Conditions: Non-Small Cell Lung Cancer
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 375
Healthy volunteers: no

Brief summary:
This open-label, multi-center study will evaluate the progression-free survival and safety of erlotinib in participants with locally advanced or metastatic non-small cell lung cancer with activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Participants will receive daily oral doses of erlotinib until disease progression or unacceptable toxicity.

Detailed description:

Arms:
arm 1: Erlotinib will be administered as a single daily oral dose of 150 milligrams until disease progression, death or unacceptable toxicity. arm 2: Participants with advanced or metastatic NSCLC were tested for EGFR mutations. Participants who did not have an EGFR mutation were excluded from the study.

Interventions: intervention 1: Erlotinib
Intervention descriptions: intervention 1: Daily oral doses administered until disease progression or unacceptable toxicity or death.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
Phase IIIb, 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: 
NCT01667562 
Document Date: 
Protocol and SAP Version 1.1: 16 Aug 2012 
 
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
1 
 
 
ROCHE D.O.O 
CLINICAL STUDY PROTOCOL 
PROTOCOL NUMBER ML 27860 
 
Phase IIIb, 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 
ESSENCE 
VERSION 1.1 DATE 16. AUG 2012 .  
PROTOCOL APPROVAL 
Protocol Number / Version: 
ML27860 version 1.1 
Date:   16. Aug 2012 
Protocol approved by:    
 
 
This protocol is intended for use in a life-threatening indication:  Yes      No    
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property 
of Roche d.o.o (or under its control), and therefore provided to you in confidence as an 
investigator, potential investigator or consultant, for review by you, your staff and an 
applicable Independent Ethics Committee/Institutional Review Board. It is understood 
that this information will not be disclosed to others without written authorization from 
Roche except to the extent necessary to obtain informed consent from those persons to 
whom the drug may be administered. 
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
2 
SYNOPSIS OF PROTOCOL NUMBER ML 27860 
 
TITLE 
Phase IIIb, 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 d.o.o 
CLINICAL 
PHASE 
IIIb 
INDICATION 
Locally advanced (stage IIIB with supraclavicular lymph node 
metastases or malignant pleural or pericardial effusion), or metastatic 
(stage IV) non-small cell lung cancer (NSCLC). 
OBJECTIVES 
Primary: 
Efficacy of erlotinib (TarcevaTM; 150 mg) on progression-free survival 
(PFS) in patients with non-small-cell lung cancer (NSCLC) in locally 
advanced or metastatic stages (stage IIIB and stage IV) 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: 
 
Response rate, 
 
Safety profile, 
 
To assess the incidence of EGFR mutations in NSCLC patients 
tested in Serbia. 
 
Quality of Life (QoL) 
TRIAL DESIGN 
Open-label, multi-center Phase IIIb study 
NUMBER OF SUBJECTS 
300 patients 
TARGET POPULATION 
Patients with histologically or cytologically confirmed locally advanced 
or metastatic (stage IIIB/IV) 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. Histologically or cytologically documented inoperable, locally 
advanced (stage IIIB with supraclavicular lymph node 
metastases or malignant pleural or pericardial effusion) or 
metastatic (stage IV) NSCLC disease who present activating 
mutations (exon 19 deletions or exon 21 substitution L858R) in 
the tyrosine kinase domain of EGFR. 
3. Measurable disease must be characterized according to the 
Response Evaluation Criteria in Solid Tumors (RECIST) 
criteria. 
4. Male or female patients aged ≥ 18 years. 
5. Eastern Cooperative Oncology Group (ECOG) performance 


Protocol ML27860, version 1.1, 16 Aug. 2012 
3 
status 0-2. 
6. Life expectancy ≥ 12 weeks. 
7. Adequate hematological function: Absolute neutrophil count 
(ANC) ≥ 1.5 x 109/L, and Platelet count ≥ 100 x 109/L, and 
Hemoglobin ≥ 9 g/dL (may be transfused to maintain or exceed 
this level). 
8. Adequate liver function: Total bilirubin < 1.5 x upper limit of 
normal (ULN), and aspartate aminotransferase (ASAT), alanine 
aminotransferase (ALAT) < 2.5 x ULN in patients without liver 
metastases; < 5 x ULN in patients with liver metastases. 
9. Adequate renal function: Serum creatinine ≤ 1.25 x ULN, 
Creatinine clearance ≥ 60 ml/min. 
10. Able to comply with the required protocol and follow-up 
procedures, and able to receive oral medications. 
11. 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. Women with an intact uterus (unless 
amenorrhoeic for the last 24 months) must have a negative 
pregnancy test (urine or serum) within 3 days prior to 
enrolment into the study. Male and female patients must use 
effective contraception during the study and for a period of 60 
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 
spermicide. 
12. 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 also will be eligible. 
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 
neoadjuvant 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 (a 2-week period is recommended). 
2. Treatment with an investigational drug agent during the 
3 weeks before enrollment in the study. 
3. History of another neoplasm other than carcinoma in situ of the 
uterine cervix, basal cell skin carcinoma treated adequately, or 


Protocol ML27860, version 1.1, 16 Aug. 2012 
4 
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. 
4. Patients with symptomatic cerebral metastases. 
5. Known hypersensitivity to erlotinib or any of its excipients. 
6. Any significant ophthalmologic abnormality, especially severe 
dry eye syndrome, keratoconjunctivitis sicca, Sjögrens 
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. 
7. Coumarins (CoumadinTM; warfarin) use. If the patient requires 
anti-coagulation therapy, the use of low molecular weight 
heparin instead of coumarins is recommended where clinically 
possible. 
8. Unstable systemic disease (including active infection, 
uncontrolled hypertension, unstable angina, congestive heart 
failure, myocardial infarction within the previous year, serious 
cardiac arrhythmia requiring medication, hepatic, renal, or 
metabolic disease). 
9. 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. 
10. Positive urine or serum pregnancy test in women of 
childbearing potential. Patients (male or female) with 
reproductive potential not willing to use effective method of 
contraception. Female patients should not be pregnant or 
breast-feeding. Oral or injectable contraceptive agents cannot 
be the sole method of contraception. 
11. Patients with pre-existing parenchymal lung disease such as 
pulmonary fibrosis, lymphangiosis carcinomatosis. 
12. Patients with known infection with HIV, HBV, HCV. Testing 
is not required in the absence of clinical signs and symptoms 
suggestive of these conditions. 
13. Patients assessed by the investigator to be unable or unwilling 
to comply with the requirements of the protocol. 
14. 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 of approximately 
24 months. 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 


Protocol ML27860, version 1.1, 16 Aug. 2012 
5 
 
PROCEDURES (summary): 
The following examinations will be made as scheduled in the attached table: 
 Interview and physical examination, including assessment of concomitant 
medications, 
weight, 
ECOG 
performance 
status, 
and 
clinical 
tumor 
measurements. This information will be obtained in the 7 days before initiation of 
treatment. A pregnancy test will be ordered if appropriate. 
and completed their last visit. For all patients who have discontinued 
study drug treatment and are alive, information on survival will be 
collected. 
INVESTIGATIONAL MEDICAL 
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 6.1.1.) 
ASSESSMENTS OF: 
 
 
EFFICACY 
Primary endpoint: 
 
PFS, defined as the time from the first dose of erlotinib to the 
date of first occurrence of disease progression or death. 
Secondary endpoints: 
 
Response rate and disease control rate based on best response 
measured according to RECIST criteria. 
 
 
 
SAFETY 
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 rash and diarrhea will be collected. 
            INCIDENCE OF EGFR    
MUTATION RATES IN 
SERBIA 
 
If patients are deemed eligible to participate in the study by the 
investigator, EGFR mutation analysis will be performed at  
 
 for oncology and radiology of 
Serbia or at Private Laboratory 
. 
Patients whose tumors present activating mutations (exon 19 deletions or 
exon 21 substitution L858R) in the TK domain of EGFR gene are eligible 
to be enrolled in therapeutic phase of the study. 
The incidence of EGFR mutations among NSCLC patients tested in 
Serbia will be assessed.  
            QUALITY OF LIFE 
Quality of life will be measured using the FACT-L  method. This is a 
validated measure of quality of life.  
FACT-L Quality of Life questionnaires will be administered to patients 
prior to therapy, at each visit and at the final study visit, 4 weeks after 
patients progressed. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
6 
 Baseline symptoms and toxicity symptoms evaluated using NCI CTC-AE version 
4.0 (Annex 1) (if NCI CTC-AE are not applicable, the MedDRA classification 
will be used). 
 Blood tests with counts of the three series (leukocytes with neutrophils, 
hemoglobin, and platelets). This information will be obtained in the 7 days before 
initiation of treatment. 
 Biochemistry: alkaline phosphatase, ASAT, ALAT, bilirubin, serum creatinine, 
creatinine clearance (if indicated). This information will be obtained in the 7 days 
before initiation of treatment. 
 Prothrombin time and INR. This information will be obtained in the 7 days before 
initiation of treatment. 
 Pregnancy test in women of childbearing age. 
 Tumor assessment, using computer tomography (CT) or magnetic resonance 
imaging (MRI) scanning of chest and upper abdomen, and other scans as 
necessary, to document all sites of the disease. 
 Other investigations as indicated clinically, including ECG. 
STATISTICAL ANALYSES: 
Sample size: 
The main evaluation criterion will be percentage of subjects with EGFR mutation. The 
sample size estimation is based on 95% confidence interval of this percentage. Under the 
assumption that the expected rate should be 10% the inclusion of 300 patients should 
allow to estimate this rate with a precision of 3.5%. 
Efficacy Analyses: 
The primary and secondary efficacy analyses will be performed on the intent-to-treat 
population, defined as all patients who are enrolled to the study and received at least one 
dose of a treatment. 
For the variable of PFS, Kaplan-Meier curve and estimate will be provided. 
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. 
Interim Analysis 
The first analysis on the incidence of EGFR mutations in patients entered in to the 
study will be conducted when EGFR mutation analysis results has been obtained for all 




Protocol ML27860, version 1.1, 16 Aug. 2012 
8 
SCHEDULE OF ASSESSMENTS 
Assessment 
Diagnostic 
phase 
Exon 19 deletion or exon 21 substitution L858R in the TK domain of EGFR gene 
Screening 
Treatment Period 
Final Visit / 
Withdrawal from 
Treatment 
Days 
Days 
Visit # (Day 1 of every 6th week 
throughout treatment period) 
End of study 
-14 to -7 
-7 
to 
-3 
-3 to 
-1 
Visit 1 
(Baseline) 
Visit – every 6th week, 
until PD, death or 
unacceptable toxicity 
Informed 
consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical 
history 
 
