Clinical trial NCT02108964
Conditions: Advanced Non-small Cell Lung Cancer
Keywords: NSCLC Non-small Cell Lung Cancer EGFRmut EGFR TKIs (EGF816) acquired T790M mutation de novo T790M mutation EGFR TKI activating mutation (i.e. L858R or ex19del) Treatment naive advanced NSCLC with EGFR activating mutations Locally advanced NSCLC (Stage IIIB NSCLC not amenable to definitive multi-modality therapy including surgery) Metastatic NSCLC refers to Stage IV NSCLC 1st line
Sponsor: Novartis Pharmaceuticals
Start date: 2014-06-06; Completion date: 2023-08-15
Enrollment: 225 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase I/II, multi-center, open-label study, composed with a Phase I part (dose-escalation phase) followed by a Phase II part (expansion phase).

The dose escalation phase was designed to determine as primary objective the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D) of EGF816 monotherapy in adult subjects with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC harboring specific EGFR mutations. Patients may have or not have received prior lines of antineoplastic therapy. An adaptive Bayesian Logistic Regression Model (BLRM) employing the escalation with overdose control (EWOC) principle will be used during the dose escalation part for dose level selection and MTD recommendation. The primary objective of the Phase II part is to estimate antitumor activity of EGF816 as measured by overall response rate (ORR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to RECIST 1.1.

Detailed description:
Following completion of screening procedures and confirmation of patient eligibility, the participants are enrolled in the study. The study treatment begin on Cycle 1, Day 1 with the first administration of EGF816. A treatment cycle is defined as 28 days. Oral EGF816 is administered once daily on a continuous schedule until patient experiences unacceptable toxicity, progressive disease (PD), and/or treatment is discontinued at the discretion of the investigator, patient withdrawal of consent, or due to any other reasons. Treatment with EGF816 may be continued beyond RECIST 1.1 defined PD, if, in the judgment of the investigator, there is evidence of clinical benefit and the patient wishes to continue with the study treatment.

Arms: arm 1: Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations will be administered escalated doses of EGF816 orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study. The starting dose for the Phase I part first cohort of patients will be 75 mg once per day capsule. arm 2: Treatment naïve participants with locally advanced or metastatic NSCLC harboring EGFR mutations will be administered with EGF816 at RP2D during Phase II part of the study.
Interventions: intervention 1: EGF816
Intervention descriptions: intervention 1: EGF816 will be dosed once daily. On the first day of each treatment cycle, the patient receives an adequate drug supply for self-administration at home. The investigator will instruct the patient to take EGF816 exactly as prescribed.

Protocol documents:
Prot_002.pdf: 
Clinical Development 
EGF816 (Nazartinib) 
Protocol CEGF816X2101 / NCT02108964
A phase I/II, multicenter, open-label study of EGFRmut–TKI 
EGF816 administered orally in adult patients with EGFRmut 
solid malignancies 
Author(s): 
Document type: 
Amended Protocol Version 
EUDRACT number 
2013-004482-14 
Version number 
07 (Clean) 
Development phase I/II 
Document status: 
final 
Release date: 
11-Mar-2020
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 7 
List of figures ...................................................................................................................... 8 
Amendment 07 (11-Mar-2020) ........................................................................................... 9 
Amendment 06 (07-Apr-2017) .......................................................................................... 11 
Amendment 05 .................................................................................................................. 22 
Amendment 04 .................................................................................................................. 24 
Amendment 03 .................................................................................................................. 34 
Amendment 02 .................................................................................................................. 37 
Amendment 01 .................................................................................................................. 38 
Protocol summary .............................................................................................................. 41 
List of abbreviations .......................................................................................................... 46 
Glossary of terms ............................................................................................................... 50 
1 
Background........................................................................................................................ 51 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 51 
1.2 
Introduction to investigational treatment(s) and other study treatment(s)............. 52 
1.2.1 
Overview of EGF816 ............................................................................ 52 
2 
Rationale ............................................................................................................................ 59 
2.1 
Study rationale and purpose................................................................................... 59 
2.2 
Rationale for the study design ............................................................................... 60 
2.3 
Rationale for dose and regimen selection .............................................................. 62 
2.4 
The recommended phase II dose (RP2D) was determined based on the safety 
and efficacy data obtained from the Phase I part (dose-escalation) at 150 
mg/day on capsules and tablets. Rationale for choice of combination drugs ........ 62 
2.5 
Rationale for choice of comparators drugs ............................................................ 62 
2.6 
Risks and benefits .................................................................................................. 62 
3 
Objectives and endpoints ................................................................................................... 63 
4 
Study design ...................................................................................................................... 65 
4.1 
Description of study design ................................................................................... 65 
4.2 
Timing of interim analyses and design adaptations ............................................... 67 
4.3 
Definition of end of the study ................................................................................ 68 
4.4 
Early study termination.......................................................................................... 68 
5 
Population .......................................................................................................................... 69 
5.1 
Patient Population .................................................................................................. 69 
5.2 
Inclusion criteria .................................................................................................... 69 
5.3 
Exclusion criteria ................................................................................................... 71 
6 
Treatment ........................................................................................................................... 74 


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6.1 
Study treatment ...................................................................................................... 74 
6.1.1 
Dosing regimen ..................................................................................... 74 
6.1.2 
Treatment duration ................................................................................ 75 
6.2 
Dose-escalation guidelines .................................................................................... 76 
6.2.1 
Starting dose rationale ........................................................................... 76 
6.2.2 
Provisional dose levels for Phase I part (dose-escalation) .................... 77 
6.2.3 
Guidance for dose escalation and determination of MTD/RP2D ......... 78 
6.2.4 
Definitions of dose-limiting toxicities (DLTs) for Phase I part 
(dose-escalation) ................................................................................... 81 
6.3 
Dose modifications for toxicities ........................................................................... 81 
6.3.1 
Dose modification and dose delay ........................................................ 81 
6.3.2 
Guidelines for screening, monitoring and management of HBV / 
HCV reactivation .................................................................................. 88 
6.3.3 
Guidelines for the management and dose modification of skin-
related toxicities .................................................................................... 93 
6.3.4 
Guidelines for the management and dose modification of non-
infectious pneumonitis/interstitial lung disease .................................... 95 
6.3.5 
Follow-up for toxicities ......................................................................... 97 
6.3.6 
Anticipated risks and safety concerns of the study drug ....................... 99 
6.4 
Concomitant medications ...................................................................................... 99 
6.4.1 
Permitted concomitant therapy ............................................................. 99 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ......... 100 
6.4.3 
Prohibited concomitant therapy .......................................................... 100 
6.5 
Patient numbering, treatment assignment or randomization ............................... 101 
6.5.1 
Patient numbering ............................................................................... 101 
6.5.2 
Treatment assignment ......................................................................... 101 
6.6 
Study drug preparation and dispensation ............................................................. 101 
6.6.1 
Study drug packaging and labeling ..................................................... 101 
6.6.2 
Drug supply and storage...................................................................... 102 
6.6.3 
Study drug compliance and accountability ......................................... 102 
6.6.4 
Disposal and destruction ..................................................................... 102 
7 
Visit schedule and assessments ....................................................................................... 103 
7.1 
Study flow and visit schedule .............................................................................. 103 
7.1.1 
Molecular pre-screening ...................................................................... 117 
7.1.2 
Screening ............................................................................................. 117 
7.1.3 
Treatment period ................................................................................. 120 
7.1.4 
Discontinuation of Study Treatment ................................................... 120 
7.1.5 
Follow-up period ................................................................................. 121 


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7.1.6 
Withdrawal of Consent ....................................................................... 122 
7.1.7 
Lost to follow-up ................................................................................. 122 
7.2 
Assessment types ................................................................................................. 123 
7.2.1 
Efficacy assessments ........................................................................... 123 
7.2.2 
Safety and tolerability assessments ..................................................... 127 
7.2.3 
Pharmacokinetics ................................................................................ 130 
7.2.4 
Biomarkers .......................................................................................... 133 
7.2.5 
[For Japan only] Radiological examinations ....................................... 137 
8 
Safety monitoring and reporting ...................................................................................... 137 
8.1 
Adverse events ..................................................................................................... 137 
8.1.1 
Definitions and reporting .................................................................... 137 
8.1.2 
Laboratory test abnormalities .............................................................. 138 
8.1.3 
Adverse events of special interest ....................................................... 139 
8.2 
Serious adverse events ......................................................................................... 139 
8.2.1 
Definitions ........................................................................................... 139 
8.2.2 
Reporting ............................................................................................. 140 
8.3 
Pregnancies .......................................................................................................... 141 
8.4 
Warnings and precautions.................................................................................... 141 
8.5 
Data Monitoring Committee ................................................................................ 141 
8.6 
Steering Committee ............................................................................................. 142 
8.7 
Blinded Independent Review Committee (BIRC) ............................................... 142 
9 
Data collection and management ..................................................................................... 142 
9.1 
Data confidentiality ............................................................................................. 142 
9.2 
Site monitoring .................................................................................................... 143 
9.3 
Data collection ..................................................................................................... 143 
9.4 
Database management and quality control .......................................................... 144 
10 Statistical methods and data analysis .............................................................................. 145 
10.1 
Analysis sets ........................................................................................................ 145 
10.1.1 
Phase I part .......................................................................................... 145 
10.1.2 
Phase II part......................................................................................... 146 
10.2 
Patient demographics/other baseline characteristics ........................................... 147 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ..................... 147 
10.3.1 
Study treatment ................................................................................... 147 
10.3.2 
Concomitant therapies ......................................................................... 147 
10.3.3 
Compliance ......................................................................................... 147 
10.4 
Primary objective ................................................................................................. 147 
10.4.1 
Variable ............................................................................................... 147 


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10.4.2 
Statistical hypothesis, model and method of analysis ......................... 148 
10.4.3 
Handling of missing values/censoring/discontinuations ..................... 150 
10.4.4 
Supportive analyses ............................................................................. 150 
10.5 
Secondary objectives ........................................................................................... 150 
10.5.1 
Safety objectives ................................................................................. 150 
10.5.2 
Efficacy objectives .............................................................................. 152 
10.5.3 
Pharmacokinetics ................................................................................ 154 
 
 155 
 
 155 
 
 155 
10.7 
Interim analysis .................................................................................................... 156 
10.8 
Sample size calculation........................................................................................ 157 
10.8.1 
Phase I part .......................................................................................... 157 
10.8.2 
Phase II part......................................................................................... 157 
10.9 
Power for analysis of key secondary variables .................................................... 157 
11 Ethical considerations and administrative procedures .................................................... 158 
11.1 
Regulatory and ethical compliance ...................................................................... 158 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 158 
11.3 
Informed consent procedures ............................................................................... 158 
11.4 
Discontinuation of the study ................................................................................ 159 
11.5 
Publication of study protocol and results............................................................. 159 
11.6 
Study documentation, record keeping and retention of documents ..................... 160 
11.7 
Confidentiality of study documents and patient records ..................................... 160 
11.8 
Audits and inspections ......................................................................................... 160 
11.9 
Financial disclosures ............................................................................................ 161 
12 Protocol adherence .......................................................................................................... 161 
12.1 
Amendments to the protocol ................................................................................ 161 
13 References (available upon request) ................................................................................ 162 
14 Appendices ...................................................................................................................... 165 
14.1 
Appendix 1 – Guidelines for response, duration of overall response, TTF, 
TTP, progression-free survival and overall survival (based on RECIST 1.1) ..... 165 
14.1.1 
Introduction ......................................................................................... 167 
14.1.2 
Efficacy assessments ........................................................................... 167 
14.1.3 
Definitions ........................................................................................... 167 
14.1.4 
Disease measurability.......................................................................... 167 
14.1.5 
Eligibility based on measurable disease .............................................. 168 
14.1.6 
Methods of tumor measurement - general guidelines ......................... 168 
14.1.7 
Baseline documentation of target and non-target lesions ................... 170 


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14.1.8 
Follow-up evaluation of target and non-target lesions ........................ 170 
14.1.9 
Follow-up and recording of lesions..................................................... 171 
14.1.10 
Non-nodal lesions................................................................................ 171 
14.1.11 
Nodal lesions ....................................................................................... 171 
14.1.12 
Determination of target lesion response .............................................. 172 
14.1.13 
Determination of non-target lesion response ...................................... 174 
14.1.14 
New lesions ......................................................................................... 175 
14.1.15 
Evaluation of overall lesion response ................................................. 175 
14.1.16 
Efficacy definitions ............................................................................. 176 
14.1.17 
Best overall response........................................................................... 176 
14.1.18 
Time to event variables ....................................................................... 178 
14.1.19 
Progression-free survival .................................................................... 178 
14.1.20 
Overall survival ................................................................................... 179 
14.1.21 
Time to progression............................................................................. 179 
14.1.22 
PFS2 .................................................................................................... 179 
14.1.23 
Time to treatment failure ..................................................................... 179 
14.1.24 
Duration of response ........................................................................... 180 
14.1.25 
Time to response ................................................................................. 181 
14.1.26 
Definition of start and end dates for time to event variables .............. 181 
14.1.27 
Handling of patients with non-measurable disease only at baseline ... 182 
14.1.28 
Sensitivity analyses ............................................................................. 183 
14.1.29 
Data handling and programming rules ................................................ 185 
14.1.30 
Study/project specific decisions .......................................................... 185 
14.1.31 
End of treatment phase completion ..................................................... 186 
14.1.32 
End of post-treatment follow-up (study phase completion) ................ 186 
14.1.33 
Medical validation of programmed overall lesion response ............... 187 
14.1.34 
Programming rules .............................................................................. 187 
14.1.35 
Calculation of ‘time to event’ variables .............................................. 187 
14.1.36 
Incomplete assessment dates ............................................................... 187 
14.1.37 
Incomplete dates for last known date patient alive or death ............... 188 
14.1.38 
Non-target lesion response .................................................................. 188 
14.1.39 
Study/project specific programming ................................................... 188 
14.1.40 
Censoring reason ................................................................................. 188 
14.1.41 
References (available upon request) ................................................... 190 
14.2 
Appendix 2 – Operating characteristics of the Bayesian logistic regression 
mode and hypothetical dose-escalation scenarios ............................................... 191 
14.2.1 
Introduction ......................................................................................... 191 
14.2.2 
Model specifications ........................................................................... 191 


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14.2.3 
Hypothetical dose-escalation scenarios ............................................... 193 
14.2.4 
References ........................................................................................... 199 
14.3 
Appendix 3- Permitted Concomitant Medications requiring caution .................. 201 
14.4 
Appendix 4 - Prohibited Concomitant Medications ............................................ 202 
 
List of tables 
Table 1-1 
Superiority of EGFR TKIs over chemotherapy in EGFRmut 
NSCLC .................................................................................................. 51 
Table 3-1 
Objectives and related endpoints (Phase I part) .................................... 63 
Table 3-2 
Objectives and related endpoints (Phase II part) ................................... 64 
Table 6-1 
Dose and treatment schedule ................................................................. 74 
Table 6-2 
Provisional dose levels for Phase I part (dose-escalation) .................... 78 
Table 6-3 
Criteria for defining dose-limiting toxicities in the Phase I part ........... 81 
Table 6-4 
Recommended dose reduction steps for the Phase I and II parts .......... 82 
Table 6-5 
Criteria for dose reduction/interruption and re-initiation of EGF816 
treatment for adverse drug reactions ..................................................... 82 
Table 6-6 
Actions to be taken based on hepatitis B results screening ................... 89 
Table 6-7 
Guidelines for management of HBV reactivation ................................. 90 
Table 6-8 
Guidelines for management of HCV reactivation ................................. 92 
Table 6-9 
Guidelines for prevention and symptomatic care of rash/skin 
toxicities ................................................................................................ 93 
Table 6-10 
Management and dose modification for maculopapular rash1, 2 ........... 93 
Table 6-11 
Management and dose modification for other rashes including 
acneiform rash ....................................................................................... 94 
Table 6-12 
Management of non-infectious pneumonitis / interstitial lung 
disease ................................................................................................... 96 
Table 6-13 
Supply and storage of study treatment ................................................ 102 
Table 7-1 
Visit evaluation schedule (Phase I Part) .............................................. 104 
Table 7-2 
Visit evaluation schedule (Phase II part) ............................................ 109 
Table 7-3 
Imaging collection plan (Phase I part) ................................................ 123 
Table 7-4 
Imaging collection plan (Phase II part) ............................................... 124 
Table 7-5 
ECOG performance status................................................................... 127 
Table 7-6 
Local clinical laboratory parameters collection plan .......................... 128 
Table 7-7 
Central ECG collection plan for all patients (for Phase I) .................. 129 
Table 7-8 
Extensive ECG collection plan (for Phase II) ..................................... 129 
Table 7-9 
Phase I part: schedule of blood sample collections for 
pharmacokinetics................................................................................. 130 


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Table 7-10 
Phase II part: schedule of blood sample collections for 
pharmacokinetics................................................................................. 132 
 
 134 
 
 135 
Table 10-1 
Noncompartmental pharmacokinetic parameters ................................ 154 
Table 10-2 
Probability of success at the primary analysis based on various 
numbers of responders observed at the IA .......................................... 156 
Table 10-3 
Operating characteristics given sample size of 40 patients and 
interim analysis at 20 patients ............................................................. 157 
Table 14-1 
Response criteria for target lesions ..................................................... 172 
Table 14-2 
Response criteria for non-target lesions .............................................. 174 
Table 14-3 
Overall lesion response at each assessment ........................................ 175 
Table 14-4 
Overall lesion response at each assessment: patients with non-
target disease only ............................................................................... 182 
Table 14-5 
Options for event dates used in PFS, TTP, duration of response ........ 183 
Table 14-6 
Prior distribution of model parameters ............................................... 192 
Table 14-7 
Summary of prior distribution of DLT rates ....................................... 192 
Table 14-8 
Hypothetical scenarios for capsule on-study decisions (cohort size: 
1-6) ...................................................................................................... 193 
Table 14-9 
Hypothetical scenarios for capsule on-study decisions (cohort size: 
3) ......................................................................................................... 195 
Table 14-10 
Hypothetical capsule dose-DLT datasets prior to the first tablet 
dose-escalation meeting ...................................................................... 197 
Table 14-11 
Hypothetical scenarios for tablet on-study decisions (cohort size: 3) 
using hypothetical capsule dataset 1 ................................................... 197 
Table 14-12 
Hypothetical scenarios for tablet on-study decisions (cohort size: 3) 
using hypothetical capsule dataset 2 ................................................... 198 
Table 14-13 
Hypothetical scenarios for tablet on-study decisions (cohort size: 3) 
using hypothetical capsule dataset 3 ................................................... 199 
Table 14-14 
Permitted concomitant medications requiring caution ........................ 201 
Table 14-15 
Prohibited concomitant medications ................................................... 202 
 
List of figures 
Figure 1-1 
Best percentage change from baseline in sum of diameters of target 
lesions as per investigator by treatment (Capsule) – Full analysis 
set .......................................................................................................... 58 
Figure 4-1 
Study design, Phase II part .................................................................... 67 
Figure 4-2 
Study visit flow (Phase I part) ............................................................... 67 
Figure 4-3 
Study visit flow (Phase II part) ............................................................. 67 


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Amendment 07 (11-Mar-2020)  
Amendment rationale  
As of the release of this amendment (11-Mar-2020), the study is closed to enrollment. In the 
phase I part (dose-escalation) of the study, 180 patients were enrolled; 11 patients are 
ongoing. Forty-five patients were enrolled in Phase 2 part (expansion phase) of this study and 
18 patients are ongoing.  
Study initiated with capsules and moved to tablets, as it became the Formulated Market Image 
(FMI) strategy. However, based on the shelf-life superiority of the capsules in comparison to 
tablets, Novartis has strategically decided to move back to capsules to provide better shelf-life 
for the market. The main purpose of this amendment is to implement the use of the capsules 
form again (25 mg / 50 mg / 100 mg) instead of tablets for the ongoing patients promptly upon 
availability. The decision to switch back from tablet to capsule is based on the following: 
- 
The capsule formulation has a superior stability profile compared to the tablets, allowing 
the assignment of longer shelf lives 
- 
Statistical analysis showed that exposures between tablet and capsule are comparable 
with geometric mean ratios of 1.04 and 1.03 for AUCtau and Cmax, respectively, 
following single 150 mg dose, and 1.06 and 1.12 for AUCtau and Cmax, respectively, 
following 150 mg QD. 
Therefore, based on this rationale, capsules will be used in a timely manner following approval 
of this amendment for the remainder of this study for all ongoing patients in phase I and phase 
II parts.  
 
