) 
 
Body system 1 
 
Xxxxx 
 
Xxxxx 
 
Xxxxx  
 
Body system 2 
 
Xxxxx 
 
Xxxxx 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
Percentage calculated within the total number of serious adverse events reported by safety population (n=xxxx). 
 
 
 
 


Statistical analysis plan 
100 | 108 
CONFIDENTIAL 
Table 35 – Adverse events with remote, possible or probable relationship with study drug – 
Safety population 
 
Total  
(n=xx) 
 
 
Adverse events with remote, possible or probable relationship 
with study drug, n (%) 
 
Body system 1 
 
Xxxxx 
 
Xxxxx 
 
Xxxxx  
 
Body system 2 
 
Xxxxx 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
Percentage calculated within the total number of adverse events with remote, possible or probable relationship with study drug 
reported by safety population (n=xxxx). 
 
 
 


Statistical analysis plan 
101 | 108 
CONFIDENTIAL 
Table 36 – Serious adverse events with remote, possible or probable relationship with study 
drug – Safety population 
 
Total  
(n=xx) 
 
 
Serious adverse events with remote, possible or probable 
relationship with study drug, n (%) 
 
Body system 1 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Body system 2 
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
Percentage calculated within the total number of serious adverse events with remote, possible or probable relationship with study 
drug reported by safety population (n=xxxx). 
 
 
 
 
 


Statistical analysis plan 
102 | 108 
CONFIDENTIAL 
Table 37 – Adverse envents of special interest: Interstitial lung disease – Safety population 
 
Total  
(n=xx) 
 
 
Time to first onset, n (%) 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Total number of episodes, n (%) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
103 | 108 
CONFIDENTIAL 
Table 38 – Adverse envents of special interest: Stevens-Johnson syndrome – Safety population 
 
Total  
(n=xx) 
 
 
Time to first onset, n (%) 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Total number of episodes, n (%) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
104 | 108 
CONFIDENTIAL 
Table 39 – Subsequent therapy for NSCLC – Safety population 
 
Total 
(n=xx) 
 
Visit XX 
 
 
 
 
Subsequent therapy, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Therapeutic line, n (%) 
 
 
Second 
 
 
Third / Fourth 
 
 
Paliative Care 
 
 
Total 
 
 
 
 
 
Treatment 
 
 
Xxxx 
 
 
Xxxx 
 
 
Xxxx 
 
 
Xxxx 
 
 
Xxxx 
 
 
Xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
105 | 108 
CONFIDENTIAL 
Appendix 7: Listings 
 
Listing 1 – Co-morbidities – ITT population 
Center 
Patient 
Co-morbidity 
Grade 
Severity 
Start year  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
106 | 108 
CONFIDENTIAL 
Listing 2 – Abnormal findings in ECOG results – ITT population 
Center 
Patient 
Date 
Location 
Result 
Description 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
107 | 108 
CONFIDENTIAL 
Listing 3 – Concomitant medication – ITT population 
Center 
Patient 
Treatment 
name 
Indication 
Dose 
Unit 
Route 
Frequency 
First taken 
Ongoing 
Last taken 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical analysis plan 
108 | 108 
CONFIDENTIAL 
Listing 4 – Adverse events – Safety population 
Center 
Patient 
Adverse 
event 
Grade 
Severity 
Relationship 
Outcome 
Action 
taken 
Seriousness 
Date 
started 
Date 
ended 
Duration 
of AE 
AE related 
Concomitant 
Medication