X 
 
 
 
 
Pregnancy 
testa 
 
 
X 
To be repeated as necessary 
Physical 
examinationb 
 
X 
 
X 
X 
 
Weight 
 
X 
 
X 
X 
 
Vital signs 
 
X 
 
X 
X 
 
ECOG PS 
 
X 
 
X 
X 
X 
ECGc 
 
X 
 
To be repeated as clinically indicated 
Mandatory 
tumor sample 
X 
 
 
 
 
 
Hematology 
 
X 
 
X 
X 
X 
Biochemistry 
 
X 
 
X 
X 
X 
Urinalysis 
 
X 
 
X 
X 
X 
Concomitant 
medications 
 
X 
 
X 
X 
X 
Tumor 
assessmentd 
 
X 
 
X 
X 
X 
QoL 
assesment 
 
X 
 
X 
X 
X 
Adverse 
eventse 
 
 
 
X 
X 
X 
Subsequent 
therapy 
for 
NSCLCf 
 
 
 
 
 
X 
Drug 
dispensing and 
accountabilityg 
 
 
 
X 
X 
X 
Patient diarye      
 
 
 
X 
X 
X 
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 – within ≤ 24 hours. 
a Urine or serum. 
b Including an ophthalmologic examination if clinically indicated. 
c At baseline and as clinically indicated throughout the study. 
d Tumor assessment consists at minimum of a chest X Ray, CT or MRI 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. CT scan of the brain is not mandatory but should be done if there is a clinical suspicion of cerebral 


Protocol ML27860, version 1.1, 16 Aug. 2012 
9 
metastasis. Post-baseline assessments are to be performed within +/- 1 week for the 6 weekly assessments. If 
there is suspicion of disease progression based on clinical or laboratory findings, a tumor assessment should be 
performed as soon as possible, before the next scheduled evaluation. 
e Graded according to NCI CTC-AE version 4.0. 
f Subsequent therapy for all patients. 
g For details on drug dispensing and accountability see Section Z. 
e Patients will keep a diary to record if study drug was taken ( each day of treatment). The patient will bring this 
diary with him/her to each study visit to allow review of taken doses and possible side effects by the investigator. 
 
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
10 
TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ..................................................................... 21 
1.1 
Background ............................................................................................. 21 
1.1.1 
Non-small cell lung cancer ..................................................................... 21 
1.1.2          Incidence of EGFR mutations and sensitivity to TKIs ........................... 22 
1.1.3          Study “Drug” .......................................................................................... 22 
1.2 
Rationale for the Study ........................................................................... 24 
2. 
OBJECTIVES ........................................................................................................... 27 
2.1 
Primary Objectives .................................................................................. 27 
2.2 
Secondary Objectives .............................................................................. 27 
3. 
STUDY DESIGN...................................................................................................... 27 
3.1 
Overview of Study Design ...................................................................... 27 
3.1.1 
Rationale for Study Design ..................................................................... 28 
3.1.2 
Rationale for Dose Selection .................................................................. 28 
3.1.3 
End of Study ........................................................................................... 28 
3.2 
Number of Patients / Assignment to Treatment Groups ......................... 29 
3.3 
Centers .................................................................................................... 29 
4. 
STUDY POPULATION ........................................................................................... 29 
4.1 
Overview ................................................................................................. 29 
4.2 
Inclusion Criteria .................................................................................... 29 
4.3 
Exclusion Criteria ................................................................................... 30 
4.4 
Concomitant Medication and Treatment................................................. 31 
4.5 
Criteria for Premature Withdrawal ......................................................... 32 
4.6 
Replacement Policy (Ensuring Adequate Numbers of Evaluable 
Patients) ................................................................................................... 33 
4.6.1 
For Patients ............................................................................................. 33 
4.6.2 
For Centers .............................................................................................. 33 
5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES ...................................... 33 
5.1 
Screening Examination and Eligibility Screening Form......................... 33 
5.2 
Procedures for Enrollment of Eligible Patients....................................... 34 
5.3 
Clinical Assessments and Procedures ..................................................... 34 
5.3.1 
Tumor Response Criteria ........................................................................ 34 
5.3.2 
Response Status at Each Visit ................................................................. 35 
5.3.3 
ECOG Performance Status ..................................................................... 35 
5.3.4 
Clinical Safety Assessments ................................................................... 35 
5.4 
Laboratory Assessments ......................................................................... 35 
5.4.1 
Efficacy Laboratory Assessments ........................................................... 35 
5.4.2 
Safety Laboratory Assessments .............................................................. 35 
5.5 
Quality of Life Assessments ................................................................... 35 


Protocol ML27860, version 1.1, 16 Aug. 2012 
11 
       
6. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ........................................ 36 
6.1 
Dose and Schedule of IMP ..................................................................... 36 
6.1.1 
Dose Modifications, Interruptions and Delays ....................................... 36 
6.2 
Preparation and Administration of IMP .............................................. 3837 
6.3 
Formulation, Packaging and Labeling .................................................... 38 
6.4 
Blinding and Unblinding ......................................................................... 38 
6.5 
Accountability of IMP and Assessment of Compliance ......................... 38 
6.5.1 
Accountability of IMP ............................................................................ 38 
6.5.2.      Assessment of Compliance ........................................................................ 38 
6.6 
Destruction of IMP ................................................................................. 39 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE ...................................................... 39 
7.1 
Adverse Events and Laboratory Abnormalities ...................................... 39 
7.1.1 
Clinical Adverse Events .......................................................................... 39 
7.1.2 
Treatment and Follow-up of AEs ........................................................... 42 
7.1.3 
Laboratory Test Abnormalities ............................................................... 43 
7.2 
Safety Parameters Assessment ............................................................ 4443 
7.2.1 
Reporting of Adverse Events .............................................................. 4443 
7.2.2 
Reporting of Serious Adverse Events (immediately reportable) ........ 4443 
7.2.3 
Pregnancy ................................................................................................ 44 
7.3 
Warnings and Precautions ....................................................................... 44 
7.3.1 
Interstitial Lung Disease (ILD)-Like Events .......................................... 44 
7.3.2 
Diarrhea, Dehydration, Electrolyte Imbalance and Renal Failure .......... 45 
7.3.3 
Hepatitis, Hepatic Failure ....................................................................... 45 
7.3.4 
Gastrointestinal perforation .................................................................... 45 
7.3.5 
Bullous and exfoliative skin disorders ................................................ 4645 
7.3.6 
Ocular Disorders ................................................................................. 4645 
7.3.7 
Toxicity Due to Drug-Drug Interactions ................................................. 46 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ...................... 46 
8.1 
Primary and Secondary Study Variables ................................................ 46 
8.1.1 
Primary Variable ..................................................................................... 46 
8.1.2 
Secondary Variables ............................................................................... 46 
8.2 
Statistical and Analytical Methods ..................................................... 4746 
8.2.1 
Types of Analyses ............................................................................... 4746 
8.2.2 
Safety Data Analysis ............................................................................... 47 
8.2.3 
Quality of Life Analysis .......................................................................... 47 
8.2.2 
Sample Size ............................................................................................. 47 
9. 
DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE ......... 48 
9.1 
Assignment of Preferred Terms and Original Terminology ................... 48 
10. REFERENCES ......................................................................................................... 49 


Protocol ML27860, version 1.1, 16 Aug. 2012 
12 
11. ETHICAL ASPECTS ............................................................................................... 53 
11.1 
Local Regulations/Declaration of Helsinki ............................................. 53 
11.2 
Informed Consent .................................................................................... 53 
11.3 
Independent Ethics Committees/Institutional Review Board ................. 53 
12. CONDITIONS FOR MODIFYING THE PROTOCOL........................................... 54 
13. CONDITIONS FOR TERMINATING THE STUDY ............................................. 54 
14. STUDY DOCUMENTATION, CRFS AND RECORD KEEPING ........................ 55 
14.1 
Investigator's Files / Retention of Documents ........................................ 55 
14.2 
Source Documents and Background Data .............................................. 55 
14.3 
Audits and Inspections ............................................................................ 56 
14.4 
Case Report Forms .................................................................................. 56 
15. MONITORING THE STUDY .................................................................................. 56 
16. CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT 
RECORDS ................................................................................................................ 56 
17. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS............ 57 
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
13 
LIST OF TABLES 
 
Table 1 
Dose Level Reductions ........................................................................... 36 
Table 2 
Guidelines for management of erlotinib-related toxic effects: ............... 36 


Protocol ML27860, version 1.1, 16 Aug. 2012 
14 
LIST OF FIGURES 
 
Figure 1: Summary of study design. ................................................................................. 28 
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
15 
LIST OF APPENDICES 
 
Appendix 1: The RECIST Criteria for Tumor Response ................................................. 58 
Appendix 2: The ECOG Performance Scale .................................................................... 69 
Appendix 3: ICH Guidelines for Clinical Safety Data Management, Definitions 
and Standards for Expedited Reporting, Topic E2 ................................. 70 
Appendix 4: Information on Potential Interactions .......................................................... 72 
Appendix 5: FACT – L questionnaire .............................................................................. 72 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


Protocol ML27860, version 1.1, 16 Aug. 2012 
16 
GLOSSARY OF ABBREVIATIONS 
 
oC 
Degrees Celsius 
oF 
Degrees Fahrenheit 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-
time curve 
b.i.d. 
Twice daily 
BP 
Blood pressure 
BSC 
Best supportive care 
C24h 
Plasma concentration at 24 hours 
post-dose 
CA 
Competent authority 
CD 
Compact disk 
CDS 
Core data sheet 
CFR 
Code of federal regulations 
CG 
Clinical genotyping 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CR 
Complete Response 
CRF 
Case report form(s) 
CRP 
C-reactive protein 
CT 
Computer Tomography 
CTC 
Common Terminology Criteria 
CTC-AE 
Common Terminology Criteria for 