Additionally, the guidelines for some selected toxicities (hepatitis B, skin rash, including 
maculo-papular rash and Interstitial Lung Disease (ILD)/pneumonitis) have been updated to 
optimize the patient’s safety. These changes are not due to new safety findings but reflects new 
internal/international clinical guidelines. 
Finally, the lists of permitted and prohibited concomitant medications included in Appendix 3 
and Appendix 4 have been revised based on periodic update.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
The following sections and tables were changed: 
• List of abbreviations – added and updated abbreviations 
• Section 2.3 – removed the reference to the use of tablets in the phase II part 
• Section 6.1.1 – introduced the implementation of capsules use based on this amendment 
rationale 
• Section 6.2.1– clarification added for the change of drug formulation pertaining to protocol 
amendment #03 
• Sections 6.2.3.2 and 10.4.2.1 – clarification added for the change of drug formulation 
pertaining to protocol amendment #07 


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• Section 6.2.3.4 – revised since all patients are on treatment at RP2D with tablets therefore 
the intra-patient dose escalation switch cannot occur 
• Section 6.3.2, Table 6-6, Table 6-7 and Table 6-8 – Guidelines for screening, monitoring 
and management of HBV/HCV reactivation updated as per new internal/international 
clinical guidelines 
• Table 6-9 - Guidelines for prevention and symptomatic care of rash/skin toxicities updated 
as per new internal/international clinical guidelines 
• Table 6-10 – Management and dose modification for maculopapular rash updated as per 
new internal/international clinical guidelines 
• Table 6-11 - Management and dose modification for other rashes including acneiform rash 
updated as per new internal/international clinical guidelines 
• Section 6.3.4 and Table 6-12 - Guidelines for the management and dose modification of 
non-infectious 
pneumonitis/interstitial 
lung 
disease 
updated 
as 
per 
new 
internal/international clinical guidelines 
• Table 7-1 and Table 7-2 – Updated to reflect the change of HBV and HCV monitoring 
• Section 13 – Updated with the addition of  the reference related to the new clinical 
guidelines for hepatitis management 
• Appendix 3 (Table 14-14) and Appendix 4 (Table 14-15): Permitted concomitant 
medications requiring caution and prohibited concomitant medications lists revised based 
on periodic update  
In addition, as part of this amendment, minor editorial changes (e.g. typographical mistakes, 
grammatical changes, rewording) to improve flow and consistency, and correction of spelling 
errors or typographical errors have been made throughout the protocol. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
 


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Amendment 06 (07-Apr-2017) 
Amendment rationale 
As of 31-Mar-2017 in the Phase I part (dose-escalation) of the study, 180 patients have been 
enrolled with 7 different dose levels at 10 sites in 8 countries; 42 patients were ongoing. During 
a dose-escalation meeting on 30-Aug-2016, the Investigators and Novartis agreed to declare the 
Recommended Phase 2 Dose (RP2D) of EGF816 (Nazartinib) capsules and tablets at the dose 
level of 150 mg QD based on the available safety, pharmacokinetic, efficacy data and on the 
Bayesian Logistic Regression Model recommendation. 
The Phase II part (expansion phase) of this study was originally planned to enroll patients in 6 
different groups defined by the prior lines of treatment and the tumor molecular status of the 
patients. However, the rapid evolving landscape including ongoing trials in this disease setting 
led to the decision not to start the enrollment of patients who received more than 1 line of prior 
antineoplastic therapy in Groups 2 to 6. Indeed, it is noteworthy that approval has been granted 
in different countries to osimertinib (Tagrisso®) for the treatment of adult patients with locally 
advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive 
non-small cell lung cancer (NSCLC) who have progressed on or after prior systemic therapy, 
including an EGFR-TKI giving patients in this setting access to 3rd generation EGFR-TKI as 
per FDA and EMA information. Therefore, the Phase II part of the study will continue as a 
single group of patients, all treated at 150 mg QD Nazartinib. 
An Investigator letter dated 07-Dec-2016 informed the investigators about the opening of the 
Phase II part of the study for enrollment in Group 1 only. This group will now enroll a minimum 
of 40 treatment-naïve patients instead of 60 patients (Section 10.8.2), who have locally 
advanced or metastatic NSCLC with EGFR activating mutation (e.g., L858R and/or ex19del), 
have not received any systemic antineoplastic therapy for advanced NSCLC, and are eligible to 
receive EGFR-TKI treatment. As of 31-Mar-2017, 8 patients have been enrolled in the Phase II 
part and were ongoing. 
In addition, a previous protocol amendment (#4 released on 05-May-2015) introduced the 
implementation of central laboratories to evaluate the safety of EGF816 (Nazartinib) (e.g., 
hematology, chemistry, urinalysis, coagulation and pregnancy test) for all 6 groups in the Phase 
II part; given that only one group will now be opened, the laboratories for screening and safety 
monitoring will continue to be implemented locally as it is currently being done in the Phase I 
part.  
The main purpose of this amendment is to implement the above-mentioned decisions that were 
already communicated to all Investigators and submitted to all Ethics Committees and Health 
Authorities in participating countries. 
Furthermore, Amendment 6 implements other substantial changes as follows: 
- 
Provides an update on EGF816 overview based on the most recent version of the 
Investigator’s Brochure (Edition 5, released on 13-Jul-2016 with a data cut-off date 18-
Dec-2015) 
- 
Introduces the RP2D that was declared on 30-Aug-2016 during the Phase I part of the 
study. All patients enrolled in the Phase II will receive the RP2D, i.e. EGF816 150 mg 
QD. The recommended dose reduction steps starting from the RP2D are also introduced in 
this amendment. 


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- 
Removes the exclusion criterion on fasting plasma glucose > 175 mg/dL (> 9.8 mmol/L) 
in the absence of evidence of interaction with glucose in light of the most recent available 
clinical data and according to the latest version of EGF816 Investigator’s Brochure (Ed. 5, 
data cut-off date 18-Dec-2015) 
- 
Updates the exclusion criterion on QTcF threshold from 480 to 470 ms as defined by 
Morganroth for oncology studies in order to provide a safety margin of 30 ms for QTc > 
500, a significant liability for TdP, and a 10 ms safety margin for the second highest QTcF 
category of >480 and also to ensure patient safety within the context of other factors, 
related to nausea and vomiting and potentially overt cardiac conditions in the patient 
population that have not been assessed or diagnosed like left ventricular hypertrophy and 
subclinical cardiomyopathy 
- 
Updates number of patients required for futility analysis in the Phase II part from 25 to 
approximately 20 patients. It may allow stopping the enrollment or treatment of patients in 
case lack of efficacy is concluded. The sample size and the primary analysis in the Phase 
II are also being revised. The expansion phase will allow to explore the hypothesis that 
targeting the activating resistance mutants together with the main EGFR resistance 
mechanism T790M may prevent the acquisition of resistance to EGFR-TKIs. A sample 
size of 40 patients will provide acceptable operating characteristics to assess the 
preliminary anti-tumor activity of the study treatment 
- 
Reinstates the collection of CT/MRI scans or other imaging data in the Phase I part of the 
study for potential retrospective central review. 
- 
Updates to clarify criteria for treatment beyond disease progression of patients as per 
Investigator’s judgment 
- 
Removes in Phase I part for all ongoing patients, the visit on Day 15 during cycles beyond 
cycle 2 for consistency with the Phase II part of the study and because of the absence of 
additional or new unexpected safety findings in light of the most recent available clinical 
data. 
- 
Updates the definition of the end of study to detail study continuation conditions after 
completion of the primary analysis until all patients are discontinued, or until another 
clinical trial becomes available for all ongoing patients to be transferred to that clinical 
study and continue to receive EGF816. 
- 
Adds follow-up requirements for potential QTcF prolongation (in case of QTcF >500 ms, 
or QTcF prolongation >60 ms from baseline) and potential drug-induced liver injury to 
align with other Novartis-sponsored study protocols 
- 
Introduces the modalities and conditions for patient re-screening after screen failure, 
together with screening assessments to be performed again during the new screening 
phase. 
- 
 
 
 
 
 
 
- 
 
 
 


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- 
Updates the exclusion criterion related to women of child-bearing potential and the 
description of imaging efficacy assessments for consistency with other Novartis Oncology 
sponsored studies. 
Other non-substantial changes were made to provide more clarity to the protocol: 
- 
Clarifies the time window for post-dose ECG during the visits with PK sampling. 
- 
Clarifies that the exclusion criterion on the QTc interval value should be based on the 
Investigator interpretation of the ECG. 
Change to the protocol  
• Protocol summary: 
• Update purpose and rationale, inclusion and exclusion criteria, data analysis 
according to the main changes provided the protocol  
• Section 1.2.1.2 Clinical experience    
• Updated according to last version of the Investigator’s Brochure (Ed. 5, data cut-off 
date 18-Dec-2015) 
• Update efficacy data based on latest data presented in a poster at ASCO 2016  
• Section 2.1: Study rationale and purpose 
• Clarify that the Phase I part will include patients with tumors harboring specific 
EGFR mutations 
• Clarify that in the Phase II part patients to be enrolled will be in first line of 
antineoplastic systemic therapy (EGFR TKI and chemotherapy naïve) and whose 
tumors harbor specific EGFR activating mutations (e.g., L858R and ex19del) 
• Remove the description of the groups 2 to 6 originally planned for the Phase II part 
• Section 2.2: Rationale for study design 
• Remove the description of groups originally planned for the Phase II part 
• Section 2.6: Risk and Benefits 
• Introduce Risk and Benefits section for consistency with other Novartis Oncology 
sponsored study protocols  
• 
 
• 
 
  
• Section 4.1: Description of study design 
• Update description of patient population and sample size of phase II part  
• Clarify that EGFR mutation status is determined by a local laboratory for patient in 
Phase II part  
• Figure 4-1: Study design, Phase II part 
• Update the Study design of Phase II part following removal of the groups 2 to 6 
initially planned  
• Table 4-1: Key features of patient population in each of the 6 groups (Phase II) 
• Remove the table entirely as the 6 groups will no longer be applicable for Phase II 
part 


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• Section 4.2: Timing for interim analysis and design adaptation 
• Remove all the 6 groups description and clarify the assessment of futility will be 
based on the calculated Bayesian probability of success (PoS). 
• Section 4.3: Definition of end of study  
• Update to clarify that primary analysis will be conducted on Phase I and II patients 
and end of study definition is applicable for Phase I and II patients 
• Remove the description of the 6 groups  
• Section 5: Population  
• Remove the description of the 6 groups and specify that patients in Phase II part must 
not have received any prior line of systemic antineoplastic therapy in the advanced 
setting (NSCLC stage IIIB or IV). However, patients who have failed no more than 1 
cycle of antineoplastic therapy in the advanced setting are allowed. 
• Section 5.2: Inclusion criteria  
• Update Inclusion criterion 4 to clarify that patients with controlled brain metastases 
may participate in the trial and must be neurologically stable, having no new 
neurologic deficits on clinical examination, and no new findings on central nervous 
system imaging. 
• Update inclusion criterion 11 to remove the 6 groups and define the patient population 
for Phase II (NSCLC with locally documented EGFR mutation L858R and/or 
ex19del, and must be naïve from any line of systemic antineoplastic therapy in the 
advanced setting) 
• Section 5.3: Exclusion criteria 
• Update exclusion criterion 7 to clarify that patient with QTcF value above 470ms 
instead of 480ms would be excluded from study provided it was defined as threshold 
for oncology studies by Morganroth, and it provides a safety margin of 30 ms for 
QTc>500ms, which constitutes a significant liability for TdP, and a 10 ms safety 
margin for the second highest QTcF category of >480ms. In addition it was clarified 
to use the mean QTcF value from triplicate screening ECGs according to 
Investigator’s assessment  
• Update exclusion criterion 11 to clarify minimum time window for patients who have 
been treated with chemotherapy or biologic therapy or other investigational agent from 
≤  1 week to ≤ 4 weeks prior to the first dose of study treatment 
• Update exclusion criterion 15 to clarify time window for patients who participated in a 
prior investigational study from within 1 week to within 4 weeks or within 5 half-lives 
of the investigational product, whichever is longer, prior to first dose of study treatment 
• Update exclusion criterion 12 to remove Fasting Plasma glucose in light of IB ed. 5 
data and add editorial updates for ANC, Hemoglobin, Platelets and Creatinine 
Clearance criteria 
• Update exclusion criteria19 and 20 to provide more clarity on pregnancy/ 
contraception and clarify when a condom should be used 
• Section 6.1.1: Dosing Regimen  


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• Clarify that for patients in Phase II part, the orally administered film-coated tablet 
formulation will be treated with RP2D and provided with 2 doses strength of 25 mg 
and 50 mg.  
• Clarify that patients in Phase I part will be continued on capsule or tablets 
formulations 
• Clarify when the dose should be taken on PK days 
• Clarify which fruits must be avoided during the treatment period of the study 
• Section 6.1.2: Treatment duration 
• Update to remove confirmation of disease progression by BIRC in Phase II 
• Add that patient may continue treatment until patient experiences unacceptable 
toxicity, disease progression and/or treatment is discontinued at the discretion of the 
investigator or withdrawal of consent. 
• Section 6.1.2.1: new section added to provide details about treatment beyond disease 
progression of patients 
• Section 6.2.1: Starting dose rationale 
• Add details on EGF816 strength and reference to support the formulation change 
from capsules to tablets 
• Table 6-4: Recommended dose reduction steps for the Phase II part 
• Update the dose reduction steps based on the declared RP2D for Phase I and II 
patients 
• Table 6-5: Criteria for reduction/interruption and re-initiation of EGF816 treatment for 
adverse drug reactions: 
• Update criteria for Isolated AST/ALT to match with CTCAE and provide guidance 
based on patient’s baseline AST/ALT values and match with new Novartis-sponsored 
study protocols 
• Ad criteria for Grade 4 QTcF 
• Update to clarify when the dose modifications/interruptions are recommendations  or 
mandatory and also align with other Novartis-sponsored study protocols 
• Table 6-8: Guidelines for management of HCV reactivation 
• Update to correct the date of viral reactivation from 22Jan to 01Jan2015 
• Table 6-10: Management and dose modification for maculopapular rash 
• Clarify that Grade ≥3 rash should be re-assessed every week and if more than 1 
episode of ≥ Grade 3 is developed, patient must be permanently discontinued 
• Clarify that study drug may be resumed although steroids for rash management are 
still ongoing or being tapered 
• Table 6-11: Management and dose modification for other rashes including acneiform rash 
• Clarify that re-assessment should be conducted every 2 weeks instead of after 2 weeks 
• Section: 6.3.5: Follow-up for toxicity 
• Add new section 6.3.5.1: follow up on potential QTcF prolongation to align with 
other Novartis-sponsored  study protocols 


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Protocol No. CEGF816X2101 
 
 
• Add new section 6.3.5.2: follow up on potential drug-induced liver injury (DILI) 
cases to align with other Novartis-sponsored  study protocols 
• Section 6.4: Concomitant medications 
• Clarify that the use of bisphosphonates is allowed as no drug-drug interaction is 
expected with EGF816 
• Editorial changes in Section 6.4.2 and 6.4.3 
• Section 6.5: Patient numbering, treatment assignment or randomization 
• Clarify that this is a non-randomized trial and Integrated Response Technology (IRT) 
will only be used for patient registration and drug supply management in the Phase II 
part 
• Remove the description of treatment assignment of 6 groups originally planned in the 
protocol 
• Section 6.6.1: Study drug packaging and labeling 
• Editorial changes to add more clarity on the packaging difference between Phase I 
and Phase II 
• Table 7-1: Visit Evaluation Schedule (Phase I part) 
• Greyed out Day 15 for all subsequent cycles after cycle 2 to reduce patient’s visits for 
ongoing Phase I patients after protocol amendment 06  
• Add footnote to clarify that EOT tumor assessment doesn’t need to be repeated if was 
performed ≤ 28 days 
• 
 
 
 
 
• Remove Body fluid collection/results as no cytology samples will be collected and 
only the cytology form needs to be completed 
• Merge Disposition for  Screening and Treatment for consistency with Table 7-2 and 
add Disposition for Disease Progression F/U as this information is collected for Phase 
I patients 
• Add row for safety follow-up as this assessment is performed for Phase I patients 
• Table 7-2: Visit Evaluation Schedule (Phase II part) 
• Greyed out all visits that are no longer applicable for Phase II patients and added the 
corresponding footnote 
• Update to clarify that EGFR mutation status needs to be confirmed by local testing 
only 
• Remove all the assessments related to Groups 2 to 6 as they are no longer applicable 
• Move Chest X-Ray (for Japanese Patients Only) from the Tumor assessment section 
to the Physical examination section for more clarity 
• Provide more details on the imaging data to be collected for tumor assessment per 
RECIST 1.1 and as per the imaging collection plan in Table 7-4  
• Update to clarify that all phase II patients will now have extensive ECG collection   