Protocol ML27860, version 1.1, 16 Aug. 2012 
17 
Adverse Events 
CYP 
Cytochrome P450 
dL 
Deciliter 
DSMB 
Data safety monitoring board 
EC50 
Plasma concentration associated with 
half-maximal effect 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology 
Group 
eCRF 
Electronic Case Report Form(s) 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic acid 
EEA 
European economic area 
EEG 
Electroencephalography 
e-Form 
Electronic Form (page) 
EGF 
Epidermal Growth Factor 
EGFR 
Epidermal Growth Factor Receptor 
ESF 
Eligibility screening form 
EU 
European Union 
EWB 
Emotional well-being 
FACIT 
Functional Assessment of Chronic 
Illness Therapy 
FACT-G 
Functional Assessment of Cancer 
Therapy – General 
FACT-L 
The Functional Assessment of 
Cancer Therapy – Lung 
FDA 
Food and Drug Administration 
FWB 
Functional well being 
g 
Gram 
GCP 
Good Clinical Practice 


Protocol ML27860, version 1.1, 16 Aug. 2012 
18 
GI 
Gastrointestinal 
H0 
Null hypothesis 
H1 
Alternative hypothesis 
H2 
Histamine 2 receptor 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator Brochure 
IC50 
Half maximal inhibitory 
concentration 
ICF 
Informed consent form 
ICH 
International Conference on 
Harmonization 
ID 
Identity 
IDRC 
Independent data review committee 
IEC 
Independent Ethics Committees 
ILD 
Interstitial lung disease 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
LC-MS/MS 
Liquid chromatography - mass 
spectrometry 
LCS 
Lung cancer subscale 
LD 
Longest diameter 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory 
Activities 
mL 
Milliliter 


Protocol ML27860, version 1.1, 16 Aug. 2012 
19 
mm 
Millimeter 
MRI 
Magnetic resonance image 
MTD 
Maximum tolerated dose  
NCI 
National Cancer Institute 
NCIC CTG 
National Cancer Institute of Canada 
Clinical Trials Group 
ng 
Nano-gram 
nM 
Nanomole 
NSAIDs 
Non-steroidal anti-inflammatory 
drugs 
NSCLC 
Non-small cell lung cancer 
 
 
               PD 
Progressive disease 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
p.o. 
Oral administration 
PS 
Performance status 
PR 
Partial response 
PWB 
Physical well being 
QOL 
Quality of life 
RECIST 
Response Evaluation Criteria in 
Solid Tumors 
SAE 
Serious adverse event 
SEAG 
Science and ethics advisory group 
SD 
Stable disease 
SDO 
Survival distribution of the parameter 
PFS 
SMT 
Study Management team 
SPC 
Summary of Product Characteristics 
SWB 
Social/family well being 


Protocol ML27860, version 1.1, 16 Aug. 2012 
20 
TI 
Therapeutic index 
TOI 
Trial outcome index 
ULN 
Upper limit of normal 
US 
Ultrasound 
WBC 
White blood cell 
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
21 
PART I: 
STUDY DESIGN AND CONDUCT 
 
1. 
BACKGROUND AND RATIONALE 
1.1 
Background 
1.1.1 
Non-small cell lung cancer 
Lung cancer is the most common cause of cancer death worldwide, accounting for up to 
18% of cancer-related deaths (Parkin et al., 2005). Non-small cell lung cancers (NSCLC) 
comprise 80% of reported lung cancer cases (Cartman et al., 2002). Indeed, the majority 
of new cases of lung cancer are advanced NSCLC (Haura, 2001). Due to late diagnosis, 
only a small proportion of NSCLC cases are operable as over 60% of patients present 
with advanced stages of the disease (Makitaro et al., 2002). In comparison with other 
solid tumors, the objective response and overall survival (OS) rates in patients with 
advanced NSCLC are low: five-year survival rates for stage IIIB inoperable disease are 
less than 10%, decreasing to less than 2% in disease stage IV (Ginsberg et al., 2001). 
For this population of patients in whom treatment is mainly palliative, the main goal is to 
achieve symptom control and prolong overall survival (Vansteenkiste, 2007). Standard of 
care for patients with locally advanced or metastatic NSCLC is platinum-based doublet 
chemotherapy (Pfister et al., 2004). Doublet chemotherapy has been found to be superior 
to single-agent chemotherapy (Delbaldo et al., 2004), with cisplatin-based therapy the 
current reference treatment for patients with advanced NSCLC. However, no doublet 
combination has been proven to be clinically superior to the others (Greco et al., 2002; 
Scagliotti et al., 2002; Schiller et al., 2002; Smit et al., 2003). Current data suggest that 
chemotherapy has reached a therapeutic plateau, conferring no improvements in survival 
despite the availability of new combinations of cytotoxic agents (Helbekkmo et al., 2007; 
Schiller et al., 2002). Overall, the survival outcomes for NSCLC patients remain poor, 
with a one-year survival rate of only 35% (Ettinger, 2002). 
Targeting the epidermal growth factor receptor (EGFR) has played an important role in 
advancing NSCLC therapy and improving patient outcomes (Gridelli et al., 2007). The 
EGFR is a promising target for the treatment of NSCLC. The EGFR family is a group of 
widely-expressed transmembrane proteins, often implicated in the development and onset 
of epithelium-derived carcinomas. Ligand binding triggers receptor homo- or hetero-
dimerization, followed by autophosphorylation of key tyrosine residues in the 
cytoplasmic domain and internalization (Schlessinger and Lemmon, 2006). This 
sequence of events leads to a downstream cascade of cellular responses, including 
proliferation, angiogenesis, metastasis, and apoptotic inhibition (Goel et al., 2007).  
Frequently expressed in solid tumors including NSCLC, the expression of the EGFR 
gene is often associated with advanced disease and poor clinical outcome (Ohsaki et al., 
2000; Nicholson et al., 2001). In human tumors, over-expression of EGFR and its ligands 
is a commonly-occurring alteration in the EGFR signaling pathway, although 
constitutively active EGFR mutants have also been observed in several tumor types, 
including lung tumors (Choi et al., 2007). Collectively, this evidence demonstrates that 


Protocol ML27860, version 1.1, 16 Aug. 2012 
22 
aberrant activation of the EGFR signaling pathway is a critical event driving tumor 
proliferation and survival. 
Hence, EGFR inhibition has been found to be a successful strategy for controlling 
tumorigenesis. Down regulation of EGFR signaling by heterologous expression of 
dominant-negative mutant receptors or antisense techniques can reduce the 
transformation and proliferation of tumor cell lines in vitro (Chakrabarty et al., 1995; De 
et al., 1996; Redemann et al., 1992). Two major methods for the pharmacologic 
inhibition of EGFR function are 1) the use of monoclonal antibodies against the 
extracellular domain of the receptor and 2) the use of quinazolinamine derivatives that 
compete for the ATP-binding site within the receptor tyrosine kinase domain. In vitro and 
in vivo studies demonstrate that targeted inhibition of the EGFR in this manner can 
trigger tumor apoptosis and induce regression in human tumor xenograph models 
(Rewcastle et al., 1998; Wu et al., 1995). Interestingly, targeted knock-out of the EGFR 
gene in mice resulted in abnormalities of the hair, skin and eyes (Luetteke et al., 1994), 
but did not affect embryonic development or birth (Sibilia and Wagner, 1995; Threadgill 
et al., 1995), suggesting that EGFR is not critical for the proliferation and differentiation 
of all cell types, including those of the developing embryo. 
Erlotinib acts via a different mechanism of action than chemotherapy agents, providing 
an important treatment alternative for those patients who do not benefit from standard 
chemotherapy. 
1.1.2 Incidence of EGFR mutations and sensitivity to TKIs 
The identification of mutations within the EGFR in the tumour tissue of a subset of 
NSCLC patients and the association of these mutations with sensitivity to gefitinib 
support the hypothesis that these are activating mutations which also render the tumours 
sensitive to the effects of other EGFR tyrosine kinase inhibitors (TKI).  
In the above mentioned studies, the reported prevalence of the mutations was 8% in 
unselected NSCLC patients. The mutations were found more frequently in 
adenocarcinoma (21%), in tumours from females (20%), and in tumours from Japanese 
patients (26%). The mutations result in increased in vitro activity of EGFR and increased 
sensitivity to EGFR tyrosine kinase inhibitors.  
Lynch et al analysed 16 patients treated with gefitinib and found mutations in 8 out of 9 
responders and 0 out of 7 non-responders. Paez et al analysed 9 patients treated with 
gefitinib and found mutations in 5 of 5 responders and 0 of 4 non-responders.  
Similar analysis was performed in patients treated with erlotinib. The response rate in 
patients with mutations was 26.7% compared to that in patients with wild type EGFR of 
6.9%. This was statistically significant (p=0.04). In a large Phase III study of 
maintenance erlotinib versus placebo following non-progression with first-line platinum-
based chemotherapy in NSCLC patients, progression free survival was found to be longer 
in patients with EGFR mutations compared to those without . 
1.1.3 Study “Drug” 
Erlotinib (OSI-774; TarcevaTM) 
Erlotinib is an orally active and potent inhibitor of EGFR developed for the treatment of 
solid tumors including NSCLC. This quinazolinamine derivative selectively inhibits the 


Protocol ML27860, version 1.1, 16 Aug. 2012 
23 
EGFR tyrosine kinase (Moyer et al., 1997; OSI Pharmaceuticals et al., 2008), and is the 
only EGFR inhibitor to confer a significantly improved survival benefit against best 
supportive care (BSC) in a second-line setting (Shepherd et al., 2005). Erlotinib was 
approved for the treatment of advanced or metastatic NSCLC after the failure of at least 
one prior chemotherapy regimen. The recommended daily dose of erlotinib is 150 mg. 
Mechanism of action 
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 tumor cells with an IC50 of 20 nM (7.86 ng/mL) (OSI 
Pharmaceuticals et al., 2008). 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 kinases 
demonstrated that erlotinib is selective for the EGFR (OSI Pharmaceuticals et al., 2008). 
Overview of erlotinib in NSCLC 
The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) BR.21 was a 
pivotal Phase III study that demonstrated a significant survival advantage for patients 
with NSCLC treated with erlotinib after other treatments had failed (Shepherd et al., 
2005). This multinational, randomized, placebo-controlled, double blind study in patients 
with advanced metastatic NSCLC showed a statistically significant and clinically 
meaningful prolongation of survival in patients treated with erlotinib. There was a 42.5% 
improvement in median OS in the erlotinib arm (6.7 months; 95% confidence interval 
(CI): 5.52-7.79), compared to placebo (4.7 months; 95% CI: 4.11-6.28; P=0.002). The 
survival benefit of erlotinib was also seen in those patients that did not show an objective 
tumor response. In the subset of patients whose best response was stable/progressive 
disease (SD/PD), those treated with erlotinib showed a median survival time of 8.3 
months, compared to 6.8 months for those on placebo (hazard ratio (HR) 0.82; 95% CI: 
0.68-0.99; p=0.037). Erlotinib conferred overall survival benefits regardless of age, 
gender, ethnicity, smoking status, performance status, or tumor histology. 
Erlotinib significantly delayed the time to deterioration for the three main symptoms of 
lung cancer in comparison with placebo (4.9 vs. 3.7 months for cough (p=0.04), 4.7 vs. 
2.9 months for dyspnea (p=0.04), and 2.8 vs. 1.9 months for pain (p=0.03)). Furthermore, 
erlotinib treatment was associated with improvements in tumor-related symptoms and 
quality of life (QOL) over placebo (Bezjak et al., 2006), particularly with respect to 
physical function and global QOL parameters. Thus, the use of erlotinib provides a 
means of achieving symptom control and improving overall survival in NSCLC patients. 
Erlotinib has been approved in the United States of America and European Union for 
second-line treatment of NSCLC (Gridelli et al., 2007). Recently erlotinib has been 
approved in the US for maintenance treatment in patients with locally advanced or 
metastatic NSCLC after four cycles of standard platinum-based first-line chemotherapy 
and in Europe for maintenance treatment in patients with locally advanced or metastatic 
NSCLC with stabile disease after four cycles of standard platinum-based first-line 
chemotherapy. The approvals based on SATURN data – a double-blind study of erlotinib 
in patients with advanced (stage IIIB or IV) NSCLC previously treated with four cycles 


Protocol ML27860, version 1.1, 16 Aug. 2012 
24 
of a platinum-based chemotherapy. At the data lock point, Study BO18192 was complete 
with 889 patients enrolled. The study met its primary and co-primary endpoints by 
demonstrating a statistically significant and clinically meaningful improvement in 
investigator assessed progression free survival (PFS). The result was robust and was 
corroborated by independent central review with a nearly identical estimate of treatment 
effect. Primary efficacy results were also supported by findings based on secondary 
endpoints. Efficacy was consistent across subgroups irrespective of histology, race, 
gender, smoking status, Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) and other clinical characteristics. Biomarkers including EGFR 
immunohistochemistry, fluorescence in situ hybridisation, and K-ras mutation status were 
not strongly predictive of outcome. Benefit in PFS was observed across all biomarker 
subgroups. While activating EGFR mutations identified patients with highest benefit, 
these mutations were not a prerequisite for effect as benefit was also seen in patients with 
wild type EGFR tumours. Quality of life did not suggest a detrimental effect from 
erlotinib compared with placebo. Erlotinib significantly improved overall survival versus 
placebo in both the overall population and in patients with EGFR wild-type tumours. 
Thus, the overall survival benefit was not driven by patients with EGFR mutation-
positive disease. Erlotinib was generally well tolerated and no new safety signals were 
identified. Data from BO18192 study indicates that the use of erlotinib in first-line 
maintenance setting has a favourable balance of benefit to risk. 
The recommended daily dose of erlotinib was established at 150 mg, to be continued 
daily until disease progression. The most frequently-reported adverse events (AEs) 
associated with single-agent erlotinib are rash (dermatosis), diarrhea, nausea, fatigue, 
stomatitis, vomiting, and headache (OSI Pharmaceuticals et al., 2008). Interestingly, skin 
rash was identified as a major indicator of erlotinib trough plasma concentrations (Rudin 
et al., 2008). These findings corroborate those from previous studies on EGFR inhibitors, 
which have shown a similar association between drug steady-state plasma concentrations 
and the intensity of rash and diarrhea (Cohen et al., 2004; Li et al., 2006). 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 (OSI Pharmaceuticals et al., 2010). Despite these observations, no dose 
adjustment is necessary in patients with moderately impaired hepatic function (OSI 
Pharmaceuticals et al., 2010). 
An overview of completed and ongoing clinical studies on erlotinib in NSCLC can be 
found in the Investigator‟s Brochure 15th Edition. 
1.2 
Rationale for the Study 
Much research has been directed towards defining the clinical characteristics which 
confer a survival advantage in NSCLC patients treated with EGFR inhibitors. 
The standard treatment for patients with non-small-cell lung carcinoma with advanced 
disease is chemotherapeutic drug doublets. A response rate of about 30-35% is obtained, 
with a median survival of 10-11 months and a 1-year survival of 25-30%, with these 


Protocol ML27860, version 1.1, 16 Aug. 2012 
25 
treatments. These treatments generally are associated with an important toxicity that can 
condition the quality of life of the patients.  
Molecular studies of tumor samples from patients who have responded to treatment with 
erlotinib have demonstrated that certain deletions and mutations in certain exons of the 
EGFR (19 and 21) occur more frequently in responders. The Spanish Lung Cancer Group 
has evaluated prospectively the presence of deletions in exon 19 or mutations in exon 21 
of the EGFR gene. It has been observed that 70-90% of patients who present some of 
these alterations respond to erlotinib treatment (Rosell et al., 2009). 
TKIs in EGFR mutated patients  
Erlotinib was shown to prolong survival in a large, randomized, placebo-controlled Phase 
III trial including 731 NSCLC patients no longer candidates for further chemotherapy 
(Study BR. 21) (24). Zhu et al evaluated the effect of KRAS and epidermal growth factor 
receptor (EGFR) genotype on the response to erlotinib treatment in the BR.21, placebo-
controlled trial above. They found that 34 (17%) of 204 patients‟ tumours analysed for 
EGFR mutations had EGFR exon 19 deletion or exon 21 mutations. Response rates to 
erlotinib were 7% for wild-type and 27% for mutant EGFR (P =.03) (24).  
Erlotinib has proven results as first-line maintenance therapy following non-progression 
of disease after first-line therapy (23). The SATURN trial investigated erlotinib 
maintenance therapy in patients with advanced NSCLC who did not progress during first-
line chemotherapy. This randomised, global, phase III study was the first to include 
prospective molecular marker analyses for erlotinib, with mandatory sample collection. 
Those with EGFR mutation-positive disease were found to derive a particularly large PFS 
benefit from erlotinib therapy (median PFS of 44.6 weeks vs 13 weeks for patients 
without mutations) (25). 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. 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 
gefitinib. (26) Erlotinib is currently being assessed as first-line treatment in advanced 
NSCLC in prospective, randomised, registration trials. There is however, already evidence 
that erlotinib works in first-line treatment. Paz-Ares (27) performed 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 
1
st 
line NSCLC.  
Summary of data included in pooled analysis  
                         Erlotinib 
Gefitinib  
Chemotherapy  
Patients 
treated in any 
line, n  
365  
1069  
375  
Patients 
treated 
in 
first-line 
57  
57  
95  


Protocol ML27860, version 1.1, 16 Aug. 2012 
26 
setting, %  
 
 
 
 
Pooled analysis of outcomes according to line of therapy  
 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 (26) 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 (28) where the PFS was 
14.0 months with erlotinib.  
These data suggest that the presence of EGFR mutations can be used to identify the 
subgroup of patients with non-small-cell lung cancer in which this growth factor plays a 
crucial role in tumor growth and in which inhibition with erlotinib would be effective in 
treatment. 
 
EGFR mutations rates in Serbia  
The rate of EGFR mutations in patients with NSCLC in Serbia is currently unknown. 
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%. 
As the rate of EGFR mutations amongst NSCLC patients in the Serbia is  
currently unknown, the health burden and economic implications of treatments directed 
specifically at patients with this characteristic cannot be accurately assessed. 
Purpose of the study 
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)  


Protocol ML27860, version 1.1, 16 Aug. 2012 
27 
Therefore ,the purpose of the current study is to test the efficacy and safety of the 
erlotinib as a first-line therapy in patients with NSCLC in locally advanced or metastatic 
stages (stage IIIB and stage IV) with activating mutations in the tyrosine kinase (TK) 
domain of the epidermal growth factor receptor (EGFR). 
Also, it will be assessed the EGFR mutation rate in Serbia NSCLC population. This will 
be done by testing Serbia patients with locally advanced or metastatic NSCLC for the 
EGFR mutations.  
 
Beside this, it will be assesed the impact of erlotinib treatment on quality of life. 
The results of this study will help to validate the utility of detecting EGFR mutations for 
improving treatment selection in this patient population, which will be beneficial. 
 
2. 
OBJECTIVES 
2.1 
Primary Objectives 
Efficacy of erlotinib (TarcevaTM; 150 mg) on progression-free survival (PFS) in patients 
with non-small-cell lung cancer (NSCLC) in locally advanced or metastatic stages (stage 
IIIB and stage IV) 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 
1. Response rate. 
2. Safety profile. 
3. To assess the incidence of EGFR mutations in NSCLC patients tested in Serbia. 
3. 
STUDY DESIGN 
3.1 
Overview of Study Design 
This is a open-label, multi-center Phase IIIb study of erlotinib 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.  
The first part of the study is the diagnostic phase which will test patients with advanced 
or metastatic NSCLC for EGFR mutations. Patients who do not have an EGFR mutation 
will be excluded from the trial. Patients found to have a tumour with EGFR mutations 
will then be offered treatment in the treatment phase of the study. The treatment phase is 
a single arm, open label study using erlotinib as first-line therapy. All enrolled patients 
into the treatment phase will receive erlotinib 150 mg/day until event. Erlotinib dose will 
be reduced for toxicities as detailed in Section 6.1.1. Event is defined as progression of 
disease, death, unacceptable toxicity or withdrawal of consent. 
Summary of the study design is shown in Figure 1. 




Protocol ML27860, version 1.1, 16 Aug. 2012 
29 
duration of the study is expected to be 36 months. The end of the trial will be when the 
last patient experiences either progressive disease, death, unacceptable toxicities or 
withdraws consent. The study will end when the last patient has stopped erlotinib therapy 
and completed their last visit.  
3.2 
Number of Patients / Assignment to Treatment Groups 
A total of approximately 300 patients will be enrolled into the diagnostic phase of this 
study. 
30 patients will be enrolled into the treatment phase of the study. 
3.3 
Centers 
This study will comprise 5 centers in Serbia. 
 