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Protocol No. CEGF816X2101 
 
 
• 
 
 
 
 
  
• Remove Body fluid collection/results as no cytology samples will be not collected 
and only the cytology form needs to be completed and submitted to central imaging 
CRO 
• Section 7.1.1: Molecular pre-screening  
• Remove all the descriptions related to patients in groups 2 to 6 
• Group 1 no longer exists as in phase II only one patient population is required and 
there is no need to have different groups 
• Clarify that EGFR activating mutation will be confirmed by local lab 
• Section 7.1.2: Screening 
• 
 
 
• Clarify that HBV and HCV tests will be performed by a local laboratory for Phase I 
and II patients 
• Section 7.1.2.1: Eligibility Screening  
• Update eligibility text by adding more details on screening/re-screening procedure 
and failures for patients enrolled in Phase II part of the study  
• Section 7.1.4 : Discontinuation of study treatment  
• Add more details on when the patient “should” and not “must” discontinue the study 
treatment 
• Add clarification about when patient is considered to have withdrawn from the study 
and when treatment is continued beyond disease progression 
• Section 7.1.5.2: Post-treatment follow-up 
• Add that antineoplastic therapies since discontinuation of study treatment should be 
collected to match with Tables 7-1 and 7-2 
• Section 7.1.5.3: Survival follow-up 
• Add that antineoplastic therapies since discontinuation of study treatment should 
continue to be collected for Phase II patients for evaluation of overall survival 
• Section 7.1.6: Withdrawal of consent  
• Add reasons when patient can withdraw consent  and clarify that the Investigator 
should make every effort to understand the primary reason of this decision  
• Section 7.2.1: Efficacy Assessment  
• Clarify that central imaging review will be done by BIRC in an ongoing basis for 
Phase II and retrospective collection and central review will be conducted for Phase I 
• Editorial changes in Section 7.2.1.1 regarding baseline imaging assessment to align 
with other Novartis-sponsored study protocols and move the text related to post-
baseline imaging assessment in section 7.2.1.2 


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Amended Protocol Version 07 (Track Changes) 
 
Protocol No. CEGF816X2101 
 
 
• Rename section 7.2.1.2 from Subsequent imaging for response assessment to post-
baseline imaging assessment to match with other Novartis-sponsored study protocols 
• Section 7.2.1.2: Post-baseline imaging assessment 
• Sub-section renamed to match with other Novartis-sponsored study protocols 
• Repetitive statements removed to add some clarity 
• 
 
• 
 
 
• Section 7.2.1.4: BIRC confirmation of disease progression 
• Delete sub-section as BIRC PD confirmation is not required and needed provided the 
primary efficacy analysis is based on ORR and not on PFS 
• Section 7.2.2.1: Physical examination 
• Define the complete and targeted physical examination  
• Section 7.2.2.5: Laboratory evaluations  
• Amend to clarify that local lab will be used for patients in Phase I and Phase II and no 
central lab will be used for patients in Phase II 
• Amend to add Phosphorus to match with inclusion criterion 
• Amend to add Amylase and Lipase in the chemistry panel to allow monitoring of 
occurring pancreatic AEs 
• Section 7.2.2.6.1: Electrocardiogram (ECG)  
• Update to clarify that extensive ECG will be done for all the patients treated in Phase 
II part provided groups 2 to 6 were removed 
• Clarify that triplicate ECGs should be performed within 15 minutes prior to the 
collection of PK sample at the matched time-point 
• Update to align wording with other Novartis-sponsored study protocols 
• Section 7.2.3: Pharmacokinetics 
• Add dose reference ID prior to PK sampling in Tables 7-9 and 7-10 
• Section 7.2.4: Biomarkers 
• Split the biomarker section into 2 sub-sections for Phase I and for Phase II part of the 
study 
 
 
 
• Add reason for biomarker collection and assessments in Phase II part of the study  
• Table 7-12: Biomarker sample collection plan for Phase II part 
• Update to remove description for biomarker collection from patients in groups 2 to 6 
• Specify that mandatory tumor samples at screening instead of pre-screening should be 
collected and block or a minimum of 11 slides instead of 6 slides are required  
• Specify that mandatory tumor samples (if available) at C1D1 instead of screening 
should be collected and block or additional 5 slides instead of 10 slides are needed 


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Protocol No. CEGF816X2101 
 
 
• Update to clarify that C1D1 optional tumor sample now include either newly obtained 
tumor biopsy or archival material (3 to 10 slides) if fresh material not available at 
C1D1 
• Add the possibility to provide optional newly acquired biopsy during the treatment 
phase for assessing the study drug effect and mechanisms of resistance to EGF816 
treatment 
• 
 
• 
 
 
 
 
 
• Add optional on treatment blood sample collection to be paired with on treatment 
newly acquired biopsy  
• Remove the tissue requirement needed in the companion protocol for phase II patients 
• Section 8.1.1: Definitions and reporting 
• Update to clarify AE reporting and align with other Novartis-sponsored study 
protocols 
• Section 8.1.3: Adverse events of special interest 
• New section added to align with other Novartis-sponsored study protocols and define 
the AESIs to be monitored for EGF816 
• Section 8.2.2: Reporting 
• Update the Serious Adverse Event reporting process to allow possible electronic 
reporting to the Sponsor and name of safety department to Chief Medical Office and 
Patient Safety (CMO&PS) 
• Section 8.3: Pregnancies 
• Replace “Drug Safety and Epidemiology Department” by “Chief Medical Office and 
Patient Safety (DS&ECMO&PS)” 
• Update: Pregnancy outcomes should be collected for the female partners 
• Section 8.5: Data Monitoring Committee 
• Update to remove description regarding groups 2 to 6 
• Section 8.7: Blinded Independent Review Committee (BIRC):  
• Reinstate that BIRC review will be performed for patients from Phase I part 
• Remove expedited PD review following local assessment of progression 
• Section 9.4: Database management and quality control 
• Update to align with other Novartis-sponsored study protocols 
• Section 10: Statistical methods and analysis: 
• Remove description regarding groups 2 to 6 
• Section 10.1: Analysis sets 
• Update to remove description regarding groups 2 to 6 and description of the 
pharmacokinetic analysis set for phase I and II 


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Protocol No. CEGF816X2101 
 
 
• Section 10.2: Patient demographics/other baseline characteristics 
• Update to remove description regarding groups 2 to 6 
• Section 10.3: Treatments 
• Update to remove description regarding groups 2 to 6 
• Section 10.4: Primary objective  
• Remove all the description regarding groups 2 to 6 
• Clarify the interim analysis for futility to be performed when approximately 20 
patients have completed at least 4 cycles or discontinued treatment prior to that time. 
• Section 10.4.3: Handling of missing values/censoring/discontinuations 
• Add “Patients who have disease progression and continue to receive study drug after 
progression will qualify for PD at the time of progression and will be counted as PD 
in the derivation of efficacy endpoints” 
• Section 10.5.1.2: Adverse events 
• Clarify that Serious adverse events, non-serious adverse events and adverse events of 
special interest during the on-treatment period will be tabulated 
• Section 10.5.1.3: Laboratory abnormalities 
• Clarify that CTCAE grades will be based on observed laboratory values 
• Section 10.5.2: Efficacy analysis  
• Clarify that analyses will be based on the FAS  
• Section 10.5.2.1: Analysis set and the grouping for analyses 
• Update to confirm phase II part analyses will be summarized for all patients 
• Section 10.5.2.2: Secondary efficacy endpoints 
• Add that Best Overall Response (BOR) will be included in the phase I/II secondary 
efficacy endpoints and BOR will be summarized by phase and group. 
• Section 10.5.3: Pharmacokinetics 
• Update to clarify the planned PK analyses 
• Update Table 10-1 to remove Cmin as it could be the concentration at the end of the 
absorption lag phase. 
• Section 10.5.3.2: Data analysis principles 
• Specify which PK plasma concentrations will be included in the analysis  
 
 
 
  
 
 
• Section 10.7: Interim  analysis 
• Remove all group 2 to 6 description  
• Table 10-2: Update the table to provide the probabilities of success at the primary analysis 
based on different numbers of responders observed at the IA 
• Section 10.8: Sample Size Calculation  
• Update to remove all the groups 2-6  


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• Clarify the number of patients to be enrolled and the number of responders required 
• Table 10-3 displays the probabilities to stop for futility at the interim analysis and to 
declare preliminary anti-tumor activity of the study treatment at the primary analysis 
(observing at least 22 responses in 40 patients) under different true ORR values 
• Section 11.5: update the section regarding the publication of study protocol and results to 
align with other Novartis-sponsored study protocols 
• Section 14.3 – Appendix 3, Table 14-14: Permitted Concomitant Medications requiring 
caution 
• Update to include last updates from the Oncology Clinical Pharmacology Drug-Drug 
Interaction Database (release date: May 2016) 
• Section 14.1 – Appendix 1 
• Update to include most recent guidelines for response version 3.2 dated 11-Feb-2016 
based on RECIST 1.1 
• Section 14.4 - Appendix 4, Table 14-15: Prohibited Concomitant Medications 
• Update to include last updates from the Oncology Clinical Pharmacology Drug-Drug 
Interaction Database (release date: May 2016) 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.  


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Amended Protocol Version 07 (Track Changes) 
 
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Amendment 05 
Amendment Rationale 
As of 23-July-2015, 121 patients have been enrolled in the Phase I part (dose-escalation) of the 
study at 9 sites in 8 countries in Asia, Europe and North America. 
As of 08-July-2015, 2 serious adverse events (SAEs) of viral hepatitis B (HBV) reactivation 
have been reported in 2 patients participating in the CEGF816X2101 study. One case had a fatal 
outcome, and the second case was medically significant. The fatal case involved a patient who 
received EGF816 at 225 mg capsule QD, had HBV infection in the past and was not on antiviral 
treatment at study entry. The patient developed a HBV reactivation during the study and died 
due to hepatic failure despite initiation of antiviral treatment after HBV reactivation was 
confirmed. The second patient also received EGF816 at 225 mg capsule QD, had a history of 
HBV and was not on antiviral treatment at the time of joining the study; however, HBV 
reactivation was detected approximately 10 weeks on study. Antiviral treatment was 
immediately initiated, EGF816 was interrupted and the HBV infection was brought under 
control. The patient later resumed EGF816 at the same dose of 225 mg QD. The viral 
reactivation in these two patients was likely due to immunosuppression related to EGF816. 
Reactivation of HBV and viral hepatitis C (HCV) has been reported with other anticancer 
therapies that suppress the immune system. To ensure the safety of all patients participating in 
CEGF816X2101 trial, changes have been made to the protocol to implement the safety 
measures regarding the reactivation of HBV and HCV. 
In addition, early preclinical and clinical findings suggest that EGF816 may have an 
immunomodulatory effect, related to its ability to inhibit the Tec family of kinases (ITK, TEC, 
and TXK). While some preclinical and clinical data suggest that Tec kinase inhibition by 
EGF816 leads to immunosuppression, other preclinical data indicate that it may lead to a shift 
in differentiation of T cell subtypes that could result in an immunostimulatory effect (Fowell et 
al., 1999, Sagiv-Barfi et al., 2015).  Changes have been made to the protocol to allow sample 
acquisition at time points at which the presence of such an effect can be evaluated.  Clinical 
data in the context of immune checkpoint inhibition have demonstrated that several months of 
treatment with an immunomodulatory agent may be necessary before changes in tumor immune 
infiltrates can be observed.  Therefore, to assess changes in tumor immune infiltrates during 
EGF816 treatment as compared to baseline, the timing of the on-treatment biopsy has been 
moved to a later time point.  In addition, to assess changes in circulating cytokines, additional 
blood collection for plasma has been added at baseline and on the first day of each cycle. 
Based on the rationales for Groups 1-6 in the Phase II part, the protocol has been amended to 
allow similar patient populations to be enrolled in the Phase I part of the study.  
Changes made to the protocol are summarized below and include: 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
• Updated Section 1.2.1.1.2 to include preclinical results showing inhibition of Tec family 
kinases by EGF816 and their potential role in EGF816 effects. 
• Updated Section 1.2.1.2 Clinical experience with new clinical data and information on the 
2 SAEs of the HBV reactivation in patients participating in CEGF816X2101. 


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• Protocol Sections 2, 4.1, 5, 7.1.1 and 10 were revised to allow NSCLC patients harboring 
specific EGFR mutations, corresponding to the groups in Phase II part, but with some 
differences in restrictions on prior lines of therapy, to be included in Phase I part 
• Protocol Sections 3, 4 and 7 were revised to be consistent with Companion Sample 
Collection Protocol languages 
• Protocol Sections 3 and 7 were revised that the assessment of progressive disease (PD) with 
newly obtained tumor samples at screening and C1D15 will be performed up to protocol 
amendment 05. After that, the on-treatment biopsy will be moved from C1D15 to C4D1, 
C6D1 (optional), C8D1 (optional) and EOT (optional). 
• 
 
• 
 
• Protocol Section 4.1, 5, Table 6-5, Sections 6.3.2, 7.1, 7.2 and Table 7-6 were revised to 
add assessment and follow up regarding HBV, HCV testing 
• Added exclusion criterion in Section 5.3 to exclude patients who 
• have a history of other malignancies. 
• have undergone a bone marrow or solid organ transplant. 
• have a known history of human immunodeficiency virus (HIV) seropositivity. 
• are receiving concomitant immunosuppressive agents or chronic corticosteroids use at 
the time of study entry. 
• have a history of Torsade de Pointes 
• Protocol Section 6.1.2, 7.1.5.2, 7.2.1.3, 7.2.1.4, 8.7 and 10.5.2 were revised to change the 
imaging assessment from BIRC to investigator assessment for the phase I part  
• Updated Section 6.4.2 to include additional permitted concomitant therapies requiring 
caution and/or action. 
• Updated Table 6-10 to recommend consideration of skin biopsy in the event of a 
maculopapular rash. 
• Study phase completion part was removed in Section 7.1.5.3 
• Pregnancy assessments were clarified in Section 7.2.2.5.6 
• Updated Table 14-14 and Table 14-15 in Section 14.3 Appendix 3. 
IRB/IEC/REB Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol (other than the Urgent Safety Measure) require 
IRB/IEC approval prior to implementation. In addition, if the changes herein affect the 
Informed Consent, sites are required to update and submit for approval a revised Informed 
Consent that takes into account the changes described in this amended protocol. 


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Amendment 04 
Amendment rationale 
As of 16-April-2015, 92 patients have been enrolled in the Phase I part (dose-escalation) of the 
study from 9 sites in 8 countries. As of 2-February-2015 data cut-off, preliminary efficacy 
results from 5 dose levels tested have showed an overall response rate (ORR) of 59.5% by 
Investigator assessment in 25 (11 confirmed and 14 awaiting confirmation) out of 42 evaluable 
patients. (Note: evaluable patients include those who were ongoing and had at least one post-
baseline tumor assessment or who discontinued study treatment as of the data cut-off date.) 
Based on these response data, changes have been made to the existing groups and two additional 
groups have been added to the Phase II part in Amendment 4. 
The primary purpose of Amendment 4 is to revise the patient populations and/or the number of 
patients to be enrolled in each group in the Phase II part.  
In addition, the number of groups in the Phase II part is revised from 4 groups (as per 
Amendment 3) to 6 groups (Amendment 4). Each group has a distinctive patient population, 
determined by the specific EGFR mutations and the number of prior lines of systemic 
antineoplastic therapy, including prior EGFR TKIs.  
Throughout Amendment 4, advanced NSCLC refers to patients with either locally advanced or 
metastatic NSCLC. Locally advanced NSCLC is defined as stage IIIB NSCLC not amenable to 
definitive multi-modality therapy including surgery. Metastatic NSCLC refers to stage IV 
NSCLC. 
The table below presents the summary of changes in the groups between Amendment 3 and 
Amendment 4 and the rationale for those changes. 


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Amended Protocol Version 07 (Track Changes) 
 
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Summary of the changes in the groups between Amendment 3 and Amendment 4 and the rationale for the changes: 
Group 
Amendment 3 
Amendment 4 
Rationale for the changes 
Patient population 
N 
Patient population 
N 
Group 1 
Advanced NSCLC EGFR 
mutant (L858R and/or 
ex19del, not T790M) 
Who are intolerant to an 
approved EGFR TKI (e.g., 
erlotinib, gefitinib, afatinib) 
and/or for whom these drugs 
are not appropriate 
~ 20 
Locally advanced or metastatic NSCLC 
with EGFR activating mutation (e.g., 
L858R and/or ex19del) 
Who have not received any systemic 
antineoplastic therapy, including EGFR 
TKI treatment, for advanced NSCLC 
Note: patients who have received no 
more than 1 cycle of chemotherapy in 
the advanced setting are allowed. 
60 
EGF816 is a 3rd-generation irreversible EGFR TKI that 
selectively inhibits activating and acquired resistance 
mutants (L858R, ex19del and T790M), while sparing WT 
EGFR. 
In preclinical study using tumor model with EGFR ex19del, 
EGF816 treatment was more efficacious compared to 
treatment with erlotinib. Other 3rd-generation EGFR TKIs, 
such as AZD9291, have shown promising preliminary data 
in this patient population (ESMO 2014); both AZD9291 and 
CO-1686 have ongoing Phase III clinical trials in the first line 
setting. 
Based on the mechanism of action (MoA), EGF816 will likely 
have similar clinical activity in this patient population. 
The sample size is increased to approximately 60 patients to 
have about 81% probability to observe an overall response 
rate ≥ 60% given the true response rate of this population is 
65%. 
Group 2 
Advanced NSCLC with an 
acquired EGFR T790M 
mutation  
Who have progressed on 
EGFR TKI (no more than 1 
previously approved EGFR 
TKI) 
~ 80 
Locally advanced or metastatic NSCLC 
with EGFR activating mutation (e.g., 
L858R and/or ex19del) and an acquired 
EGFR T790M mutation 
Who have progressed on 1 and only 1 
prior treatment with a 1st-generation 
EGFR TKI (e.g., erlotinib, gefitinib or 
icotinib) or 2nd-generation EGFR TKI 
(e.g., afatinib or dacomitinib) 
No more than 3 prior lines of systemic 
antineoplastic therapies (including EGFR 
TKI) in the advanced setting 
EGFR TKI treatment must be the last 
prior treatment before study entry. 
120 
EGF816 is a 3rd-generation irreversible EGFR TKI that 
selectively inhibits activating and acquired resistance 
mutants (L858R, ex19del and T790M), while sparing WT 
EGFR.  
Preliminary efficacy results from the Phase I part in 
advanced NSCLC patients with both EGFR activating 
mutation (L858R and/or ex19del) and T790M mutation 
showed significant antitumor activity of EGF816 that is in 
line with other 3rd-generation EGFR TKIs, and a tolerable 
safety profile 
The increase in sample size will permit a more accurate 
assessment of overall response rate and a better 
understanding of the frequency and types of adverse events 
reported during treatment with EGF816. 
EGFR TKI treatment is required to be the last prior treatment 
before study entry to avoid potential “re-challenge” effect. 