4. 
STUDY POPULATION 
Under no circumstances are patients who enroll in this study permitted to be re-enrolled 
for a second course of treatment. 
4.1 
Overview 
The target population of this study is patients with histologically or cytologically 
confirmed locally advanced or metastatic (stage IIIB/IV) NSCLC who have not received 
previous chemotherapy for their disease (diagnostic phase) and who present activating 
mutations in the TK domain of the EGFR (treatment phase).  
All patients with diagnosed histologically confirmed locally advanced or metastatic 
(stage IIIB/IV) NSCLC who have not received previous chemotherapy for their disease 
will be offered screening for EGFR mutations. All patients found to have exon 19 
deletion or exon 21 mutation of the EGFR will be offered treatment with erlotinib in the 
treatment phase of the study. Patients who do not have an EGFR mutation or deletion will 
be excluded from the study. 
4.2 
Inclusion Criteria 
 
Diagnostic phase 
1. Patients able and willing to give written informed consent. Consent must be obtained 
prior to any study-specific procedure. 
2. Histologically or cytologically documented inoperable, locally advanced (stage IIIB 
with supraclavicular lymph node metastases or malignant pleural or pericardial 
effusion) or metastatic (stage IV) NSCLC disease  
3. Measurable disease must be characterized according to the Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria. 
4. Male or female patients aged ≥ 18 years. 
5.  ECOG performance status 0-2. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
30 
6. Life expectancy ≥ 12 weeks. 
Treatment phase 
1.  Patients must have been proven to have a histologically confirmed EGFR mutation in 
the diagnostic phase of the study 
2.  Adequate hematological function: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, 
and Platelet count ≥ 100 x 109/L, and Hemoglobin ≥ 9 g/dL (may be transfused to 
maintain or exceed this level). 
3.  Adequate liver function: Total bilirubin < 1.5 x upper limit of normal (ULN), and 
aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) < 2.5 x ULN in 
patients without liver metastases; < 5 x ULN in patients with liver metastases. 
4.  Adequate renal function: Serum creatinine ≤ 1.25 x ULN, Creatinine clearance ≥ 60 
ml/min. 
5.  Able to comply with the required protocol and follow-up procedures, including 
answering the QoL questionnaire and able to receive oral medications. 
6.  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. Women with an intact 
uterus (unless amenorrhoeic for the last 24 months) must have a negative pregnancy test 
(urine or serum) within 3 days prior to enrolment into the study. Male and female patients 
must use effective contraception during the study and for a period of 60 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 spermicide. 
7.  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 also will be eligible. 
4.3 
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 neoadjuvant 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 (a 2-week period is recommended). 
2. Treatment with an investigational drug agent during the 3 weeks before enrollment in 
the study. 
3. 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 


Protocol ML27860, version 1.1, 16 Aug. 2012 
31 
(Gleason  6) treated radically. History of another neoplasm treated curatively and 
without evidence of disease in the last 5 years. 
4. Patients with symptomatic cerebral metastases. 
5. Known hypersensitivity to erlotinib or any of its excipients. 
6. Any significant ophthalmologic abnormality, especially severe dry eye syndrome, 
keratoconjunctivitis sicca, Sjögrens 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. 
7. Coumarins (CoumadinTM; warfarin) use. If the patient requires anti-coagulation 
therapy, the use of low molecular weight heparin instead of coumarins is 
recommended where clinically possible. 
8. Unstable systemic disease (including active infection, uncontrolled hypertension, 
unstable angina, congestive heart failure, myocardial infarction within the previous 
year, serious cardiac arrhythmia requiring medication, hepatic, renal, or metabolic 
disease). 
9. 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. 
10. Positive urine or serum pregnancy test in women of childbearing potential. Patients 
(male or female) with reproductive potential not willing to use effective method of 
contraception. Female patients should not be pregnant or breast-feeding. Oral or 
injectable contraceptive agents cannot be the sole method of contraception. 
11. Patients with pre-existing parenchymal lung disease such as pulmonary fibrosis, 
lymphangiosis carcinomatosis. 
12. Patients with known infection with HIV, HBV, HCV. Testing is not required in the 
absence of clinical signs and symptoms suggestive of these conditions. 
13. Patients assessed by the investigator to be unable or unwilling to comply with the 
requirements of the protocol. 
14. Incapacity to take oral medication or previous surgical procedures that affect 
absorption and imply the need for intravenous or parenteral feeding. 
4.4 
Concomitant Medication and Treatment 
All concomitant medications and blood products administered to patients after the first 
dose of study drug, until 60 days after the last dose of study drug must be recorded on the 
case report form (CRF). 
Permitted medication and therapies: 


Protocol ML27860, version 1.1, 16 Aug. 2012 
32 
 Patients may receive non-myelosuppressive palliative radiation therapy if 
required. Concomitant radiation therapy with erlotinib treatment is allowed. 
 Patients will receive full supportive care throughout the study, including 
transfusion of blood products, treatment with antibiotics, anti-emetics, anti-
diarrheals, and analgesics as appropriate. 
 Patients exhibiting dry eyes should be advised to use an ocular lubricant. 
Not permitted: 
 Administration 
of 
any 
other 
anti-cancer 
therapy 
(cytotoxic 
or 
biological/immunotherapy) is not permitted until after disease progression has 
been documented. 
 Patients who have received study drug should not receive any other 
investigational drugs until after the post-treatment assessment (at least 60 days 
after the final dose of study drug). 
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. 
4.5 
Criteria for Premature Withdrawal 
Patients have the right to withdraw from the study at any time for any reason. 
In the case that the patient 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 CRF. If lost to follow-up, the investigator should contact the patient 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 patient‟s withdrawal should be made with an explanation of 
why the patient is withdrawing from the study. 
When applicable, patients should be informed of circumstances under which their 
participation may be discontinued by the investigator without the patient‟s consent. The 
investigator may withdraw patients 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 patient to be 
withdrawn from the study. Any administrative or other reasons for withdrawal must be 
documented and explained to the patient. 
If the reason for removal of a patient from the study is an adverse event, the principal 
specific event will be recorded on the CRF. The patient should be followed until the 
adverse event has resolved, if possible. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
33 
4.6 
Replacement Policy (Ensuring Adequate Numbers of Evaluable 
Patients) 
4.6.1 
For Patients 
Patients enrolled into the study will not be replaced. 
4.6.2 
For Centers 
A center may be replaced for the following administrative reasons: 
 Excessively slow recruitment. 
 Poor protocol adherence. 
 
5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
The complete schedule of assessments is tabled in the synopsis of protocol (see Schedule 
of Assessments, page 8). 
5.1 
Screening Examination and Eligibility Screening Form 
The screening visit must occur no more than 7 days prior to the start of therapy. 
Information according to the Schedule of study assessments will be provided. 
All patients must provide written informed consent before any study-specific assessments 
or procedures are performed. 
Diagnostic Phase  
 
Patients must meet all inclusion criteria and no exclusion criteria to be eligible for 
enrollment in the study. 
After signing an Informed Consent Form (ICF) the patient‟s demographic data will be 
recorded in the Case Report Form (CRF) and the mandatory tumour sample will be taken 
in order to assess EGFR status. If a biopsy sample has already been taken prior to entry 
into the study, there is no need to re-take a new biopsy specimen for the purposes of the 
study. Tumour samples will be sent to laboratory for determination of EGFR mutation 
status. EGFR mutation analysis will be performed at  
 
for oncology and radiology of Serbia or at Private Laboratory 
. 
 
Treatment Phase  
The screening visit must occur no more than 7 days prior to the start of therapy. The 
following information will be recorded for all patients. 
• Review of medical history 
• A physical examination including measurement of weight 
• Vital signs including ECG 
• Assessment of ECOG performance status 
Concomitant medications 
• Tumour assessment 


Protocol ML27860, version 1.1, 16 Aug. 2012 
34 
• Pregnancy test negativity (in women of childbearing potential). Patients who are 
amenorrheic for at least 12 months are not considered of childbearing potential. This 
must be performed within 3 days prior to starting therapy. 
Samples will be collected for: 
• Haematology 
• Biochemistry 
Patients will also be provided with the quality of life questionnaire (EQ5D) for 
completion at the screening visit. 
 
 
5.2 
Procedures for Enrollment of Eligible Patients 
After signing an Informed Consent Form (ICF) the patient‟s demographic data will be 
recorded in the Case Report Form (CRF) and the mandatory tumor sample will be taken 
in order to assess EGFR status. 
5.3 
Clinical Assessments and Procedures 
Clinical and safety assessments will be performed at Screening and Baseline and on Day 
1 of every 6th week until PD, death, or unacceptable toxicity, as indicated in the Schedule 
of Assessments. 
5.3.1 
Tumor Response Criteria 
Tumor response will be evaluated according to RECIST criteria (Eisenhauer et al., 2009) 
(see Appendix 1). 
Methods of measurement 
The same method of tumor measurement and assessment must be used to characterize 
each lesion throughout the study. 
Scheduling of tumor assessments 
In this study, assessment of tumor progression during treatment with erlotinib will be 
performed every 6th week during the study visits and on the End of Study visit (as given 
in the Schedule of Assessments). Baseline total tumor burden must be assessed within a 
maximum of 2 weeks before first dose of study drug treatment. Post-baseline assessments 
are to be performed within +/- 1 week for the 6 weekly assessments. If there is suspicion 
of disease progression based on clinical or laboratory findings, a tumor assessment 
should be performed as soon as possible, before the next scheduled evaluation. 
If a patient inadvertently misses a prescribed tumor evaluation or a technical error 
prevents the evaluation, the patient may continue treatment until the next scheduled 
assessment, unless signs of clinical progression are present. 
Tumor response should be confirmed at a minimum of 4 weeks after initial response was 
noted, or at the next scheduled tumor assessment if it will occur more than 4 weeks after 
the response was first noted. 
For the confirmation of Stable Disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 6 weeks. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
35 
The diagnosis of disease progression will be made by objective criteria (RECIST criteria) 
on the target lesion(s), or by documenting, with CT/MRI scans or X-Rays, the presence 
of newly occurring lesion(s) arising outside the scanned areas of the target lesions. 
5.3.2 
Response Status at Each Visit 
All patients will have their response classified at each visit according to the RECIST 
criteria (see Appendix 1). 
5.3.3 
ECOG Performance Status 
Performance status will be measured using the ECOG performance scale (see Appendix 
2), at screening, baseline and at each study visit on Day 1 of every 6th week of treatment 
period, and on the final visit at End of Study. It is recommended that a patient‟s 
performance status is assessed by the same person throughout the study. 
5.3.4 
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. 
Safety assessments will consist of monitoring and recording all AEs and serious adverse 
events (SAEs); regular monitoring of hematology, biochemical analyses, and urine test 
results, regular measurement of vital signs, and physical examinations. Twelve lead ECG 
recordings will be performed as part of the screening (baseline) assessments and at end of 
study. Additional electrocardiogram (ECG) monitoring will be performed if clinically 
indicated throughout the study. 
5.4 
Laboratory Assessments  
Normal ranges for the study laboratory parameters must be supplied to Roche before the 
study starts. 
5.4.1 
Efficacy Laboratory Assessments 
Laboratory parameters will not be considered for the purpose of efficacy assessment. 
5.4.2 
Safety Laboratory Assessments 
All safety laboratory assessments will be performed at local laboratories. 
The safety laboratory assessments will be completed according to the Schedule of 
Assessments. 
5.5.           Quality of Life Assessments 
Quality of life will be measured using the FACT-L  method. This is a validated measure 
of quality of life.  
 
FACT-L Quality of Life questionnaires will be administered to patients prior to therapy, 
at each visit and at the final study visit, 4 weeks after patients progressed. See Appendix 
5 


Protocol ML27860, version 1.1, 16 Aug. 2012 
36 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
6.1 
Dose and Schedule of IMP  
Erlotinib will be administered as a single daily oral dose of 150 mg. No dose escalation 
of erlotinib is permitted. Protocol treatment will begin within 24 hours after receiving 
positive activating EGFR mutation test result (exon 19 deletion or exon 21 substitution 
L858R) and will continue until disease progression, death or unacceptable toxicity. 
6.1.1 
Dose Modifications, Interruptions and Delays 
Reduction/interruption of dosing for adverse events may take place at any time during the 
study. 
Diarrhea 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, 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. 
Upon the onset of an AE deemed by the investigator to be related to the study drug, 
treatment will be interrupted until AE resolution and then restarted at reduced dose of 
erlotinib. Once a patient has a dose reduction for toxicity, the dose will not be re-
escalated except in the case of erlotinib related rash. 
The dose of erlotinib will be decreased in 50 mg steps according to the schedule 
displayed in Table 1. 
 
 
Table 1 
Dose Level Reductions 
Starting Dose 
First reduction 
Second reduction 
150 mg/day 
100 mg/day 
50 mg/day 
 
The following guidelines in Table 2 outlines dose adjustments according to the most 
common toxic effects. In the event of a rash, dose can be re-escalated when rash is ≤ 
grade 2. Should a patient experience more than one toxic effect, the dose should be 
reduced. 
Table 2 
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 


Protocol ML27860, version 1.1, 16 Aug. 2012 
37 
on treatment. 
 
≥ 3 
Discontinue treatment and seek 
ophthalmological advice 
 
Diarrhea 
1 
No intervention 
None 
2 
Loperamide (4 mg at first 
onset, followed by 2 mg every 
2-4 hours until diarrhea-free for 
12 hours) 
None** 
3 
Hold until recovery 
to ≤ grade 1, and 
then restart at 
reduced dose. 
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 diarrhea, 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. 
 
If symptoms of the same degree reoccur after re-initiating the treatment at reduced dose a 
further dose reduction will be required or patients should be discontinued from the study. 
Dosing may be interrupted for a maximum of 14 days if clinically indicated and if the 
toxicity is not controlled by optimal supportive medication. Patients who require an 
interruption in dosing of > 14 days will discontinue treatment and be taken off study. 
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. 
Patients will keep a diary to record if study drug was taken (each day of treatment). The 
patient will bring this diary with him/her to each study visit to allow review of taken 
doses and possible side effects by the investigator.  
A study medication will be given to the patient on Day 1 of each dosing cycle. Patients 
will be instructed not to open a new blister card until the previous has 


Protocol ML27860, version 1.1, 16 Aug. 2012 
38 
been finished and to bring their study medication and blister cards (used or unused) back 
to the clinic at the next study visit for reconciliation. 
6.2 
Preparation and Administration of IMP  
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 medications should be consumed between two hours before and one hour 
after ingestion of erlotinib. 
6.3 
Formulation, Packaging and Labeling 
Erlotinib will be supplied as 150 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 does not require special storing precautions and should not be used past 
the expiry date. 
6.4 
Blinding and Unblinding 
The study is open label, single arm trial. 
6.5 
Accountability of IMP and Assessment of Compliance 
 
6.5.1 
Accountability of IMP 
The investigator is responsible for the control of drugs under investigation. Adequate 
records for the receipts (e.g. Drug Receipt Record) and disposition (e.g. Drug Dispensing 
Log) of the study drug must be maintained. Accountability and subject compliance will 
be assessed by maintaining adequate “drug dispensing” and return records. 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 allocated 
• the date(s), quantity of the study medication allocated to the patient 
• the initials of the person allocating the study medication 
This inventory must be available for inspection by the Monitor. All supplies, including 
partially used or empty containers must be destroyed at the site following full drug 
accountability by the monitor. Dispensing logs, must be retained by the site and a copy 
returned to the Roche Monitor at the end of the study. 
6.5.2.      Assessment of Compliance 
The investigator is responsible for the control of drugs under investigation. Adequate 
records for the receipts (e.g. Drug Receipt Record) and disposition (e.g. Drug Dispensing 
Log) of the study drug must be maintained. Accountability and patient compliance will be 
assessed by maintaining adequate “drug dispensing” and return records. 
A Drug Dispensing Log must be kept current and should contain the following 
information:  


Protocol ML27860, version 1.1, 16 Aug. 2012 
39 
 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 IMP 
Local or institutional regulations may require destruction of used investigational product 
for safety reasons. In these cases, it may be acceptable for investigational site staff to 
destroy dispensed investigational product 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 and destroyed. 
Written authorization must be obtained from the sponsor or sponsor‟s representative 
before destruction. 
Written documentation of destruction must contain the following: 
 Identity (batch numbers or patient numbers) of investigational product(s) 
destroyed. 
 Quantity of investigational product(s) destroyed. 
 Date of destruction (date discarded in designated hazardous container for 
destruction). 
 Method of destruction (the site must provide the sponsor with documentation of 
their institutional policy and procedures for handling and disposing of hazardous 
drugs). 
 Name and signature of responsible person who discarded the investigational 
product in a hazardous container for destruction. 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 
Adverse Events and Laboratory Abnormalities 
7.1.1 
Clinical Adverse Events 
According to the International Conference of Harmonization (ICH), an adverse event 
(AE) is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product. Pre-existing conditions 
which worsen during a study are to be reported as AEs. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
40 
7.1.1.1 
Intensity 
Intensity of all adverse events will be graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a five-point 
scale (Grade 1 to 5) and reported in detail on the CRF. 
Adverse events not listed on the CTCAE should be graded as follows: 
CTC Grade 
Equivalent To: Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily 
activity.  
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated although 
this could improve the overall well-being or symptoms of 
the patient. 
Grade 3 
Severe 
Inability to work or perform normal daily activity; 
treatment or medical intervention is indicated in order to 
improve the overall well-being or symptoms; delaying the 
onset of treatment is not putting the survival of the patient 
at direct risk. 
Grade 4 
Life 
threatening/ 
disabling 
An immediate threat to life or leading to a permanent 
mental or physical conditions that prevents work or 
performing normal daily activities; treatment or medical 
intervention is required in order to maintain survival. 
Grade 5 
Death  
AE resulting in death. 
 
7.1.1.2 
Drug – Adverse Event relationship 
The causality relationship of study drug to the adverse event will be assessed by the 
investigator as either: 
Yes or No 
If there is a reasonable suspected causal relationship to the study medication, i.e. there are 
facts (evidence) or arguments to suggest a causal relationship, drug-event relationship 
should be assessed as Yes. 
The following criteria should be considered in order to assess the relationship as Yes: 
 Reasonable temporal association with drug administration. 
 It may or may not have been produced by the patient‟s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
patient. 
 Known response pattern to suspected drug. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
41 
 Disappears or decreases on cessation or reduction in dose. 
 Reappears on rechallenge. 
 
The following criteria should be considered in order to assess the relationship as No: 
 It does not follow a reasonable temporal sequence from administration of the 
drug. 
 It may readily have been produced by the patient‟s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient. 
 It does not follow a known pattern of response to the suspected drug. 
 It does not reappear or worsen when the drug is re-administered. 
7.1.1.3 
Serious Adverse Events (Immediately Reportable to Roche) 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution. It is any adverse event that at any dose fulfils 
at least one of the following criteria: 
 Is fatal (results in death; NOTE: death is an outcome, not an event). 
 Is Life-Threatening (NOTE: the term "Life-Threatening" refers to an event in 
which the patient was at immediate risk of death at the time of the event; it does 
not refer to an event which could hypothetically have caused a death had it been 
more severe). 
 Requires in-patient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect. 
– Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
The term sudden death should be used only when the cause is of a cardiac origin as 
per standard definition. The terms death and sudden death are clearly distinct and 
must not be used interchangeably. 
The study will comply with all local regulatory requirements and adhere to the full 
requirements of the ICH Guideline for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2 (see Appendix 3). 
7.1.1.4 
Progression of Underlying Malignancy 
Progression of underlying malignancy is not reported as an adverse event if it is 
clearly consistent with the suspected progression of the underlying cancer as defined by 
RECIST criteria, or other criteria as determined by protocol. Hospitalization due solely to 
the progression of underlying malignancy should NOT be reported as a serious adverse 
event. Clinical symptoms of progression may be reported as adverse events if the 