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Group 
Amendment 3 
Amendment 4 
Rationale for the changes 
Patient population 
N 
Patient population 
N 
Group 3 
Advanced NSCLC with a “de 
novo” EGFR T790M mutation 
Who have not received prior 
treatment with an EGFR TKI 
~ 80 
Locally advanced or metastatic NSCLC 
with a “de novo” EGFR T790M mutation 
For purposes of this protocol, “de novo” 
T790M will be defined as the presence 
of EGFR T790M mutation in NSCLC 
patients who have NOT been previously 
treated with any therapy known to inhibit 
EGFR. 
No more than 3 prior lines of systemic 
antineoplastic therapies in the advanced 
setting 
No prior treatment with any therapy 
known to inhibit EGFR, including EGFR 
TKI 
40 
3rd-generation EGFR TKIs, due to their ability to inhibit 
EGFR T790M mutation, should have antitumor activity in 
this patient population. Of note, one NSCLC patient with a 
“de novo” T790M mutation has been enrolled in the Phase I 
part (dose-escalation) of this study. This patient has been 
treated with 225 mg of EGF816 and showed a tumor 
reduction of 41.54% from baseline and continued the study 
treatment for at least 5 months.  
The estimated incidence of “de novo” T790M mutation is low 
(~1%). Thus, the sample size is decreased to 40 patients to 
allow completion of enrollment within a reasonable 
timeframe. With a sample size of approximately 40 patients, 
there is about ≥ 78% probability to observe an overall 
response rate ≥ 55% given the true response rate of this 
population is 60%. 
Group 4 
Advanced solid tumor 
harboring any EGFR mutation 
and NOT be otherwise eligible 
for groups 1-3 
No limitation of previous anti-
neoplastic therapies in the 
advanced setting 
>10 
Locally advanced or metastatic NSCLC 
whose tumor harbors EGFR exon 20 
insertion or deletion 
No more than 3 prior lines of systemic 
antineoplastic therapies, including EGFR 
TKI, in the advanced setting 
~ 
10 
The patient population in Group 4 was not well defined 
under Amendment 3.  
EGFR exon 20 insertion/deletions are resistant to clinically 
achievable doses of marketed or investigational EGFR 
inhibitors, such as gefitinib, erlotinib, neratinib, afatinib, and 
PF00299804. This group of patients currently represents a 
high unmet medical need.  
In a preclinical study, treatment with EGF816 demonstrated 
promising efficacy and tolerability in an exon 20 insertion 
model. Thus, EGFR816 may have the potential to provide 
clinical benefit to this patient population. 
Group 5 
New group (added under 
Amendment 4) 
- 
Locally advanced or metastatic NSCLC 
with EGFR activating mutation (e.g., 
L858R and/or ex19del) AND without an 
acquired EGFR T790M mutation  
Who have progressed on 1 and only 1 
prior treatment with a 1st-generation 
EGFR TKI (e.g., erlotinib, gefitinib or 
icotinib), or 2nd-generation EGFR TKI 
(e.g., afatinib or dacomitinib) 
No more than 3 prior lines of systemic 
60 
Promising clinical activity has been observed in this patient 
population with treatment of other 3rd-generation EGFR 
TKIs, such as AZD9291 and CO-1686, with the overall 
response rates ranging from 21%-36%. 
Given similar MoA between EGF816 and other 3rd-
generation EGFR TKIs, EGF816 may exhibit similar clinical 
activity in this patient population. 


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Group 
Amendment 3 
Amendment 4 
Rationale for the changes 
Patient population 
N 
Patient population 
N 
antineoplastic therapies, including EGFR 
TKI, in the advanced setting 
EGFR TKI treatment must be the last 
prior treatment before study entry. 
Group 6 
New group (added under 
Amendment 4) 
- 
Locally advanced or metastatic NSCLC 
with EGFR activating mutations (e.g., 
L858R or ex19del) and an acquired 
T790M mutation  
Who have had treatment with a 1st/2nd-
generation EGFR TKI 
Who have progressed on or are 
intolerant to a 3rd-generation EGFR TKI 
(e.g., AZD9291, CO-1686, or ASP8273) 
No more than 3 prior lines of systemic  
antineoplastic therapies, including EGFR 
TKIs, in the advanced setting 
80 
The scaffold of EGF816 is different from those of AZD9291 
and CO-1686, thus it is possible that tumors which are 
resistant to treatment with AZD9291 or CO-1686 may 
respond to treatment with EGF816. Additionally, the safety 
profile of EGF816 is different from other 3rd-generation 
EGFR TKIs; therefore, patients who are intolerant to 
treatment with those agents may be able to tolerate EGF816 
treatment. 
Patients who have progressed on or are intolerant to a 3rd-
generation EGFR TKI represent a population with a 
significant unmet medical need. 
Data may provide further understanding of the mechanism 
of resistance to 3rd-generation EGFR TKIs. 


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Furthermore, Amendment 4 implements other important changes affecting the Phase II part 
of this trial as follows:  
• Implements Interactive Response Technology (IRT) to track patient enrollment, document 
key eligibility criteria, allocate patients into 6 different groups based on their disease 
characteristics at study entry, and track EGF816 drug dispensing. 
• Implements a Blinded Independent Review Committee (BIRC) for tumor assessment to 
allow an independent and unbiased evaluation of tumor response for the Phase I part and 
Phase II part.  
• Implements the central laboratories to evaluate the safety of EGF816 (e.g., hematology, 
chemistry, urinalysis, coagulation and pregnancy test) for all 6 groups. The use of a central 
laboratory will allow a consistent laboratory assessment and interpretation of the results 
across a multitude of countries participating in this study. 
• Implements the central laboratory to determine the EGFR mutation status for Groups 2 and 
5, and only required for Group 3 when the local test does not meet the protocol specified 
criteria. The use of a central laboratory will allow a consistent determination of the EGFR 
mutation status across a multitude of countries participating in this study. 
• Implements a requirement of ECOG performance status of 0-1 for all patients enrolled in 
the Phase II part to ensure that patients will be able to receive potential benefit from study 
treatment. It has been well documented that performance status is among the most important 
prognostic factors for survival of patients with NSCLC.  
• Added overall survival (OS) as a secondary objective to assess clinical benefit and to obtain 
additional information for the future trial planning.  
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
In addition, for the Phase I part, BIRC will be implemented retroactively to one of the secondary 
objectives to evaluate ORR, duration of response (DOR), disease control rate (DCR), 
progression-free survival (PFS), and time to response (TTR). 
Changes to the protocol include: 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 


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• Section 1.1 Overview of disease pathogenesis, epidemiology and current treatment 
• Added a sentence to provide the rationale for Group 5. 
• Section 1.2.1.1.1 Non-clinical pharmacokinetics and metabolism 
• Removed the restriction on use of concomitant medications which are sensitive 
substrates of CYP2C8 and CYP2D6.  
• Section 1.2.1.2 Clinical experience 
• Added the efficacy and safety summaries of EGF816 based on the data from 2-Feb-
2015 (data cut-off date). 
• Added Figure 1-1 to provide EGF816 clinical activity observed at all dose levels 
tested. 
• Added the description to define the purpose of the Phase II. 
• Section 2.2 Rationale for the study design 
• Added descriptions to define the 6 groups of the Phase II part and corresponding 
rationales. 
• Section 2.3 Rationale for dose and regimen selection 
• Deleted the rationale for once daily dosing. 
• Added a sentence to describe that the recommended phase II dose (RP2D) will be 
based on the efficacy and safety data of the Phase I part. 
• Section 3 Objectives and endpoints  
• Separated the Phase I objectives and related endpoints (Table 3-1) from the Phase II 
objectives and related endpoints (Table 3-2). 
• Added BIRC to one of the secondary objectives for the Phase I part 
• Revised the primary endpoint of Phase II to add overall response rate (ORR) by BIRC 
• Added the secondary objectives and related endpoints for the Phase II part. 
• 
 
 
 
• 
 
• Added a sentence to state that patients enrolled in the Phase I part will follow the visit 
schedule noted in Table 7-1. 
• Moved up the paragraph “Patients may have tumor tissues…once approved and open” 
and stated it is for the Phase I part. 
• Added the descriptions for the six distinctive groups, corresponding sample size for 
each respective group and key changes in Amendment 4. 
• Figure 4-1 was revised to reflect the current study design of the Phase II part under 
Amendment 4. 
• Table 4-1 was added to provide key features of patient population in each of the 6 
groups. 
• In Figure 4-2, the sequence of the study visit flow was revised so that the 30 days 
follow-up period is now before the disease progression follow-up period and the 


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survival follow-up period was added following the disease progression follow-up 
period. 
• Created Figure 4-3 for the Phase II part 
• Section 4.2 Timing of interim analyses and design adaptations 
• New description was added to describe the updated information for the interim futility 
analyses. The previous description of the interim analyses for Phase II was deleted. 
• Section 4.4 Early study termination 
• Added “discontinued or” and deleted “prematurely” per the guidelines for 
discontinuation of clinical trial protocol (CTP) elements. 
• Section 5 Population 
• Deleted the previous language for describing the different groups in Phase II and 
added new descriptions for these groups. 
• Added a sentence to define treatment failure. 
• Added “Patients enrolled in the study are not permitted to participate in additional 
parallel investigational drug or device studies.” 
• Section 5.1 Patient population 
• Added clarification that exceptions to the inclusion/exclusion criteria in the Phase II 
part are not allowed. 
• Section 5.2 Inclusion criteria 
• Added the corresponding inclusion criteria for each of the 6 groups in Phase II. 
• Added clarification that an ECOG performance status of 0, 1 or 2 will be required for 
Phase I and an ECOG performance status of 0 or 1 will be required for Phase II. 
• Section 5.3 Exclusion criteria 
• Added the corresponding exclusion criteria for each of the 6 groups in Phase II. 
• In Prior therapies exclusion criterion, remove “phototoxicity” as EGF816 may have 
photosensitivity. 
• The renal function exclusion criterion was changed to measured or calculated 
creatinine clearance <45 mL/min. 
• For exclusion criteria, highly effective methods of contraception or condom must be 
used while taking the study drug and for 3 months after stopping treatment. 
• Section 6.1.1 Dosing regimen 
• Added clarification that the 25 mg tablet will be available at the start of Phase II. The 
50 mg tablet will be available at a later time during the study. 
• Table 6-4 of Amendment 3 was moved up to this section to better align with the 
heading. A footnote was added to clarify that the 50 mg tablet will be available at a 
later time. 
• Section 6.1.2 Treatment duration 
• Added new criteria or definitions for treatment discontinuation. 
• Section 6.2.1 Starting dose rationale 


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• Deleted “The highest provisional dose planned (1000 mg, qd) can be dissolved in less 
than 10 ml of various aqueous solutions tested, far below 250 mg which is the 
standard volume of water required for the administration of the drug.” 
• Table 6-2 Provision dose levels: added a row for 100 mg dose. 
• Section 6.2.3.2 Change of drug formulation 
• Added clarification that the EGF816 tablet will be used in Phase II. 
• Section 6.3.1 Dose modification and dose delay 
• Added the guidelines for the management and dose modification of skin-related 
toxicities. 
• Added the guidelines for the management and dose modification of non-infectious 
pneumonitis/interstitial lung disease. 
• Section 6.4.1 Permitted concomitant therapy 
• Added clarification that radiotherapy is permitted for patients who develop 
progressive disease limited to bone in addition to CNS involvement. 
• Section 6.5.1 Patient numbering 
• Added a new description about implementation of IRT for Phase II. 
• Section 6.5.2 Treatment assignment 
• Revised the description about IRT for the Phase II part. 
• Section 6.6 Study drug preparation and dispensation 
• As described above under Section 6.1.1, Table 6-4 was deleted and moved up to 
Section 6.1.1.  
• Section 7.1 Study flow and visit schedule 
• Added the description that written informed consent must be obtained before any 
study specific assessments are performed. 
• Added clarifications for visit and schedule windows for Phase I and Phase II. 
• Added a separate visit evaluation schedule (Table 7-2) for Phase II.  
• Added clarification that Phase I and Phase II will follow visit evaluation schedule 
outlined in Table 7-1 and Table 7-2, respectively. 
• Deleted any assessments that are applicable to Phase II from Table 7-1. 
• The Japan only requirement regarding hospitalization during C1 was removed. 
• Section 7.1.1 Molecular pre-screening 
• Modified the descriptions for the requirements of the local/central laboratory testing 
of the EGFR mutation status for the Phase I part and Phase II part. 
• Section 7.1.2 Screening 
• Modified the descriptions for the screening period. 
• Section 7.1.2.1 Eligibility screening 
• A new section titled “Eligibility screening” was added. 
• Section 7.1.2.2 Information to be collected on screening failures 


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• Section 7.1.2.1 titled “Information to be collected on screening failures” was revised 
and is now numbered as Section 7.1.2.2. The eCRF pages to be completed for 
screening failure patients are listed. 
• Section 7.1.2.3 Patient demographics and other baseline characteristics 
• Section 7.1.2.2 titled “Patient demographics and other baseline characteristics” was 
revised and is now numbered as Section 7.1.2.3. The types of data to be collected are 
outlined. 
• Section 7.1.4 End of treatment visit including study completion and premature withdrawal 
• Section 7.1.4 in Amendment 3 was deleted to better align with the guidelines for 
discontinuation of CTP elements. 
• Section 7.1.4.1 Criteria for premature patient withdrawal 
• Section 7.1.4 in Amendment 3 was deleted to better align with the guidelines for 
discontinuation of CTP elements. 
• Section 7.1.4 Discontinuation of study treatment 
• Section 7.1.4 Discontinuation of study treatment was added to replace Section 7.1.4 
Criteria for premature patient withdrawal per the guidelines for discontinuation of 
CTP elements. 
• Section 7.1.4.2 Replacement policy 
• Section 7.1.4.2 Replacement policy in Amendment 3 was moved to a later part of the 
amendment and is now numbered as Section 7.1.5.5. 
• Section 7.1.5 Follow up period 
• Section Disease progression follow-up and Section 30 day safety follow-up were 
deleted and replaced with Section 7.1.5.1 Follow-up for safety evaluations, Section 
7.1.5.2 Post-treatment follow-up, Section 7.1.5.3 Study phase completion and Section 
7.1.5.4 Survival follow-up. 
• Section 7.1.6 Withdrawal of consent 
• Section 7.1.6 was added per the guidelines for discontinuation of CTP elements. 
• Section 7.1.7 Lost to follow-up 
• Section 7.1.7 was added per the guidelines for discontinuation of CTP elements. 
• Section 7.2.1 Efficacy assessment 
• Imaging collection plans were separated for Phase I and Phase II. 
• Table 7-4 was added to introduce the imaging collection plan for the Phase II part. 
• Section 7.2.1.1 Baseline imaging assessment 
• Additional descriptions were added to this section for imaging requirement at baseline 
and tumor assessments required at baseline. 
• Section 7.2.1.2 Subsequent imaging for response assessment was added. 
• Section 7.2.1.3 Transmission of efficacy data to BIRC was added per BIRC 
implementation. 
• Section 7.2.1.4 BIRC confirmation of disease progression was added per BIRC 
implementation. 
• Section 7.2.2.5 Laboratory evaluations 


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• Descriptions were added per implementation of central laboratory for safety 
evaluations. 
• Table 7-6 was relabeled as “Central/local clinical laboratory parameters collection 
plan.” 
• Section 7.2.2.6.1 Electrocardiogram (ECG) 
• Table 7-7 was revised with the following changes: 1) Central ECG collection plan for 
all patients; 2) Triplicates are added for pre-dose timepoints; 3) The requirement for 
Japan only was removed. 
• Table 7-8 was added for implementation of extensive ECG collection plan at pre-
selected sites. 
• Section 7.2.3.1 Pharmacokinetic blood sample collection and handling 
• Table 7-10 was revised with the following changes: 1) “scheme 1” was removed from 
the table title; 2) “first 10 patients in each group” was removed from the table title; 3) 
the 12 hr timepoint was removed from the table and the dose reference IDs and 
footnotes were updated accordingly. 
• Table 7-11 was removed as Phase II part PK scheme 2 was not needed. 
• 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
. 
• Section 8.7 Blinded Independent Review Committee (BIRC) was added per BIRC 
implementation. 
• Section 10.4.2.2 
• Modified the statistical success criterial for Groups 1, 2, and 3, and added statistical 
analysis and success criterial for Groups 5 and 6. 
• Section 10.5.2 
• Clarified the definition of all the efficacy objectives. 
 