Protocol ML27860, version 1.1, 16 Aug. 2012 
42 
symptom cannot be determined as exclusively due to the progression of the underlying 
malignancy, or does not fit the expected pattern of progression for the disease under 
study. 
Symptomatic deterioration may occur in some patients. In this situation, progression is 
evident in the patient‟s clinical symptoms, but is not supported by the tumor 
measurements. Alternatively, the disease progression is so evident that the investigator 
may elect not to perform further disease assessments. In such cases, the determination of 
clinical progression is based on symptomatic deterioration. These determinations should 
be a rare exception as every effort should be made to document the objective progression 
of underlying malignancy. 
If there is any uncertainty about an adverse event being due only to the disease under 
study, it should be reported as an AE or SAE. 
7.1.2 
Treatment and Follow-up of AEs  
The final outcome of each AE must be recorded on the CRF. All AEs will be followed up 
according to the guidelines below: 
Related AEs 
Continue to follow up until one of the outcomes listed below is reached: 
 Resolved or improved to baseline. 
 Relationship is reassessed as unrelated. 
 Death. 
 Start of new anti-cancer regimen. 
 Investigator confirms that no further improvement can be expected. 
 Clinical or safety data will no longer be collected or final database closure. 
Unrelated severe or life threatening AEs 
Continue to follow up until one of the outcomes listed below is reached: 
 Resolved or improved to baseline. 
 Severity improved to Grade 2. 
 Death. 
 Start of new anti-cancer regimen. 
 Investigator confirms that no further improvement can be expected. 
 Clinical or safety data will no longer be collected or final database closure. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
43 
Unrelated Grade 1 or Grade 2 AEs: 
To be followed up until one of the outcomes listed below is reached: 
 Resolved or improved to baseline. 
 Start of a new anti-cancer regimen. 
 Investigator confirms that no further improvement can be expected. 
 Clinical or safety data will no longer be collected or final database closure. 
The final outcome of each adverse event must be recorded on the CRF. 
7.1.3 
Laboratory Test Abnormalities 
Laboratory test results will be recorded on the laboratory results electronic form of the 
CRF, or appear on electronically produced laboratory reports submitted directly from the 
central laboratory, if applicable.  
Any laboratory result abnormality fulfilling the criteria for a serious adverse event  
should be reported as such, in addition to being recorded as an AE in the CRF. 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., 
meeting one or more of the following conditions, should be recorded as a single diagnosis 
on the adverse event page in the CRF: 
 Accompanied by clinical symptoms. 
 Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation). 
 Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
This applies to any protocol and non-protocol specified safety and efficacy laboratory 
result from tests performed after the first dose of study medication, which falls outside 
the laboratory reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result which falls outside the laboratory 
reference range but which does not meet the clinical significance criteria (which will be 
analyzed and reported as laboratory abnormalities); those which are considered AEs of 
the type explicitly exempted by the protocol; or are a result of an AE which has already 
been reported and considered ongoing. 
7.1.3.1 
Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found. If a clear explanation is 
established it should be recorded on the CRF. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
44 
7.2 
Safety Parameters Assessment 
7.2.1 
Reporting of Adverse Events 
All AEs (regardless of relationship to the study medication) occurring during the study 
and up to 60 days after the last dose of study medication must be reported in the AE CRF. 
7.2.2 
Reporting of Serious Adverse Events (immediately reportable) 
Any clinical adverse event or abnormal laboratory test value that is serious and which 
occurs during the course of the study from the first study-specific procedure, regardless 
of the treatment arm, must be reported to Roche within 24 (twenty-four) hours of the 
investigator becoming aware of the event (expedited reporting). The investigator must 
complete the SAE Reporting Form and forward it to the SAE Responsible in Roche 
within given timeframe. 
Related Serious Adverse Events MUST be collected and reported regardless of the time 
elapsed from the last study drug administration, even if the study has been closed.  
Unrelated Serious Adverse Events must be collected and reported during the study and 
for up to 60 days after the last dose of study medication. 
This study adheres to the definition and reporting requirements of the ICH Guideline for 
Clinical Safety Data Management, Definitions and Standards for Expedited Reporting, 
Topic E2. Complete information can be found in Appendix 3. 
7.2.3 
Pregnancy 
A female patient must be instructed to stop taking the study medication and immediately 
inform the investigator if she becomes pregnant during the study. The investigator should 
report all pregnancies within 24 hours to the sponsor, using the Clinical Trial Pregnancy 
Reporting Form. The investigator should counsel the patient, discuss the risks of 
continuing with the pregnancy and the possible effects on the fetus. Monitoring of the 
patient should continue until conclusion of the pregnancy. If pregnancy outcome is a live 
infant, the infant should be followed up as well. Pregnancies occurring up to 90 days after 
the completion of the study medication must also be reported to the investigator. 
If pregnancy occurring in the female partner of a male patient participating in the study or 
up to 90 days after the completion of the study medication, every effort must be made to 
obtain the pregnant partner signed consent using a Pregnant Partner Data Release Form 
and to follow up and report to the investigator and the sponsor the outcome of the 
pregnancy using a Clinical Trial Pregnancy Reporting Form. The partner should be 
counseled, the risks of continuing the pregnancy discussed, as well as the possible effects 
on the fetus. Monitoring of the partner should continue until conclusion of the pregnancy. 
If pregnancy outcome is a live infant, the infant should be followed up as well. 
7.3 
Warnings and Precautions  
7.3.1 
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 tumors. 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 


Protocol ML27860, version 1.1, 16 Aug. 2012 
45 
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 dyspnea, 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 (Core data sheet, 2009). 
7.3.2 
Diarrhea, Dehydration, Electrolyte Imbalance and Renal Failure 
Diarrhea has occurred in patients on erlotinib, and moderate or severe diarrhea should be 
treated with loperamide. In some cases, dose reduction may be necessary. In the event of 
severe or persistent diarrhea, 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 diarrhea, vomiting and/or anorexia while others were confounded by concomitant 
chemotherapy. In more severe or persistent cases of diarrhea, 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 
(Core data sheet, 2009). 
7.3.3 
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 (Core data sheet, 2009). 
7.3.4 
Gastrointestinal perforation 
Patients receiving erlotinib are at increased risk of developing gastrointestinal 
perforation, which was observed uncommonly. 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 (Core data sheet, 2009). 


Protocol ML27860, version 1.1, 16 Aug. 2012 
46 
7.3.5 
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 (Core data sheet, 2009). 
7.3.6 
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 (Core data 
sheet, 2009). 
7.3.7 
Toxicity Due to Drug-Drug Interactions 
Erlotinib has a potential for clinically significant drug-drug interactions (See Appendix 
4). 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
This is a 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. 
All patients who receive at least one dose of erlotinib will be included in a descriptive 
safety analysis. Descriptive summary tables will be presented on safety parameters. 
8.1 
Primary and Secondary Study Variables 
8.1.1 
Primary Variable 
The primary efficacy variable is progression free survival (PFS). The time to progression 
is defined as the time from start of treatment to the date of the first documented 
progression (according to RECIST criteria) or the date of death for any reason in the 
absence of PD. Patients who have not died or progressed at the time of the final analysis 
will be censored at the date of last contact. 
8.1.2 
Secondary Variables 
The secondary efficacy variables are the following:  
 Response and disease control rates: measured according to RECIST criteria. A patient 
is defined as a responder if they sustain a complete response (CR) or partial response 
(PR) for at least 4 weeks during treatment (confirmed response). Disease control is 
defined as response – as defined above – or stable disease (SD) for at least 6 weeks. 
 Incidence of EGFR mutations will be calculated based on evaluable biopsy samples 
obtained from patients entered into the diagnostic phase of the study. 
 Safety of the treatment will be evaluated in the safety population by: adverse events, 
laboratory tests, vital signs, performance status  
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
47 
 A mean Quality of Life score will be calculated for the QoL tool (FACT-L) at each 
timepoint for all non-progressing patients. Changes from baseline in patients‟ QoL 
score will be summarised for each time point during the study. 
 
8.2 
Statistical and Analytical Methods 
The variable of PFS will be summarized using Kaplan-Meier methodology. 
8.2.1 
Types of Analyses 
 
8.2.1.1.        Efficacy Analysis  
For the primary endpoint the analysis will be based on all patients entered in to the diagnostic 
phase of the study.  
 
8.2.1.2.       Intent to Treat Population 
This includes all patients who are enrolled to study treatment. 
8.2.1.3 
Safety Population 
All patients who received at least one dose of study medication and had a safety 
assessment performed post baseline will be included in the safety population. Patients 
will be analyzed according to the first dose received during the study. 
 
8.2.1.4        Per-protocol population:  
Patients will be considered evaluable if:  
 
1. they receive at least one dose of study drug and undergo at least one post-baseline 
efficacy assessment at 6 weeks (time window ± 3 days), and  
2. they are not a major protocol violator. 
 
8.2.1.5 
 Interim Analysis 
The first analysis on the incidence of EGFR mutations in patients entered in to the 
study will be conducted when EGFR mutation analysis results has been obtained for all 
patients which is anticipated 24 months after entry of the first subject. Subsequent interim 
analysis for secondary endpoints will be conducted when at least 75% of patients have 
experienced an end of study event. 
8.2.2 
Safety Data Analysis 
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. In tables showing the overall incidence of AEs, patients who experienced the 
same event on more than one occasion are counted only once in the calculation of the 
event frequency. 
All AEs and laboratory variables will be assessed according to the NCI CTC-AE version 
4.0 grading system. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
48 
Vital signs will be reported in listings and summary tables. Laboratory values will be 
listed with flagging of values outside of normal range, and summarized in shift from 
baseline tables. 
Information on the study drug will be summarized by duration, starting dose, dose per 
day and cumulative dose using descriptive statistics. 
8.2.3 Quality of Life Analysis  
Quality of life assessments will be used to derive pre-specified QoL scores according to 
the QoL manual. These scores will be summarized by descriptive summary tables at 
baseline and over time. The overall health score will be further analysed for the 
assessment at the end of treatment with baseline and treatment as covariates in an 
analysis of covariance model. Missing data will be replaced by the last valid post baseline 
assessment before. 
8.3. 
Sample Size 
The main evaluation criterion will be percentage of subjects with EGFR mutation. The 
sample size estimation is based on 95% confidence interval of this percentage. Under the 
assumption that the expected rate should be 10% the inclusion of 300 pts should allow to 
estimate this rate with a precision of 3.5%.  
 