 
 
 
 
• Section 10.7 
• The interim futility analysis for Group 2 (per Amendment 3) was removed due to 
encouraging preliminary clinical activity observed with EGF816 treatment which is in 
line with other 3rd-generation EGFR TKIs and better than the current standard-of-care 


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chemotherapy (ORR of 34% observed for platinum doublet [IMPRESS trial, ESMO 
2014]). 
• Modified the interim analysis method for Groups 1 and 3, and added the interim 
analysis method for Groups 5 and 6. 
• Section 10.8 
• Modified the sample size rationale for Groups 1, 2, and 3, and added the sample size 
rationale for Groups 5 and 6. 
IRB/IEC/REB Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 
Amendment 03 
Amendment rationale 
In order to create a commercially viable format, tablet is going to be introduced to the study.  
The main purpose of this amendment is to allow for the possibility of a formulation change 
during dose escalation from capsule to tablet, and the determination of a MTD and/or RP2D 
with either formulation.  
Additional changes to the protocol: 
• Clarification of appropriate methodologies regarding patient selection strategy. Protocol is 
amended to mandate that T790M positivity be defined by central lab using therascreen 
EGFR RGQ PCR kits (Qiagen) for Group 2 and Group 3 in phase II part. This change is 
necessary to minimize the variance in testing methodologies and to meet health authorities 
standards. The addition of this requirement necessitated several modifications to other 
specific parts including statistical part in protocol. 
• Clarification and modification of inclusion/exclusion criteria regarding previous number of 
treatments allowable for Groups 1 and Group 4 in phase II part in order to include patients 
with good performance status but who have received multiple standards of care. 
• Clarification and modification of inclusion/exclusion criteria regarding washout time from 
previous treatments to be aligned with the current standard approach to treat patients with 
EGFR TKIs and to minimize tumor flare following EGFR TKI withdrawal. 
• 
 
 
 
• Minor changes to address consistencies within protocol 


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Changes to the protocol include: 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Table 3-1 Objectives and related endpoints 
 
 
Section 4.1 Description of study design 
• Added requirement that for patients to be recruited to Group 2 and Group 3, T790M 
positivity must be defined by therascreen EGFR RGQ PCR kits (Qiagen) at a Novartis- 
designated central laboratory.  
Section 5.2 Inclusion criteria 
• Group 1: added “Patients who were found to also have a T790M mutation by local 
assessment that cannot be confirmed by central Qiagen Therasreen testing will be 
considered as not having T790M (for purposes of this protocol) and will be eligible for 
this group.” 
• Group 2 and Group 3: changed the documentation of EGFR mutational status to be 
compliant with description of study design. 
• Group 2 and Group 3: clarified that only adenocarcinoma patients will be included. 
Modifications were made in other parts of protocol to be consistent with this change. 
• Group 2: removed “according to RECIST v1.1” when defining “acquired T790M mutation 
following progression on EGFR TKI. 
Section 5.3 Exclusion criteria 
• Excluded in phase I part patients “previously treated with any investigational EGFR-TKI 
targeting EGFRmut-T790M”. 
• Revised to allow “no limitation of previous antineoplastic therapies in the advanced 
setting” for Group 1 and Group 4 in phase II part. 
• Modified washout time frame for previous treatment. In particular, “patients who have 
been treated with chemotherapy or biologic therapy or other investigational agent ≤ 1 
week prior to first dose of study treatment.” 
• Modified washout time frame for radiation therapy and/or surgery for brain metastases to 
be consistent with exclusion number 5. And clarified that patients with controlled brain 
metastases may participate in this trial. 
Table 6-1 Dose and treatment schedule 
• Added the dose and frequency of tablet and moved the table to Section 6.6. 
• Clarified that the administration instruction will be the same as for tablet. 
Section 6.2.1 Starting dose rationale 
• Added starting dose rationale for tablet. 
Section 6.2.3.1 Definition and estimation of MTD/RP2D 
• Added “MTD/RP2D for each drug formulation or dosing schedule may be established 
when appropriate”. 
Section 6.2.3.2 Dose cohort modification 


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• Revised wording from “for the purposes of dose escalation decisions, each cohort will 
consist of 1 to 3 newly enrolled evaluable patients who will be treated at the specified 
dose level” to “for the purposes of dose escalation decisions, each cohort will consist of 1 
to 6 newly enrolled evaluable patients who will be treated at the specified dose level.” 
• Added wording to “if significant activity is seen early in the dose escalation, then a 
recommended dose may be identified and the phase II groups may be initiated without 
determination of the MTD; therefore fewer than 21 patients may be required.” 
• Added wording to allow cohort modification in case of “change of formulation”. 
Section 6.2.3.4 Intra-patient dose escalation 
• Added “patients still on capsule treatment may switch to tablets at same dose level or 
following the same intra-patient dose procedure as for capsule”. 
Section 6.2.4 Definitions of dose-limiting toxicities (DLTs) 
• Clarified that the definition of DLT is for phase I part only. 
Table 6-2 Criteria for defining dose-limiting toxicities 
• Clarified that definition of grade 3 serum creatinine according to CTCAE.  
• Deleted criteria for “pancreas”. 
Table 6-3 Criteria for interruption and re-initiation of EGF816 treatment 
• Changed guidance for Grade 3 serum creatinine increase and Grade 2 Bilirubin increase. 
 
 
 
Section 7.1.1 Molecular pre-screening 
• Changed the documentation of EGFR mutational status to be compliant with description 
of study design. 
Section 7.2.1 Efficacy assessments 
• Clarified that imagining data will be centrally collected and checked for quality for Group 
2 and Group 3 only in Phase II part. 
 
 
 
 
 
 
Table 7-6, Table 7-7 and Table 7-8: Schedule of blood sample collections for pharmacokinetics 
• Clarified in footnote that “If biopsy is collected on cycle 1 day 15, no unscheduled blood 
PK sample needs to be collected”. 
 
 
 
Section 10.4.2 Statistical hypothesis, model and method of analysis 
• Added wording for “change in drug formulation”. 


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Section 14.2 Operational characteristics of the Bayesian logistic regression mode and 
hypothetical dose escalation scenarios 
• Added specification of the statistical model for tablet and the corresponding hypothetical 
scenarios. 
Added or revised wording regarding optional companion sample collection protocol in Section 
4, Table 7-1, Table 7-9, Section 7.2.4, Section 8.2 and Section 9. 
Replaced “RDE” with “RP2D” throughout the protocol. 
IRB/IEC/REB Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 
Amendment 02 
Amendment 02 rationale 
The rational for the amendment is to address changes requested by health authority (i.e. Japan 
PMDA) and includes the following:  
• Clarify the definition of “women of childbearing potential” 
• Add “glucose” into chemistry panel in laboratory parameters 
 
 
[For Japan only] 
• Add a description in the protocol that in Japan, written consent is necessary both from the 
patient and his/her legal representative if he/she is under the age of 20 years. 
• Specify that Japanese patients will be hospitalized during Cycle 1, vital signs will be 
obtained during the first week of hospitalization, chest X-ray will be obtained per cycle 
with an additional ECG on C1D1 per Japanese standards/concerns regarding EGFR TKI 
development. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Section 5.3 exclusion criteria 
• Added definition of “women of childbearing potential” 
Table 7-4 local clinical laboratory parameters collection plan 
• Added “glucose” into chemistry panel 
Section 7.2.4 biomarker 


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• Added “Results of biomarker analysis whose clinical reliability has been validated will be 
communicated back to the investigator, who may discuss them with the patient.” 
[For Japan only] 
Section 5.2 inclusion criteria 
• Added “[For Japan only, written consent is necessary both from the patient and his/her 
legal representative if he/she is under the age of 20 years.]” 
Section 5.3 exclusion criteria 
• Added “[For Japan only: Patients with a current or past history of interstitial lung 
disease.]” 
Table 7-1 visit evaluation schedule, footnote 
• Added “[For Japan only, patients are required to be hospitalized in Cycle 1” and 
“percutaneous oxygen saturation (SpO2) will be measured every time physical 
examination is performed. In addition, SpO2 and vital signs will be measured on Days 2-7 
in Cycle 1]”.  
Table 7-1 visit evaluation schedule and section 7.2.5.1 chest X-ray:  
• Added “[For Japan only: A 2-view chest X-ray will be performed at screening, Day 15 of 
cycle1, and on Day1 of cycle 2 and thereafter. If a chest CT scan is performed, a chest X-
ray can be skipped except for at screening. ]” 
Table 7-5 central ECG collection plan 
• Added “[For Japan only: triplicate 12-lead ECG at 2 hr post dose (±30 minutes) on 
C1D1]” 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRB/IEC/REB Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 
Amendment 01 
Amendment rationale 
The rationale for the amendment is to comply with health authority’s request to add a generic 
statement to this first-in-man trial: “that all patients participating in this clinical trial must have 
recurred or progressed following standard therapy, unless no standard therapy exists, is 
tolerated or appropriate”. The addition of this generic statement however necessitated several 
modifications to specific inclusion criteria as outlined: 


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1. Specified that all patients participating in this clinical trial must have recurred or 
progressed following standard therapy, unless no standard therapy exists, is tolerated or 
appropriate 
2. Revised that Phase I part will recruit NSCLC patients harboring a documented EGFR 
T790M mutation 
3. Revised that the group 1 in Phase II part will recruit patients have advanced NSCLC with 
EGFR mutation (L858R or ex19del, not T790M) and are intolerant to an approved EGFR 
TKI (e.g., erlotinib, gefitinib, afatinib); and/or for whom these drugs are not appropriate. 
Furthermore, times of blood pressure and time interval of 3 sequential ECGs were deleted to 
allow sites perform the assessments only to comply with institutional standards. 
In addition, this amendment was used to make a few other changes for clarification (please see 
below Changes to the protocol for details). 
Changes to the protocol 
Section 2.1 Study rational and purpose 
Section 2.2 Rational for study design 
Section 4.1 Description of study design 
• Revised wording in these 3 sections to be consistent with changes in inclusion criteria 
Section 5.2 – Inclusion criteria 
• Added one inclusion criteria to specify patient population as stated above 
• Revised inclusion criteria for Phase I part as stated above 
• Revised inclusion criteria for group 1 in Phase II part as stated above 
Section 5.3 – Exclusion criteria 
• Revised wording of prior treatment to be consistent with changes in inclusion criteria 
Table 6-4 Criteria for interruption and re-initiation of EGF816 treatment 
• Deleted “2 of three measures performed five minutes apart under standard conditions” for 
hypertension 
Section 7.2.6.6.1 Electrocardiogram (ECG) 
• Time internal requirement (“separated by 10-15 minutes”) was deleted for 3-sequential 
ECGs 
Section 8.7 Warnings and precautions 
• Deleted due to duplication with Section 8.4 
Section 10.8 Sample size calculation 
• Revised wording to be consistent with changes in inclusion criteria 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 


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IRB/IEC/REB Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 


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Protocol summary 
Protocol number 
CEGF816X2101 
Title 
A phase I/II, multicenter, open-label study of EGFRmut–TKI EGF816, administered orally 
in adult patients with EGFRmut solid malignancies 
Brief title 
n/a 
Sponsor and 
Clinical Phase 
Novartis 
Phase I/II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of the Phase I part (dose-escalation) of this study is to determine the 
maximum tolerated dose (MTD) or recommended phase II dose (RP2D) and to evaluate 
the preliminary antitumor activity of single-agent EGF816 in adult patients with locally 
advanced (stage IIIB) or metastatic (stage IV) NSCLC harboring a documented EGFR 
mutation. Based on preclinical data for EGF816 and the known clinical activity of other 3rd-
generation epidermal growth factor receptor (EGFR) inhibitors, it is expected that EGF816 
would exhibit to significant antitumor activity in non-small cell lung cancer (NSCLC) 
patients harboring the activating EGFR mutations (e.g., L858R and ex19del) and/or the 
acquired/resistant “gatekeeper” T790M mutation while sparing wild-type (WT) EGFR. 
The purpose of the Phase II part is to evaluate the efficacy and safety of single-agent 
EGF816 in adult patients with locally advanced (stage IIIB) or metastatic (stage IV) 
NSCLC whose tumors harbor specific EGFR mutations. The Phase II part will consist in 
enrolling treatment naïve patients (i.e. have not received any systemic antineoplastic 
therapy for advanced NSCLC. Patients who have failed no more than 1 cycle of 
antineoplastic therapy in the advanced setting are allowed. Treatment failure is defined as 
documented disease progression or intolerance to treatment. Neo-adjuvant and adjuvant 
systemic therapies will be counted as 1 prior line of treatment if relapse occurred within 12 
months from the end of the neo-adjuvant/adjuvant systemic therapy. 
Note: throughout this protocol, advanced NSCLC refers to patients with either locally 
advanced or metastatic NSCLC. Locally advanced NSCLC is defined as stage IIIB NSCLC 
not amenable to definitive multi-modality therapy including surgery. Metastatic NSCLC 
refers to stage IV NSCLC. 
Primary 
Objective(s) 
Phase I part (dose-escalation) 
• 
To estimate the MTD or RP2D of EGF816 as assessed by incidence of dose-limiting 
toxicities (DLTs) during the first 28 days of dosing. 
Phase II part 
• 
To evaluate the antitumor activity of EGF816 as measured by overall  response rate 
(ORR) determined by Blinded Independent Review Committee (BIRC) assessment in 
accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
Secondary 
Objectives 
Phase I part (dose-escalation) 
• 
To characterize the safety and tolerability of EGF816 
• 
To evaluate ORR, duration of response (DOR), disease control rate (DCR), 
progression-free survival (PFS), and time to response (TTR) by Investigator 
assessments in accordance to RECIST 1.1 
• 
To characterize the pharmacokinetics (PK) properties of EGF816 and metabolite 
LMI258 
• 
To assess the tumor EGFR signaling inhibition by EGF816 (prior to protocol 
amendment 05) 
Phase II part  
• 
To further characterize the safety and tolerability of EGF816 


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• 
To evaluate ORR by Investigator assessment in accordance to RECIST 1.1 
• 
To evaluate DOR, DCR, PFS and TTR by BIRC and by investigator assessments in 
accordance to RECIST 1.1 
• 
To evaluate overall survival (OS) 
• 
To characterize the pharmacokinetics (PK) properties of EGF816 and metabolite 
LMI258  
Note: ORR is defined as the proportion of patients with best overall response of PR+CR 
per RECIST 1.1; DOR is defined as the time from first documented response (PR or CR) 
to the date of first documented disease progression or death due to any cause; DCR is 
defined as the proportion of patients with best overall response of CR, PR, or SD; PFS is 
defined as time from date of first dose of study treatment to date of first documented 
disease progression; TTR is defined as the time from the date of first dose of study 
treatment to the date of first documented response (CR or PR). OS is defined as the time 
from the date of first dose of study treatment to the date of death due to any cause. 
Study design 
This is a Phase I/II, multi-center, open-label study starting with a Phase I part (dose-
escalation) followed by a Phase II part. Oral EGF816 will be administered once daily on a 
continuous schedule until patient experiences unacceptable toxicity, progressive disease 
(PD), and/or treatment is discontinued at the discretion of the investigator, patient 
withdrawal of consent, or due to any other reasons. 
Treatment with EGF816 may be continued beyond RECIST 1.1 defined PD, if, in the 
judgment of the investigator, there is evidence of clinical benefit and the patient wishes to 
continue with the study treatment. A treatment cycle is defined as 28 days. 
Population 
Adult patients with locally advanced or metastatic NSCLC with specific EGFR mutations. 
Locally advanced is defined as stage IIIB not amenable to definitive multi-modality therapy 
including surgery. Metastatic NSCLC refers to stage IV NSCLC. 
For the Phase I part all patients must have locally advanced or metastatic NSCLC 
harboring specific EGFR mutations. For the Phase II part, treatment naïve adult patients 
with locally advanced or metastatic NSCLC harboring specific EGFR mutations will be 
enrolled. Note: Patients who have failed no more than 1 cycle of systemic antineoplastic 
therapy in the advanced setting are allowed. Treatment failure is defined as documented 
disease progression or intolerance to treatment. Neo-adjuvant and adjuvant systemic 
therapies will be counted as 1 prior line of treatment if relapse occurred within 12 months 
from the end of the neo-adjuvant/adjuvant systemic therapy. 
Inclusion criteria 
For all patients (unless otherwise specified): 
1. 
Written informed consent obtained prior to any screening procedures 
2. 
Patient (male or female) ≥ 18 years of age  
[For Japan only: written consent is necessary both from the patient and his/her legal 
representative if he/she is under the age of 20 years.] 
3. 
Patients must have histologically or cytologically confirmed locally advanced (stage 
IIIB not amendable to definitive multi-modality therapy including surgery) or metastatic 
(stage IV) EGFR mutant NSCLC  
4. 
Patients with controlled brain metastases may participate in the trial. If applicable, 
they must complete any planned radiation therapy and/or surgery > 2 weeks prior to 
the first dose of study treatment and remain asymptomatic. Patients on steroids must 
have been on a stable low dose for 2 weeks prior to initiating study treatment. Patients 
must be neurologically stable, having no new neurologic deficits on clinical 
examination, and no new findings on central nervous system imaging. 
5. 
ECOG performance status: Phase I part: 0, 1, or 2; Phase II part: 0 or 1 
6. 
Presence of at least one measurable lesion according to RECIST 1.1 per Investigator 
assessment. A previously irradiated site lesion may be counted as a target lesion only 
if there is clear sign of progression since the irradiation (see Section 14.1 Appendix 1) 
7. 
Patients must be screened for HBV. Patients who are either HBsAq positive or HBV-


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DNA positive must be willing to take antiviral therapy 1-2 weeks prior to 1st dose of 
EGF816 treatment and continue on antiviral therapy for at least 4 weeks after the last 
dose of EGF816. 
8. 
Patients must be screened for HCV. Patients must have negative hepatitis C antibody 
(HCV-Ab) or positive HCV-Ab but undetectable level of HCV-RNA. Note patients with 
detectable HCV-RNA are not eligible to enroll into the study. 
9. 
Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests and other study procedures 
10. Requirements of EGFR mutation status and prior lines of treatment for Phase I 
patients 
Patients must meet one of the following criteria: 
• 
Locally advanced or metastatic NSCLC with EGFR activating mutation (e.g., L858R 
and/or ex19del); Who have not received any systemic antineoplastic therapy, 
including EGFR TKI treatment, for advanced NSCLC; Note: patients who have 
received no more than 1 cycle of chemotherapy in the advanced setting are allowed. 
• 
Locally advanced or metastatic NSCLC with EGFR activating mutation (e.g., L858R 
and/or ex19del) AND an acquired EGFR T790M mutation following progression on 
prior treatment with a 1st-generation EGFR TKI (e.g., erlotinib, gefitinib or icotinib) or 
2nd-generation EGFR TKI (e.g., afatinib or dacomitinib); No more than 3 prior lines of 
systemic antineoplastic therapies, including EGFR TKI and may not have received 
any agent targeting EGFR T790M mutation (e.g.,. 3rd generation  EGFR TKI) 
• 
Locally advanced or metastatic NSCLC with a “de novo” EGFR T790M mutation; For 
purposes of this protocol,  “de novo” T790M will be defined as the presence of EGFR 
T790M mutation in NSCLC patients who have NOT been previously treated with any 
therapy known to inhibit EGFR; No more than 3 prior lines of systemic antineoplastic 
therapies; No prior treatment with any therapy known to inhibit EGFR, including EGFR 
TKI 
• 
Locally advanced or metastatic NSCLC whose tumor harbors EGFR exon 20 insertion 
or deletion; No more than 3 prior lines of systemic antineoplastic therapies, including 
EGFR TKI 
• 
Locally advanced or metastatic NSCLC with EGFR activating mutation (e.g., L858R 
and/or ex19del) AND without an acquired EGFR T790M mutation; Who have 
progressed on prior treatment with a 1st-generation EGFR TKI (e.g., erlotinib, gefitinib 
or icotinib), or 2nd-generation EGFR TKI (e.g. afatinib or dacomitinib); No more than 3 
prior lines of systemic antineoplastic therapies, including EGFR TKI 
• 
Locally advanced or metastatic NSCLC with EGFR activating mutations (e.g., L858R 
or ex19del) and an acquired T790M mutation; Who have had treatment with a 1st/2nd-
generation EGFR TKI; Who have progressed on or are intolerant to a 3rd-generation 
EGFR TKI (e.g., AZD9291, CO-1686, or ASP8273); No more than 3 prior lines of 
systemic antineoplastic therapies, including EGFR TKIs 
11. Requirements of EGFR mutation status and prior lines of treatment for Phase II 
patients: 
• 
Locally advanced or metastatic NSCLC with EGFR activating mutation (e.g., L858R 
and/or ex19del); Who have not received any systemic antineoplastic therapy, 
including EGFR TKI treatment, for advanced NSCLC; Note: patients who have failed 
no more than 1 cycle of systemic antineoplastic therapy in the advanced setting are 
allowed. Treatment failure is defined as documented disease progression or 
intolerance to treatment. Note: Neo-adjuvant and adjuvant systemic therapies will be 
counted as 1 prior line of treatment if relapse occurred within 12 months from the end 
of the neo-adjuvant/adjuvant systemic therapy. 
Exclusion criteria 
For All patients (unless otherwise specified): 
1. 
Patients with a history or presence of interstitial lung disease or interstitial 
pneumonitis, including clinically significant radiation pneumonitis (i.e. affecting 


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activities of daily living or requiring therapeutic intervention) 
2. 
Patients with unstable brain metastases. 
3. 
Presence or History of another malignancy 
Exception: Patients who have been disease-free for 3 years, or patients with a history 
of adequately treated in-situ carcinoma of the uterine cervix, basal or squamous cell 
carcinoma, non-melanomatous cancer of skin, history of stage IA melanoma that has 
been cured, are eligible. 
4. 
Undergone a bone marrow or solid organ transplant 
5. 
Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is 
not mandatory) 
6. 
Patients receiving concomitant immunosuppressive agents or chronic corticosteroids 
use at the time of study entry except for control of brain metastases, topical 
applications, inhaled sprays, eye drops or local injections 
7. 
Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns or compliance with clinical 
study procedures 
8. 
Patients with out of range laboratory values defined as: 
• 
Absolute Neutrophil Count (ANC) < 1.5 x 109/L (1.5 x 103/µL) 
• 
Hemoglobin (Hgb) < 9 g/dL (90 g/L) 
• 
Platelets < 75 x 109/L (75 x 103/µL) 
• 
Total bilirubin >1.5 x upper limit of normal (ULN). For patients with Gilbert’s 
syndrome total bilirubin >3.0 x ULN) 
• 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 x 
ULN for patients without hepatic metastasis 
• 
AST and/or ALT >5 x ULN for patients with hepatic metastasis 
• 
Alkaline phosphatase (ALP) > 5 x ULN 
• 
Measured or calculated creatinine clearance < 45 mL/min (0.75 mL/sec) 
9. 
Patients with electrolytes outside the laboratory normal limits that cannot be corrected 
with supplements during screening: 
• 
Potassium 
• 
Magnesium 
• 
Phosphorus 
• 
Total calcium (corrected for serum albumin) 
10. Patients receiving treatment with medications that are known to be strong inhibitors or 
inducers of CYP3A4/5 and cannot be discontinued 1 week prior to the start of 
EGF816 treatment and for the duration of the study 
Additional exclusion criteria are listed in Section 5.3. 
Investigational 
and reference 
therapy 
EGF816 (Nazartinib) 
Efficacy 
assessments 
Tumor assessment per RECIST 1.1 
Safety 
assessments 
Incidence and severity of AEs and SAEs, including changes in laboratory values, vital 
signs and ECGs 
Other 
Plasma concentration vs. time profiles, plasma PK parameters 


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assessments 
  
 
Data analysis 
Phase I part (dose-escalation) 
Patients treated during the Phase I part (dose-escalation) with the same dose level, 
formulation (capsule vs. tablet) and schedule of EGF816 will be pooled into a single 
treatment group. All summaries, listings, figures and analyses will be performed by 
treatment group and formulation (unless otherwise specified). Subgroup analyses by 
mutation type and prior lines of systemic antineoplastic therapy(s) may be performed as 
appropriate. 
An adaptive, 2 parameter Bayesian logistic regression model (BLRM) guided by the 
escalation with overdose control principle will be used to make dose recommendations 
and estimate the MTD/RP2D during the Phase I part study. 
Phase II part  
The primary analysis will be performed when patients have completed at least 6 cycles of 
treatment or discontinued treatment prior to that time. Any additional data for patients 
continuing to receive study treatment past the data cut-off date for the primary analysis will 
be reported in the final CSR at the end of the study. 
One interim futility analysis will be performed when approximately 20 patients have 
completed at least 4 cycles of treatment or discontinued treatment prior to that time.  
Primary endpoint: ORR by BIRC assessment will be summarized along with 95% 
confidence interval. 
Key words 
NSCLC, EGF816, Nazartinib, EGFR, TKI, T790M+, T790M-, acquired, de novo 


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List of abbreviations 
Ab 
Antibody 
ADME 
Absorption, Distribution, Metabolism and Excretion 
AE 
Adverse Event 
Ag 
Antigen 
AKT 
Also known as Protein Kinase B 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolute Neutrophil Count 
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomy Therapeutic Chemical  
AUC 
Area Under the Curve 
BAL 
Bronchoalveolar Lavage 
BCRP 
Breast Cancer Resistance Protein 
BCS 
Biopharmaceutics Classification System 
BIRC 
Blinded Independent Review Committee 
BLRM 
Bayesian Logistic Regression Model 
BOR 
Best Overall Response 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration after a single dose 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR 
addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP 
Clinical trial protocol 
 
 
CYP 
Cytochrome 
DCR 
Disease Control Rate 


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DDS 
Dose Determining Set 
DLT 
Dose-Limiting Toxicity 
DMC 
Data Monitoring Committee 
DOR 
Duration Of Response 
DS&E 
Drug Safety and Epidemiology 
DUSP6 
Dual Specificity Phosphatase 6  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EGF 
Epidermal growth factor 
EGFR 
Epidermal Growth Factor Receptor; also known as ErbB1 
EOT 
End of Treatment 
ERKs 
Extracellular signal-Regulated Kinases  
EWOC 
Escalation With Overdose Control 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed, paraffin embedded 
FMI 
Formulated Market Image 
GGT 
Gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HBV-DNA 
Hepatitis B virus-DNA 
HCVAb 
Hepatitis C antibody 
HCV 
Hepatitis C virus 
HCV-RNA 
Hepatitis C virus-RNA 
hCG 
Human Chorionic Gonadotropin 
HDL 
High-Density Lipoprotein 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus  
HNSTD 
Highest Non-Severely Toxic Dose 
HR 
Hazard Ratio 
i.v. 
Intravenous(ly) 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 


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IEC 
Independent Ethics Committee 
ILD 
Interstitial Lung Disease 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology  
ITK 
interleukin-2-inducible T-cell kinase 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
KLH 
Keyhole Limpet Hemocyanin 
LC-MS 
Liquid Chromatography-Mass Spectrometry 
LDL 
Low-Density Lipoprotein 
LFT 
Liver Function Test  
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
LPLV 
Last patient last visit 
LPS 
Lipopolysaccharide  
MAPKs 
Mitogen-Activated Protein Kinases  
MATE 
Multidrug and toxin extrusion transporter 
mPFS 
Median Progression-Free Survival 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NGS 
Next Generation Sequencing 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Overall Response Rate 
OS 
Overall survival 
p.o. 
Oral  
PAS 
Pharmacokinetic Analysis Set 
PD 
Pharmacodynamics or Progressive disease 
PET 
Positron Emission Tomography 
PFS 
Progression-free survival 
P-gp 
p-glycoprotein 
PHA 
Phytohemagglutinin  
PHI 
Protected Health Information 
PI3K 
Phosphoinositide 3-Kinase 
PK 
Pharmacokinetics 
PLT 
Platelet 


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PPOS 
Predictive Probability of Success 
PR 
Partial Response 
PT 
Prothrombin Time 
q.d. 
quaque die/every day 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses 
RP2D 
Recommended Phase II Dose 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease or Standard Deviation 
SEC 
Safety Event Categories 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOP 
Standard Operating Procedure 
STD10 
Severely Toxic Dose in 10% of animal 
T1/2 
Median terminal elimination half-life  
TBIL  
Total bilirubin 
TEC 
Tec protein tyrosine kinase 
TKI 
Tyrosine Kinase Inhibitor 
Tmax 
Peak plasma concentration  
TT 
Tetanus Toxin 
TTR 
Time to response 
TXK 
TXK tyrosine kinase 
ULN 
Upper Limit of Normal 
VATS 
Video-assisted thoracic surgery 
WCLC 
World Conference on Lung Cancer 
WT 
Wild Type 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., q28 days) 
Dose level 
The dose of drug given to the patient (total daily dose) 
CMO&PS 
Chief Medical Office and Patient Safety 
Enrollment 
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug.” 
Investigational 
treatment 
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes approved 
drugs used outside of their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or allowed by 
the protocol when used in within approved indication/dosage 
Locally advanced 
Stage IIIB not amenable to definitive multi-modality therapy including surgery 
Medication number 
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study 
Metastatic NSCLC 
Stage IV NSCLC 
Patient Number 
(Patient No.) 
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional segments 
such as molecular pre-screening, screening, treatment, end of treatment, etc 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether the cancer has spread from the original site to other parts of the body 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins. In specific examples, it is important to judge investigational 
treatment component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational treatments 
in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for any reason 
Supportive treatment 
Refers to any treatment required by the exposure to a study treatment e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed disodium 
Treatment group 
A treatment group defines the dose and regimen and may consist of 1 or more 
cohorts. Cohorts are not expanded, new cohorts are enrolled 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points 
Withdrawal of 
Consent 
Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not 
want any further study related contact 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Worldwide, lung cancer accounts for 13% (1.6 million) of all total cancer cases and 18% (1.4 
million) of cancer deaths. In the US, lung cancer accounts for over 160000 deaths per year 
(Sangodkar et al 2010; Brawley et al 2011). In Western countries, 10-15% non-small cell lung 
cancer (NSCLC) patients express epidermal growth factor receptor (EGFR) mutations in their 
tumors (accounting for 20000 to 30000 new patients per year in the US), and Asian countries 
have reported rates as high as 30-40%. The predominant oncogenic EGFR mutations (L858R 
and ex19del) account for about 90% of EGFR NSCLC. This results in the activation of multiple 
pathways that promote survival, proliferation, angiogenesis and metastasis. Tumor dependence 
on EGFR signaling has been shown to correlate to tumors with high gene copy number and/or 
with activating mutations in EGFR (Mendelsohn et al 2000; Hirsch et al 2003; Lynch et al 2004; 
Paez et al 2004; Pao et al 2004). 
EGFR is an established critical therapeutic target for lung cancer. Numerous trials with 1st-
generation (i.e. reversible) EGFR tyrosine kinase inhibitors (TKIs) (e.g., erlotinib and gefitinib) 
and more recently with the 2nd-generation (i.e. irreversible agents that covalently bind to 
cysteine 797 at the EGFR ATP site; potent on both activating [L858R, ex19del] and acquired 
T790M mutations in pre-clinical models, but also equally potent on wild-type (WT)) EGFR 
TKIs (e.g., afatinib and dacomitinib) have been conducted in the EGFR mutant NSCLC 
population. These trials have consistently demonstrated superior efficacy of EGFR TKIs over 
chemotherapy in this population (Table 1-1). EGFR TKIs’ response rates in EGFR mutant 
NSCLC patients range from approximately 60 to 80% versus 20 to 30% for the chemotherapy 
control arms. Similarly, median progression-free survival (mPFS) is prolonged via EGFR TKI 
treatment on average by 50%; ranging from 8 to11 months, as compared to 4 to 6 months for 
chemotherapy control arms. However, the improved response rates and increases in mPFS have 
not been shown to definitively translate into prolonged overall survival. 
Table 1-1 
Superiority of EGFR TKIs over chemotherapy in EGFRmut NSCLC 
Trial 
Compound 
RR (%) 
Median PFS (mo) 
Median OS (mo) 
TKI 
Chemo 
TKI 
Chemo 
TKI 
Chemo 
IPASS (mut+) 
(Mok et al 2009) 
gefitinib 
71.2 
47.3 
9.5 
6.3 
21.6 
21.9 
First-SIGNAL (mut+) 
(Han et al 2012) 
gefitinib 
84.6 
37.5 
8.4 
6.7 
30.6 
26.5 
WJTOG 
(Mitsudomi et al 2010) 
gefitinib 
62.1 
32.2 
9.2 
6.3 
30.9 
NR 
NEJ002 
(Inoue et al 2009) 
gefitinib 
73.7 
30.7 
10.8 
5.4 
27.7 
26.6 
OPTIMAL 
(Zhou et al 2011) 
erlotinib 
83 
36 
13.7 
4.6 
22.6 
28.8 
EURTAC 
(Rosell et al 2012) 
erlotinib 
58 
15 
9.7 
5.2 
19.3 
19.5 
Afatinib (LUX-Lung 3) 
(Sequist et al 2013) 
afatinib 
56.1 
23 
13.6 
6.9 
28.1 
28.2 
Afatinib (LUX-Lung 6) 
(Wu et al 2014) 
afatinib 
66.9 
23 
11 
5.6 
22.1 
22.2 


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In up to 50% of NSCLC patients harboring a primary EGFR mutation treated with first 
generation EGFR TKIs, a secondary “gatekeeper” T790M mutation develops. Although T790M 
is also in the tyrosine kinase domain of EGFR, it likely results in steric hindrance to EGFR 
TKIs, and restores the affinity for ATP to comparable levels observed for WT EGFR (Yu et al 
2013; Kobayashi et al 2005). In addition to being the predominant mechanism of resistance, 
multiple groups have reported various rates of T790M mutation in pre-treatment specimens, 
although this could be dependent on the sensitivity of the method of testing and may reflect 
underlying tumor heterogeneity (Rosell et al 2011; Su et al 2012; Kobayashi et al 2005; 
Takezawa et al 2012; Bean et al 2007; Engelman et al 2007; Yu et al 2013; Sequist et al 2011). 
Third-generation (i.e. irreversible; WT EGFR sparing; relative equal potency for activating 
EGFR mutations [L858R, ex19del] and acquired T790M) EGFR TKIs are beginning to enter 
clinical development and showing significant initial promise (e.g., CO-1686: ORR of 67% in 
28 evaluable T790M+ NSCLC patients treated at the clinical doses (EORTC-NCI-AACR 2014); 
AZD9291: ORR of 70% (30/43) in T790M+ NSCLC patients treated at the RP2D (ESMO 
2014)). In addition, encouraging antitumor activity has been observed for 3rd-generation EGFR 
TKIs (AZD9291 and CO-1686) in advanced NSCLC patients without an acquired EGFR 
T790M mutation, who have become resistant to a 1st/2nd-generation EGFR TKI, with the ORRs 
ranging from 21% to 36% (ESMO 2014, EORTC-NCI-AACR 2014).  
Despite the progress and efficacy of EGFR TKIs, a definitive improvement in overall survival 
has not been demonstrated and there is still a need for better treatment options for patients with 
EGFR mutant NSCLC. Novel 3rd-generation EGFR therapies, that can target not only the 
primary activating mutations but also the acquired gatekeeper T790M mutation while sparing 
WT EGFR inhibition and thus reducing toxicity, are therefore urgently needed. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of EGF816 
EGF816 is a targeted covalent irreversible EGFR inhibitor that selectively inhibits activating 
and acquired resistance mutants (L858R, ex19del and T790M), while sparing WT EGFR. 
EGF816 has shown significant efficacy in EGFR mutant (L858R, ex19del and T790M) cancer 
models (in vitro and in vivo) with no indication of WT EGFR inhibition at clinically relevant 
efficacious concentrations. 
1.2.1.1 
Non-clinical experience 
1.2.1.1.1 
Non-clinical pharmacokinetics and metabolism 
The pharmacokinetics (PK) of EGF816 was investigated in the mouse, rat and dog. Following 
intravenous administration, EGF816 exhibited: moderate plasma clearance, a large volume of 
distribution and a short terminal half-life (~3 h) in rodents; a high clearance, a high volume of 
distribution and a relatively long terminal half-life (~13 h) in the dog.  
Following single dose oral administration, EGF816 showed good oral bioavailability (>55%) 
in mouse, rat and dog, with Tmax reached at 1-3 h post-dose. EGF816 is highly permeable 
across the intestinal membrane as determined in the Caco2 monolayer system. Given the high 
solubility of EGF816 observed across the pH range and in simulated intestinal fluid for both 


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fasted and fed state, it is considered a biopharmaceutics classification system (BCS) class I 
compound with low food effect risk. 
EGF816 plasma protein binding is high and averaged 96.4%, 91.9%, 89.9% and 93.8% in 
mouse, rat, dog and human plasma, respectively. Following administration of 14C-EGF816 in 
rat, retention of radioactivity in blood was observed with a half-life of 80-90 hours compared 
to the half-life of 3 hours in plasma. More than 75% of the EGF816 derived radioactivity in 
blood was covalently bound to red blood cells. 
Tissue distribution showed that 14C-EGF816 derived radioactivity was high in limited numbers 
of tissues. At 24h, colon wall, esophagus, harderian gland, kidney medulla, liver, uveal tract 
and skin showed higher radioactivity concentration than blood. At 168h, only pituitary gland, 
pigmented skin and uveal tract showed higher concentration than blood, indicating affinity of 
EGF816-derived radioactivity to melanin-rich tissues, and the amount of radioactivity 
associated with blood was 0.04% of the dose. The penetration to brain was minimal with brain 
to blood ratio of 0.03-0.08. 
In rat dosed with 14C-EGF816, the recovery of radioactivity was almost complete (>97%) with 
only ~1% of the dose remaining in the carcass. The predominant route of elimination was via 
fecal excretion with renal excretion a minor pathway. The predominant circulating component 
in rat plasma was the parent compound. The cross-species metabolism comparison in 
hepatocytes showed that no human specific metabolite was observed, and that the N-
demethylation pathway was more predominant in human than that in dog and rat. The N-
demethylated metabolite (LMI258) showed similar pharmacological activity to EGF816 in vitro. 
The exposure of LMI258 was 3-9% and 20-40% of the parent exposure in rat and dog 4-week 
toxicology studies, respectively. 
EGF816 is primarily metabolized by CYP3A4. CYP3A inhibitors ketoconazole and 
azamulin completely inhibited the metabolism of EGF816 in human liver microsomes. EGF816 
showed weak to moderate inhibition of CYP2D6 (Ki 3.3 µM, unbound) and CYP2C8 (IC50 ~11 
µM, unbound) whereas metabolite LMI258 showed relatively strong inhibition of CYP2D6 (Ki 
0.41 µM) and weak inhibition of CYP3A4 (IC50 12 µM) in vitro.  Physiology-based 
pharmacokinetic (PBPK) predictions performed using SimCYP to further evaluate the DDI 
potential between EGF816 and a CYP2D6 substrate (dextromethorphan) or CYP2C8 substrate 
(repaglinide) did not suggest clinically relevant interactions. The predicted change in AUC ratio 
of dextromethorphan or repaglinide was less than 1.25 and hence a drug-drug interaction is 
unlikely in the presence of EGF816. EGF816 is a p-glycoprotein (P-gp) substrate with a Km 
value of 5.0 to 16 µM, and an inhibitor of breast cancer resistance protein (BCRP) with an 
estimated IC50 value of 4.0 µM. 
1.2.1.1.2 
Pharmacology and toxicology 
Non-clinical pharmacology 
EGF816 is a potent third generation, irreversible EGFR mutant-selective inhibitor. It covalently 
links to Cys797 at ATP site of EGFR. In cell-based target modulation assays, EGF816 inhibits 
both oncogenic (L858R, ex19del) and TKI-resistance (L858R/T790M) lines with single digit 
nM potency and demonstrates good selectivity (~40-60 fold vs. the least active mutant line) 
over WT-EGFR cell lines. The potency and WT-selectivity of EGF816 was further confirmed 
in a receptor occupancy study using 14C-labeled EGF816. Profiling against several large panels 