9. 
DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Standard Operational Procedures. 
Accurate and reliable data collection will be assured by verification and cross–check of 
the CRFs 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 CRF and 
back-end checks in the study database will verify the data and discrepancies will be 
generated accordingly. Queries on the discrepancies are transferred to the CRF at the site 
for resolution by the investigator. 
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 CRF, 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 ML27860, version 1.1, 16 Aug. 2012 
49 
10. 
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Nagase,A., Miyokawa,N., Hirata,S., and Kikuchi,K. (2000). Epidermal growth factor 
receptor expression correlates with poor prognosis in non-small cell lung cancer patients 
with p53 overexpression. Oncol. Rep. 7, 603-607. 
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Pfister,D.G., Johnson,D.H., Azzoli,C.G., Sause,W., Smith,T.J., Baker S Jr, Olak,J., 
Stover,D., Strawn,J.R., Turrisi,A.T., and Somerfield,M.R. (2004). American Society of 
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Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer; N Engl J 
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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 patient. For studies conducted in the European Union (EU)/ 
European Economic Area (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” exist, 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 
patient prior to participating in this study after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study. For the patient not 
qualified or incapable of giving legal consent, written consent must be obtained from the 
legally acceptable representative. In the case where both the patient and his/her legally 
acceptable representative are unable to read, an impartial witness should be present 
during the entire informed consent discussion. After the patient 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. The 
investigator or designee must also explain that the patients are completely free to refuse 
to enter the study or to withdraw from it at any time, for any reason. The CRF for this 
study contain a section for documenting patient 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 patients (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. 
11.3 
Independent Ethics Committees/Institutional Review Board 
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. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
54 
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 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 CA 
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 International Medical Leader 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 
Both the sponsor and the investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange the procedures on an individual study 
basis after review and consultation. In terminating the study, Roche and the investigator 
will assure that adequate consideration is given to the protection of the patient‟s interests. 
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
55 
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) patient clinical source documents. 
The Investigator's Study File will contain the protocol/amendments CRF and Schedule of 
Assessments, IEC/IRB and governmental approval with correspondence, sample 
informed consent, drug records, staff curriculum vitae and authorization forms and other 
appropriate documents/correspondence, etc. In addition at the end of the study the 
investigator will receive the patient 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 compact disk (CD) which also has to be kept with 
the Investigator‟s Study File. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the CRF) would include patient hospital/clinic 
records, physician's and nurse's notes, appointment book, original laboratory reports, 
ECG, electroencephalography (EEG), X-ray, pathology and special assessment reports, 
signed informed consent forms, consultant letters, and patient screening and enrollment 
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 patient, appropriate copies should be 
made for storing outside of the site. 
ICH Good Clinical Practice (GCP) guidelines require that Investigators maintain 
information in the study patient‟s records which corroborate data collected and entered 
into the CRF. 
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 patient confidentiality is protected. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
56 
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. The verification of the CRF data must be by direct inspection of source 
documents. 
14.4 
Case Report Forms 
Data for this study will be captured by using CRFs. 
For each patient enrolled, an CRF must be completed and 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 screening period if an CRF 
was initiated). If a patient withdraws from the study, the reason must be noted on the 
CRF. 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 CRFs and in all required reports. 
 
15. 
MONITORING THE STUDY 
It is understood that the responsible Roche monitor will contact and visit the investigator 
regularly and will be allowed, on request, to inspect the various records of the trial (CRF 
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 CRF 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. The monitor should have access to laboratory test 
reports and other patient records needed to verify the entries on the CRF. 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 PATIENT 
RECORDS 
The investigator must assure that patients‟ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On CRFs 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 enrollment 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 


Protocol ML27860, version 1.1, 16 Aug. 2012 
57 
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 
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 center data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
Any formal publication of the study in which input of Roche personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and 
the appropriate Roche personnel. Authorship will be determined by mutual agreement. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
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Appendix 1: 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 tumour at baseline 
1. Definitions 
At baseline, tumour lesions/lymph nodes will be categorized measurable or non-
measurable as follows: 
 
1.1. Measurable 
Tumour 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. 
• 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:. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
59 
• 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:  
• Tumour 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 characterise 
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 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). 
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
60 
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 utilisation of these techniques for objective tumour 
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. 
 
Tumour markers: Tumour markers alone cannot be used to assess objective tumour 
response. If markers are initially above the upper normal limit, however, they must 
normalise 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. 
 
Tumour 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). 


Protocol ML27860, version 1.1, 16 Aug. 2012 
61 
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 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 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 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 


Protocol ML27860, version 1.1, 16 Aug. 2012 
62 
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 sumdiameterswhile 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 aremet, since a normal lymph node is defined as having a short 
axis of < 10mm. Case report forms or other data collectionmethodsmay 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 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. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
63 
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 normalisation 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 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 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 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 localised 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 increasemust 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 


Protocol ML27860, version 1.1, 16 Aug. 2012 
64 
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 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 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-randomised 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. 
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
65 
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. 
 
 
4.2. Missing assessments and inevaluable designation 


Protocol ML27860, version 1.1, 16 Aug. 2012 
66 
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 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, 


Protocol ML27860, version 1.1, 16 Aug. 2012 
67 
this means that patients with CR may not have a total sum of „zero‟ on the case report 
form (CRF). 
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 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 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 IIIb 
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 


Protocol ML27860, version 1.1, 16 Aug. 2012 
68 
(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) 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-randomised 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 randomised trials (phase II or III) or studies where stable 
disease or progression are the primary endpoints, confirmation of response is not 
requiredsince 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 randomised trials, from date 
of randomisation) 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 ML27860, version 1.1, 16 Aug. 2012 
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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. 
 


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Appendix 3: ICH Guidelines for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2 
 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution. It is any AE that at any dose fulfills at least 
one of the following criteria: 
 Is fatal (results in death) (NOTE: death is an outcome, not an event). 
 Is Life-Threatening (NOTE: the term "Life-Threatening" refers to an event in 
which the patient was at immediate risk of death at the time of the event; it does 
not refer to an event which could hypothetically have caused a death had it been 
more severe). 
 Required in-patient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect. 
 Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the sponsor is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the outcomes 
listed in the definitions above. These situations should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the investigator. For Serious Adverse Events, possible 
causes of the event are indicated by selecting one or more options. (Check all that apply)  
 Pre-existing/Underlying disease – specify.  
 Study treatment – specify the drug(s) related to the event. 
 Other treatment (concomitant or previous) – specify. 
 Protocol-related procedure. 
 Other (e.g. accident, new or intercurrent illness) – specify. 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious. For 
example, nausea of several hours' duration may be rated as severe, but may not be clinically 
serious. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
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A serious adverse event occurring during the study or which comes to the attention of the 
investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported. In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported. 
Such preliminary reports will be followed by detailed descriptions later which will 
include copies of hospital case reports, autopsy reports and other documents when 
requested and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs page 
of the CRF: intensity, relationship to test substance, action taken, and outcome to date. 
The investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for SAEs: Local Monitor. 
ROCHE HEADQUARTERS CONTACT for SAEs and other medical emergencies: 
Clinical Operations/Clinical Science. 
24 HOUR MEDICAL COVERAGE: Call the local emergency contact number 
provided by the Monitor. 
 
IMPORTANT NOTE 
Progressive Disease And Death Due To Progressive Disease Will NOT Be Regarded 
As Reportable As A SAE In This Study. 
Progression or deterioration of the malignancy under study (including new sites of 
metastasis and death due to disease progression) should be recorded as part of the 
efficacy evaluation and should not be reported as AEs/SAEs. 


Protocol ML27860, version 1.1, 16 Aug. 2012 
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Appendix 4: 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 po 
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 


Protocol ML27860, version 1.1, 16 Aug. 2012 
73 
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 antagonist such as ranitidine should be 
considered and used in a staggered manner. Erlotinib must be taken at least 2 hours 
before or 10 hours after the H2-receptor antagonist dosing. 
International Normalized Ratio (INR) elevations and bleeding events, including 
gastrointestinal bleeding, have been reported in clinical studies, some associated with 
concomitant warfarin administration. Coumarins (CoumadinTM; warfarin) use is an 
exclusion criteria. If the patient requires anti-coagulation therapy, then the use of low 
molecular weight heparin instead of coumarins is recommended where clinically 
possible. 
In a phase Ib study, there were no significant effects of gemcitabine on the 
pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the 
pharmacokinetics of gemcitabine (Core data sheet, 2009). 
The following potent CYP3A4 inhibitors may increase erlotinib toxicity:  
 Systemic antifungals (e.g. ketoconazole, itraconazole, miconazole).  
 Erythromycin, clarithromycin, troleandomycin. 
 Selective serotonin reuptake inhibitors (e.g. nefazodone). 
The following medications could decrease plasma levels of erlotinib and hence decrease 
efficacy, but they probably do not represent a safety concern: 
 Antiepileptics (e.g. carbamazepine, phenobarbital, phenytoin). 
 Rifampin, rifabutin. 
 Troglitazone. 
 Barbiturates. 
 Glucocorticoids. 
 Saint John‟s wort. 
 
 
 
 
 
 
 
 
 
 
 


Protocol ML27860, version 1.1, 16 Aug. 2012 
74 
Appendix 5: FACT – L questionnaire  
 
FACT-L (Version 4) 
 
 
 
Below is a list of statements that other people with your illness have said are 
important. Please circle or mark one number per line to indicate your 
response as it applies to the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GP1 
I have a lack of energy ........................................................
0 
1 
2 
3 
4 
GP2 
I have nausea .......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family ..........................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ...........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment ..........................
0 
1 
2 
3 
4 
GP6 
I feel ill ................................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed .........................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my friends .....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family .............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends .............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness .....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ...............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 


Protocol ML27860, version 1.1, 16 Aug. 2012 
75 
 
 
 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GE1 
I feel sad .............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness .........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness .................
0 
1 
2 
3 
4 
GE4 
I feel nervous ......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying ............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ...........................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling.....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life .........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ..................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ...............................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life ............................................
0 
1 
2 
3 
4 


Protocol ML27860, version 1.1, 16 Aug. 2012 
76 
GF7 
I am content with the quality of my life right now .............
0 
1 
2 
3 
4 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
B1 
I have been short of breath ..................................................
0 
1 
2 
3 
4 
C2 
I am losing weight ..............................................................
0 
1 
2 
3 
4 
L1 
My thinking is clear ............................................................
0 
1 
2 
3 
4 
L2 
I have been coughing ..........................................................
0 
1 
2 
3 
4 
B5 
I am bothered by hair loss ...................................................
0 
1 
2 
3 
4 
C6 
I have a good appetite .........................................................
0 
1 
2 
3 
4 
L3 
I feel tightness in my chest .................................................
0 
1 
2 
3 
4 
L4 
Breathing is easy for me .....................................................
0 
1 
2 
3 
4 
Q3 
Have you ever smoked?  
No ___  Yes ___  If yes: 
L5 
I regret my smoking ............................................................
0 
1 
2 
3 
4