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of kinases indicates that EGF816 is highly selective. The confirmed off-target activities are 
mostly on kinases containing a similarly located cysteine as Cys797 in EGFR. 
As evidenced from in vivo metabolism studies (see Section 1.2.1.1.1), several metabolic 
pathways have been identified. The major metabolite, LMI258, has a very similar overall profile 
as EGF816. It is slightly more active than the parent compound across all cellular assays, while 
retaining comparable WT-EGFR selectivity. 
EGF816 demonstrated strong tumor regressions in several EGFR activating and resistant tumor 
models in vivo. These include HCC827 (ex19del), H3255 (L858R) and H1975 (L858R; T790M) 
that are representative of the relevant clinical settings. In all of the models EGF816 inhibited 
tumor growth in a dose-dependent manner and achieved regressions of established tumors at 
well tolerated doses. 
The HCC827 (ex19del activating mutation) mouse xenograft model was very sensitive to 
EGF816. Even at the lowest tested daily dose of 3 mg/kg, significant tumor regression was 
achieved. The effect was comparable to erlotinib at 60 mg/kg, a clinically relevant dose, which 
gave free plasma exposure similar to that observed at clinical efficacious dose. At doses of 10 
mg/kg q.d. or above, EGF816 showed maximum regression similar to erlotinib at its maximum 
tolerated dose (MTD) of 120 mg/kg. EGF816 was very well tolerated, with no body weight loss 
observed up to 100 mg/kg, while erlotinib at 120 mg/kg showed significant body weight loss 
(~10%). 
In the H3255 (L858R) mouse xenograft model, EGF816 was tested at 30 mg/kg and 
demonstrated strong tumor regression with no effect on body weight compared to vehicle. 
In the H1975 (L858R/T790M) mouse and rat xenograft models, significant tumor regression 
was achieved at doses ≥ 30 mg/kg. Importantly, EGF816 demonstrated much improved 
tolerability with superior efficacy as compared to second-generation irreversible pan-EGFR 
inhibitor afatinib. 
Dose-dependent inhibition of pEGFR and its down-stream pharmacodynamics (PD) markers 
were observed following single oral dose of EGF816 at several dose levels. Sustained inhibition 
of pEGFR relative to plasma PK was evident in either model, and is consistent with the 
irreversible binding mechanism of action. 
Targeted inhibition of WT EGFR in cells also inhibits dual specificity phosphatase 6 (DUSP6) 
(Vecchione et al 2011). In an effort to compare the in vivo WT EGFR selectivity of EGF816 
and afatinib, the DUSP6 gene expression was measured in the skin of treated animals. While 
afatinib caused significant DUSP6 inhibition, EGF816 had no effect at the efficacious doses. 
Together with the in vitro data, this indicates EGF816 exhibits antitumor activity in the relevant 
patient-derived tumor cell lines at well tolerated doses and is predicted to have antitumor 
activity in humans with known EGFR-driven cancers. 
Toxicology 
In the 4-week GLP study in rats clinical signs associated with EGF816 were noted at a dose of 
75 mg/kg/day in both sexes and included chromorhinorrhea (red secretion from noses), 
salivation, piloerection, staining of the fur, discolored skin and/or an increased incidence of 
scab(s)/scratches/abrasions and hair loss. Chromorhinorrhea and scab(s)/scratches/abrasions 
were also noted in 3 females, as well as an increased incidence of hair loss at a dose of 50 


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mg/kg/day. The scab(s)/scratches/abrasions were generally noted during the latter part of the 
dosing period and abated in the majority of animals during the recovery period. Discolored skin 
was noted during the last week of the dosing period and/or up to recovery day 9. There were no 
test article-related clinical signs noted at doses ≤ 50 mg/kg/day in males or at 30 mg/kg/day in 
females. 
Hematologic changes reflected the presence of mild, dose-dependent inflammation, 
characterized by increases in absolute neutrophil, monocyte and/or platelet counts, decreased 
hemoglobin concentrations and mean corpuscular hemoglobin and increased plasma fibrinogen 
concentrations. Following compound withdrawal, neutrophil and monocyte counts remained 
mildly increased in both male and female rats dosed at 75 mg/kg/day, correlating with the skin 
changes described histologically. In clinical chemistry, mild, reversible decreases in serum 
triglyceride concentrations were noted in male rats dosed at 75 mg/kg/day and female rats dosed 
at ≥ 50 mg/kg/day, consistent with mildly decreased food consumption. No changes in 
urinalysis parameters were noted. 
Target organs in the rat included skin/eyelids (inflammation around hair follicles and in 
epidermis), lungs (foamy macrophages-phospholipidosis), lymphoid organs (cell depletion), 
vagina (atrophy of epithelium), uterus (atrophy of endometrium), anal (sebaceous) glands 
(inflammation). 
In conclusion the severely toxic dose to 10% of animals (STD10) in rodents was 75 mg/kg/day. 
In the 4-week GLP study in beagle dogs, clinical signs associated with EGF816 were noted at 
a dose of 20 mg/kg/day and included emesis and salivation during the first week of dosing. 
Clinical signs of fecal changes including decreased/soft feces and diarrhea, absent feces, and 
feces with apparent blood were noted on 1 or 2 occasions during the dosing period. Discolored 
urine was noted in one animal on study day 7 and in another animal on 4 occasions between 
study days 7 and 16; subsequently, this animal was noted to have decreased motor activity 
intermittently on study days 23 through 30 and was recumbent on study day 23. One male dog 
had reddened conjunctiva, excessive blinking and/or ptosis intermittently on study day 6 
through recovery day 1. During the recovery period at the 20 mg/kg/day dose level, soft feces 
and diarrhea were noted. Discolored skin, reddened skin and hair loss were noted during the 
non-dosing period and generally persisted through the end of the recovery period. Skin swelling, 
scab(s)/scratches/abrasions and reddened ears were also noted. In males at a dose of 8 
mg/kg/day, emesis was noted on study day 3 and salivation on 2 occasions in one dog. In 
females at a dose of 8 mg/kg/day, emesis with apparent compound was noted on one occasion 
in a single animal. There were no test article-related clinical signs noted in either sex at a dose 
of 4 mg/kg/day. Test article-related effects on body weight parameters were noted at doses ≥ 8 
mg/kg/day in males and females. In all males (5/5) at a dose of 20 mg/kg/day, body weight loss 
of 0.5 to 0.8 kg (5.3 to 12.8%) was noted between day 1 to 29. During the non-dosing period, 
body weights rebounded resulting in 6.3 to 7.2% body weight increases from recovery days 1 
to 29. In females at a dose of 20 mg/kg/day, body weight loss of 0.6 kg (9.6 to 10.3%) was 
noted in 2 out of 5 animals. During the recovery period, body weight gains rebounded (0.5 to 
0.8 kg) in animals given 20 mg/kg/day resulting in 10.9 to 15.4% body weight increases 
between recovery days 1 to 29. Mild effects on body weight in males and no effects on body 
weights in females were observed at a dose of 8 mg/kg/day; no effects were seen for either sex 
at a dose of 4 mg/kg/day. 


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Hematology and coagulation changes were noted in male and female dogs dosed at ≥ 8 
mg/kg/day when results were compared to those from the pretest period, and included increased 
neutrophil and monocyte counts (≥ +100%), decreased RBC counts, hemoglobin concentration 
and hematocrit (≥ -25%), and decreased albumin (≥ -20%) and increased globulins (≥ +25%). 
Target organs in the dog included cornea (epithelial thinning), and various glands throughout 
the organ system (atrophy). The highest non-severely toxic dose (HNSTD) was determined to 
be 20 mg/kg/day. 
EGF816 showed a potential for phototoxicity in the 3T3 NRU in vitro assay. 
The Ames assay for EGF816 indicated that it was not a potential mutagen and the chromosomal 
aberration assay in human peripheral blood lymphocytes did not indicate the potential to cause 
chromosomal aberrations. An in vivo evaluation of the bone marrow for the presence of 
micronuclei was negative in rats. The IC50 for the hERG potassium channel is 6 µM. 
The confirmed off-target activities of EGF816 in cellular assays are mostly on Cys-kinases (i.e., 
kinases containing an analogous cysteine as Cys797 in EGFR). These kinases include Tec 
family kinases (TEC, ITK, TXK) with IC50=31 nM. EGF816 showed >5 fold selectivity versus 
Tec family kinases with respect to H3255 (L858R) activity (IC50=5 nM). Because Tec kinases 
are involved in T cell function, T cell proliferation induced by tetanus toxin (TT) as antigen, 
lipopolysaccharide (LPS) and phytohemagglutinin (PHA) as mitogens were measured in the 
absence or presence of EGF816. All stimuli increased T cell proliferation compared to DMSO 
controls. EGF816 suppressed this T cell proliferation at concentrations of 0.037 μM to 3 μM. 
An in vivo study that examined the potential immunomodulatory effect of EGF816 was also 
conducted. Rats were immunized subcutaneously on Days 11 and 21 with keyhole limpet 
hemocyanin (KLH) antigen during 28 continuous days of oral exposure to EGF816 at 30 or 50 
mg/kg or to Prograf at 3 mg/kg as a positive control (an immunosuppressive compound used in 
transplantation). Serum was collected from all animals and KLH-specific IgM and IgG antibody 
concentrations were measured by ELISA. Dose-related immunomodulatory responses in 
EGF816-treated animals following sensitization with KLH immunization were noted when 
values were compared to concurrent vehicle controls. Recovery following withdrawal of 
EGF816 treatment was noted, indicating that the EGF816-related decrease of anti- KLH 
antibody production was reversible. This included both the primary response (anti-KLH IgM), 
and the isotype switch as measured by secondary anti-KLH IgG production.  
In conclusion, EGF816 dampened the antibody response to a neoantigen (KLH) in rats as 
measured by anti-KLH IgM and IgG antibody titers. This effect was reversed after withdrawal 
of EGF816. The clinical translation of this effect is not known. 
1.2.1.2 
Clinical experience 
CEGF816X2101 is the first-in-human Phase I/II study of single-agent oral EGF816. 
As of the cut-off date of 18-Dec-2015 (cut-off date of the Investigator’s Brochure ed. 5) 148 
patients have been treated with EGF816 capsules or tablets at seven dose levels: 75 mg QD 
(N=7), 100 mg q.d. (N=29), 150 mg QD. (N=64), 200 mg QD (N=8), 225 mg QD (N=24), 300 
mg QD (N=5) and 350 mg QD (N=11). Eighty-four patients (56.8%) were still receiving 
treatment and 64 patients (43.2%) had discontinued treatment. Of these 64 patients, reasons for 
discontinuation were: progressive disease (53 patients), adverse events (3 patients), death (3 
patients), subject guardian decision (3 patients), physician decision (2 patients). Of the three 


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patients who discontinued treatment due to AE, one patient at the 350 mg QD reported Grade 
3 maculopapular rash, one patient at the 150 mg daily dose reported Grade 3 interstitial lung 
disease, and one patient at the 300 mg daily dose reported Grade 3 pulmonary edema. Of the 
three patients who discontinued treatment due to death, one patient died due to sepsis 
(considered not related to study treatment), one patient died due to hepatitis B virus (HBV) 
reactivation (considered related to study treatment), and one patient died due to pneumonia 
(considered not related to study treatment). 
As of 18-Dec-2015, dose-limiting toxicities (DLT) were reported in five patients: one patient 
at the dose level of 150 mg capsule reported Grade 3 maculopapular rash that resulted in 
temporary treatment interruption, one patient at the dose level of 225 mg capsule reported Grade 
3 maculopapular rash that resulted in temporary treatment interruption, one patient at the dose 
level of 350 mg capsule reported Grade 3 acute kidney failure and Grade 3 maculopapular rash 
that resulted in temporary treatment interruption, one patient at the dose level of 350 mg capsule 
reported Grade 3 maculopapular rash that resulted in permanent discontinuation of treatment, 
and one patient at the dose level of 350 mg capsule reported Grade 3 enteritis and Grade 3 
dehydration that resulted in temporary treatment interruption. The maximum tolerated dose 
(MTD) has not been determined for EGF816 as a single agent. 
As of the data cut-off date of 18-Dec-2015, 142 patients (95.9%) who were treated with EGF816 
capsules or tablets experienced at least one AE of any grade, regardless of relationship to the 
study drug. The most frequent AEs (all CTCAE grades, >10% of patients) regardless of study 
drug relationship at the seven dose levels were rash (group term) (56.1%), diarrhea (41.9%), 
maculopapular rash, pruritus (36.5%), fatigue (27.0%), stomatitis (27.0%), dry skin (24.3%), 
nausea (23.6%), cough (20.9%), decreased appetite (20.3%), vomiting (14.9%), constipation 
(14.2%), headache (12.8%), anemia (12.2%), paronychia (11.5%), pyrexia (11.5%), dyspnea 
(10.8%), edema peripheral (10.8%), back pain (10.1%), and upper respiratory tract infection 
(10.1%).Seventy (47.3%) patients who were treated with EGF816 capsules or tablets at any 
dose experienced Grade 3 or Grade 4 AEs regardless of relationship to the study drug. Grade 
3/4 AEs occurring in ≥ 2% of patients were rash (grouped term) (15.5%), anemia (5.4%), 
pneumonia (5.4%), diarrhea (4.7%), fatigue (2.7%), dyspnea (2.7%), urticaria (2.7%), 
hypertension (2.7%), stomatitis (2.0%), decreased appetite (2.0%), hyperuricemia (2.0%), and 
seizure (2.0%).As of the data cut-off date (18-Dec-2015) SAEs, regardless of study drug 
relationship, were reported in 48 patients (32.4%) who received at least one dose of single agent 
EGF816 capsules or tablets.  
Of these 48 patients, 15 experienced SAEs that were suspected to be related to study drug, 
please refer to Investigator’s Brochure ed. 5. In summary, the outcome of SAEs suspected to 
be related to study treatment was recovered or recovering in 12 of 15 patients. One patient died 
due to hepatic failure secondary to HBV reactivation, one patient was reported as not recovered 
from Grade 3 maculopapular rash, and one patient was reported as not recovered from Grade 3 
anemia. 
As of 18-Dec-2015, 2 SAEs of HBV reactivation have been reported in 2 patients participating 
in the CEGF816X2101 study. One case had a fatal outcome, and the second case was considered 
medically significant. The fatal case involved a patient who received EGF816 at 225 mg QD, 
had a history of HBV infection and was not on antiviral treatment at study entry. The patient 
developed HBV reactivation during the study and died due to hepatic failure despite initiation 
of antiviral treatment after HBV reactivation had been confirmed. The second patient also 
received EGF816 at 225 mg QD, had a history of HBV and was not on antiviral treatment at 


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the time of joining the study, HBV reactivation was detected after the patient had been on study 
for approximately 10 weeks. Antiviral treatment was immediately initiated, EGF816 was 
interrupted and the HBV infection was brought under control. The patient later resumed 
EGF816 at the same dose of 225 mg q.d. while continuing on antiviral medication. The viral 
reactivation in these two patients was likely due to immunosuppression related to EGF816. 
Reactivation of HBV and hepatitis C virus (HCV) has been reported with anticancer therapies 
that suppress the immune system. 
It should be noted that the maculopapular rash associated with EGF816 treatment appears to be 
different from the typical EGFR TKI-related rash (e.g., acneiform rash). Its onset was generally 
in the first 2-3 weeks of study treatment however it could be sporadic. The rash typically appears 
on the trunk, spreads out to the extremities, and in general spares the palms and soles. EGF816-
associated rash was well managed with dose interruption and/or steroid and antihistamine 
treatments. In most cases, the rash resolved completely or almost completely within 1 week 
after drug interruption, and patients were able to restart study treatment, at the same dose or a 
reduced dose, without recurrence of the maculopapular rash. 
As of the data cut off of 29-Jan-2016, preliminary efficacy results showed an overall response 
rate (ORR) of 46.9 % by Investigator assessment in 69 out of 147  evaluable patients treated at 
all dose levels. Note: evaluable patients include those who were ongoing and had at least one 
post-baseline tumor assessment or who discontinued study treatment as of the data cut-off date. 
The antitumor activity of EGF816 is presented in Figure 1-1. 
Please refer to the current Investigator’s Brochure for more details. 
Figure 1-1 
Best percentage change from baseline in sum of diameters of target 
lesions as per investigator by treatment (Capsule) – Full analysis set  
 
*Patient discontinued. † Patient’s NSCLC was negative for EGFR T790M. 
n: number of evaluable patients responders, N: number of patients enrolled 
(Evaluable patients include those who are ongoing with study treatment and have ≥ 1 post-baseline 
response assessment  


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or who have discontinued study treatment. This total is used for percentage calculation) (Tan S-W D, 
Yang C-H J (2016) 
As of 14-Sep-2015, data on EGF816 PK parameters are available following treatment with 
capsules or tablets at 75, 100, 150, 200, 225, 300, and 350 mg/day in patients. For a similar 
dose, similar exposure was observed with capsules and tablets. Systemic exposure to EGF816 
generally increased with the dose, with a median Tmax of 3-6 hr. The steady state was reached 
by cycle 1 day 15. The terminal half-life T1/2 ranged from 13 to 18 hr. Accumulation of 
EGF816 following repeated administration is low with an accumulation ratio of up to 2-fold. 
2 
Rationale 
2.1 
Study rationale and purpose 
Note: throughout this protocol, advanced NSCLC refers to patients with either locally advanced 
or metastatic NSCLC. Locally advanced NSCLC is defined as stage IIIB NSCLC not amenable 
to definitive multi-modality therapy including surgery. Metastatic NSCLC refers to stage IV 
NSCLC. 
Inhibitors of EGFR-mutant L858R and ex19del have been well validated as therapeutic agents 
for advanced NSCLC patients. However, the narrow therapeutic window of currently available 
EGFR inhibitors limits the potential of this class of drugs. In spite of the proven clinical benefit 
of 1st- and 2nd-generation of EGFR TKIs, the overall survival has not improved and the dose-
limiting toxicities, particularly affecting the skin and gastrointestinal (GI) due to cross-activity 
with WT EGFR, are frequently reported. Novel EGFR therapies such as 3rd-generation EGFR 
TKIs that can target not only the primary activating mutations, but also the acquired T790M 
mutation while sparing WT EGFR, are urgently needed. The sparing of WT EGFR appears to 
improve the most common toxicities (rash and diarrhea) associated with EGFR TKIs. The 3rd-
generation of irreversible EGFR TKIs (e.g., CO-1686 and AZD9291) is entering clinical 
development and has shown significant initial promise. EGF816 is a 3rd-generation irreversible 
EGFR TKI that selectively inhibits activating and acquired resistance mutants (L858R, ex19del 
and T790M+), while sparing WT EGFR.  
The purpose of the Phase I part (dose-escalation) of this study is to determine the maximum 
tolerated dose (MTD) or recommended phase II dose (RP2D) and to evaluate the preliminary 
antitumor activity of single-agent EGF816 in adult patients with locally advanced (stage IIIB) 
or metastatic (stage IV) NSCLC. The Phase I part will include patients with tumors harboring 
specific EGFR mutations (refer to Section 2.2). The purpose of the Phase II part of this study is 
to evaluate the efficacy and safety of single-agent EGF816 in adult patients with locally 
advanced (stage IIIB) or metastatic (stage IV) NSCLC whose tumors harbor specific EGFR 
activating mutations (e.g., L858R and ex19del) in first line setting (EGFR TKI and 
chemotherapy naïve). 
Based on the preclinical data of EGF816 and the known clinical activity of other 3rd-generation 
EGFR inhibitors in advanced NSCLC patients harboring EGFR mutations, it is expected that 
EGF816 would have significant antitumor activity in NSCLC patients harboring the activating 
EGFR mutations (e.g., L858R and ex19del) and/or the acquired/resistant “gatekeeper” T790M 
mutation. While sparing WT EGFR, EGF816 is also expected to be better tolerated than 
currently available treatment options. Taking into consideration of efficacy and safety, EGF816 


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treatment should translate into longer sustained responses and improvement in patients’ quality 
of life. 
The preliminary results from this study in advanced NSCLC patients with EGFR mutations 
(L858R and/or ex19del, T790M+) have shown a tolerable safety profile and significant 
antitumor activity of EGF816 at different dose levels (75 mg, 150 mg, 225 mg and 350 mg) 
including the lowest dose tested, that is in line with other 3rd-generation EGFR TKIs such as 
AZD9291 and CO-1686 (see Section 1.2.1.2). 
2.2 
Rationale for the study design 
Phase I part  
This open-label, Phase I part (dose-escalation) of the first-in-human study is designed to 
determine the MTD or RP2D of EGF816 in adult patients with locally advanced (stage IIIB) or 
metastatic (stage IV) NSCLC harboring specific EGFR mutations, The acceptable safety profile 
observed in the patients treated in the Phase I part to date supports the expansion of the eligible 
Phase I population.  The Phase I part will consist of the following: 
• Treatment naive patients, who have locally advanced or metastatic NSCLC with EGFR 
activating mutation (e.g., L858R and/or ex19del), have not received any systemic 
antineoplastic therapy for advanced NSCLC and are eligible to receive EGFR TKI 
treatment. Note: patients who have received only one cycle of chemotherapy in the 
advanced setting are allowed. 
• Patients who have locally advanced or metastatic NSCLC with EGFR activating mutation 
AND an acquired T790M mutation (e.g., L858R and/or ex19del, T790M+) following 
progression on prior treatment with a 1st-generation EGFR TKI (e.g., erlotinib, gefitinib or 
icotinib) or 2nd-generation EGFR TKI (e.g., afatinib or dacomitinib). These patients may 
not have received more than 3 prior lines of antineoplastic therapy, including EGFR TKI, 
and may not have received any agent targeting EGFR T790M mutation (i.e. 3rd-generation 
EGFR TKI). 
• Patients who have locally advanced or metastatic NSCLC with a “de novo” T790M 
mutation (i.e. no prior treatment with any agent known to inhibit EGFR including EGFR 
TKI). These patients may not have received more than 3 prior lines of antineoplastic 
therapy, and may not have received any prior agent known to inhibit EGFR, including 
EGFR TKIs. 
• Patients who have locally advanced or metastatic NSCLC harboring EGFR exon 20 
insertion or deletion.  These patients may not have received more than 3 prior lines of 
antineoplastic therapy, including EGFR TKIs. 
• Patients who have locally advanced or metastatic NSCLC with EGFR activating mutation 
AND without an acquired T790M mutation (e.g., L858R and/or ex19del, T790M-) 
following progression on a 1st-generation EGFR TKI (e.g., erlotinib, gefitinib or icotinib) 
or 2nd-generation EGFR TKI (e.g., afatinib or dacomitinib). These patients may not have 
received more than 3 prior lines of antineoplastic therapy, including EGFR TKIs, and may 
not have received any agent targeting EGFR T790M (i.e. 3rd-generation EGFR TKI).  
• Patients who have locally advanced or metastatic NSCLC with EGFR activating mutation 
and an acquired T790M mutation (e.g., L858R or ex19del, T790M+) following 
progression on a prior treatment with a 1st/2nd-generation EGFR TKI, and have progressed 


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on or are intolerant to a 3rd-generation EGFR TKI (e.g., AZD9291, CO-1686, or 
ASP8273).  These patients may not have received more than 3 prior lines of antineoplastic 
therapy, including EGFR TKIs.  
This study will utilize a Bayesian logistic regression model (BLRM) to guide dose escalation 
and predict the MTD or determine the RP2D for EGF816. The BLRM with escalation with 
overdose control (EWOC) enables incorporation of available prior information and updates the 
model parameters based upon new information about observed dose-limiting toxicities seen in 
the clinical study. The dose recommended by the model at any stage of the trial is based on the 
entire history of all available DLT information from previous cohorts as opposed to only the 
number of DLTs observed in the last group of patients. The updated model then provides 
information on the probabilities of DLTs from the current dose to the next predicted dose level. 
The use of Bayesian response adaptive models for small datasets has been accepted by EMEA 
(“Guideline on clinical trials in small populations”, February 1, 2007) and endorsed by 
numerous publications (Babb et al 1998, Neuenschwander et al 2008, Neuenschwander et al 
2010), and its development and appropriate use is one aspect of the FDA’s Critical Path 
Initiative. The decision to dose escalate is made by the Investigators and Novartis study 
personnel and will be based upon the recommendations made by the BLRM, patient tolerability 
and safety, PK, PD and efficacy information available to date. 
Phase II part 
The Phase II part will open at the MTD or RP2D using the tablet formulation. The purpose of 
the Phase II part is to characterize the antitumor activity, safety, tolerability, PK and PD of 
EGF816 at the selected dose level. The primary objective is to evaluate the antitumor activity 
of EGF816 in the described patient population. The primary endpoint of antitumor activity is 
the overall response rate (ORR) per RECIST 1.1 as determined by the Blinded Independent 
Review Committee (BIRC) to ensure unbiased assessment. A supportive analysis of ORR will 
be performed based on the Investigators’ assessment. 
The Phase II part will enroll a minimum of 40 treatment naïve patients, who have locally 
advanced or metastatic NSCLC with locally documented EGFR activating mutation (L858R, 
ex19del). The patients will have not received any systemic antineoplastic therapy for advanced 
NSCLC and will be eligible to receive EGFR TKI treatment. Note: patients who have failed no 
more than 1 cycle of systemic antineoplastic therapy in the advanced setting are allowed. 
Treatment failure is defined as documented disease progression or intolerance to treatment. 
Neo-adjuvant and adjuvant systemic therapies will be counted as 1 prior line of treatment if 
relapse occurred within 12 months from the end of the neo-adjuvant/adjuvant systemic therapy. 
EGF816 is a 3rd generation irreversible EGFR TKI that selectively inhibits activating and 
acquired resistance mutants (L858R, ex19del and T790M), while sparing WT EGFR. Inhibitors 
of EGFR-mutant L858R and ex19del, such as 1st and 2nd generation EGFR TKIs, have been 
well validated as therapeutic agents for advanced NSCLC patients who are treatment naïve. 
Novel EGFR therapies such as 3rd generation EGFR TKIs can also target the primary activating 
mutations. In a preclinical study using tumor model with EGFR ex19del, EGF816 treatment 
was more efficacious compared to treatment with erlotinib. Other 3rd generation EGFR TKIs, 
such as AZD9291, have shown promising preliminary data in this patient population (Jänne et 
al. 2015). AZD9291 has an ongoing Phase III clinical trial in the first line setting. Based on the 
mechanism of action, EGF816 will likely have similar clinical activity in this patient population.  


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In the Phase II part, the patients will enter the study in the 1st line setting, i.e. will not have 
received any prior systemic antineoplastic therapy for advanced disease. Note: patients who 
have failed no more than 1 cycle of systemic antineoplastic therapy in the advanced setting are 
allowed. Treatment failure is defined as documented disease progression or intolerance to 
treatment. Neo-adjuvant and adjuvant systemic therapies will be counted as 1 prior line of 
treatment if relapse occurred within 12 months from the end of the neo-adjuvant/adjuvant 
systemic therapy 
Details of the statistical hypothesis, model and analysis are provided in Section 10.4.2 and 
sample size is provided in Section 10.8  
2.3 
Rationale for dose and regimen selection 
The human starting dose for EGF816 is 75 mg administered orally on a continuous, once daily 
dosing schedule. The starting dose was determined based on GLP-toxicology studies using rat 
as the toxicology species according the regulatory guidance (see Section 6.2.1). 
2.4 
The recommended phase II dose (RP2D) was determined based 
on the safety and efficacy data obtained from the Phase I part 
(dose-escalation) at 150 mg/day on capsules and tablets. 
Rationale for choice of combination drugs 
Not applicable 
2.5 
Rationale for choice of comparators drugs 
Not applicable 
2.6 
Risks and benefits 
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules, are included in Section 5 and Section 6 of this protocol. 
Recommended guidelines for prophylactic or supportive management of study-drug induced 
adverse events are provided in Section 6.3. The risks to subjects in this trial may be minimized 
by compliance with the eligibility criteria and study procedures as well as close monitoring. 
The preliminary results from this study in advanced NSCLC patients with EGFR mutations 
(L858R and/or ex19del, T790M) have shown a tolerable safety profile and significant antitumor 
activity of EGF816 at different dose levels (75 mg, 150 mg, 225 mg and 350 mg) including the 
lowest dose tested, that is in line with other 3rd-generation EGFR TKIs such as AZD9291. All 
available safety and pharmacokinetic data have been reviewed by participating investigators 
and Novartis at dose escalation teleconferences of the Phase I after the completion of each 
cohort. In these dose escalation meetings, all participants have reached a consensus to declare 
RP2D at 150 mg of EGF816. 
As of 18-Dec-2015, there have been 2 reported SAEs of viral hepatitis B reactivation related to 
EGF816 reported in 2 patients participating in the EGF816 single agent study 
(CEGF816X2101). One case had a fatal outcome, and the second case was medically significant. 
The viral hepatitis reactivation is likely related to immunosuppression caused by EGF816 
although the exact mechanism of the reactivation is unknown. Reactivation of HBV and HCV 
has been reported with other anticancer therapies and immunosuppressive agents. To minimize 


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the risk to all trial subjects and to manage the potential risk of severe liver toxicity associated 
with hepatitis reactivation, Novartis has amended the protocols for all clinical trials involving 
EGF816 to provide guidance for patients with evidence of current or prior HBV/HCV infection. 
However, there may be unforeseen risks with the study treatment which could be serious. Refer 
to the EGF816 Investigator’s Brochure for further information regarding clinical toxicity.  
Based on the available pre-clinical and clinical data for EGF816 and the known clinical activity 
of other 3rd-generation EGFR inhibitors in advanced NSCLC patients harboring EGFR 
mutations, it is foreseeable that EGF816 will continue to demonstrate significant antitumor 
activity in NSCLC patients harboring the activating EGFR mutations (i.e. L858R and ex19del) 
and/or the acquired/resistant “gatekeeper” T790M mutation with better tolerability than the 
currently available treatment options due to sparing of the WT EGFR. The improved efficacy 
and tolerability reported with EGF816 treatment should translate into prolonged and sustained 
responses with improved quality of life. 
Therefore evidence and current clinical experience, the overall risk/benefit assessment of 
EGF816 is predicted to be favorable in treatment naïve patients with advanced NSCLC tumors 
harboring EGFR activating mutations. 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 and Table 3-2 below. 
Table 3-1 
Objectives and related endpoints (Phase I part) 
Objective 
Endpoint 
Analysis 
Primary 
Refer to Section 10.4 
To estimate the maximum tolerated 
dose (MTD) or recommended phase 2 
dose (RP2D) of EGF816 
Incidence of dose-limiting toxicity (DLT) 
during the first 28 days of dosing 
Refer to Section 10.4 
Secondary 
Refer to Section 10.5 
To characterize the safety and 
tolerability of EGF816 
Safety: Incidence and severity of AEs and 
SAEs, including changes in laboratory 
values, vital signs and ECGs 
Tolerability: Dose interruptions and 
reductions 
Refer to Section 
10.5.1 
To evaluate overall response rate 
(ORR), duration of response (DOR), 
disease control rate (DCR), 
progression-free survival (PFS), and 
time to response (TTR) determined by 
Investigator assessments 
The following endpoints will be evaluated 
by  Investigator assessments in 
accordance to  Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1): 
ORR, DOR, DCR, PFS and TTR* 
Refer to Section 
10.5.2 
To characterize the pharmacokinetics 
(PK) properties of EGF816 and 
metabolite LMI258  
Plasma concentration vs. time profiles, 
plasma PK parameters 
Refer to Section 
10.5.3 
To assess the tumor EGFR signaling 
inhibition by EGF816 (prior to Protocol 
amendment 05) 
Pre- and on- treatment 
immunohistochemistry of EGFR pathway 
molecules (e.g., p-EGFR, p-AKT, p-ERK) 
in newly obtained tumor samples 
Refer to Section 
10.6.2 


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Objective 
Endpoint 
Analysis 
*ORR is defined as proportion of patients with best overall response of PR+CR per RECIST 1.1; DOR is 
defined as the time from first documented response (PR or CR) to the date of first documented disease 
progression or death due to any cause; DCR is defined as the proportion of patients with best overall response 
of CR, PR, or SD; PFS is defined as the time from the date of first dose of study treatment to the date of first 
documented disease progression (per RECIST 1.1) or death due to any cause; TTR is defined as the time 
between date of start of treatment until first documented response (CR or PR). 
Table 3-2 
Objectives and related endpoints (Phase II part) 
Objective 
Endpoint 
Analysis 
Primary 
Refer to Section 10.4 
To investigate the antitumor activity of 
EGF81 6 
Overall response rate (ORR) by Blinded 
Independent Review Committee (BIRC) 
assessment in accordance to Response 
Evaluation Criteria in Solid Tumors 
(RECIST 1.1) 
Refer to Section 10.4 
Secondary 
Refer to Section 10.5 
To further characterize the safety and 
tolerability of EGF816 
Safety: Incidence and severity of AEs and 
SAEs, including changes in laboratory 
values, vital signs and ECGs 
Tolerability: Dose interruptions and 
reductions 
Refer to Section 
10.5.1 
To evaluate ORR 
ORR by Investigator assessment in 
accordance to RECIST 1.1 
Refer to Section 
10.5.2 
To evaluate duration of response 
(DOR), disease control rate (DCR), 
progression-free survival (PFS) and 
time to response (TTR)  
The following endpoints will be evaluated 
by BIRC assessment in accordance to  
RECIST 1.1: DOR, DCR, PFS and TTR*   
Refer to Section 
10.5.2 
To evaluate DOR, DCR, PFS and TTR   
The following endpoints will be evaluated 
by Investigator assessment in accordance 
to RECIST 1.1: DOR, DCR, PFS and 
TTR*   
Refer to Section 
10.5.2 
To evaluate overall survival (OS) 
OS 
 


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Objective 
Endpoint 
Analysis 
To characterize the pharmacokinetics 
(PK) properties of EGF816 and 
metabolite LMI258 for all groups 
Plasma concentration vs. time profiles, 
and plasma PK parameters as 
appropriate 
Refer to Section 
10.5.3 
*ORR is defined as proportion of patients with best overall response of PR+CR per RECIST 1.1; DOR is 
defined as the time from first documented response (PR or CR) to the date of first documented disease 
progression or death due to any cause; DCR is defined as the proportion of patients with best overall response 
of CR, PR, or SD; PFS is defined as the time from the date of first dose of study treatment to the date of first 
documented disease progression (per RECIST 1.1) or death due to any cause; TTR is defined as the time 
between date of start of treatment until first documented response (CR or PR); OS is defined as the time from 
first dose of study treatment to the date of death due to any cause. 
4 
Study design 
4.1 
Description of study design 
This is a Phase I/II, multi-center, open-label study starting with a Phase I part (dose-escalation) 
followed by a Phase II part. Oral EGF816 will be administered once daily on a continuous 
schedule until patient experiences unacceptable toxicity, progressive disease (PD) and/or 
treatment is discontinued at the discretion of the investigator, patient withdraws consent or due 
to any other reasons. Treatment with EGF816 may be continued beyond RECIST 1.1 defined 
PD, if, in the judgment of the investigator, there is evidence of clinical benefit and the patient 
wishes to continue with the study treatment (see Section 6.1.2 for details). 
A treatment cycle is defined as 28 days. 


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Per protocol definition, advanced NSCLC refers to patients with either locally advanced or 
metastatic NSCLC. Locally advanced NSCLC is defined as stage IIIB NSCLC not amenable to 
definitive multi-modality therapy including surgery. Metastatic NSCLC refers to stage IV 
NSCLC. 
Phase I part 
In the Phase I part, patients must have locally advanced (stage IIIB) or metastatic (stage IV) 
NSCLC harboring specific EGFR mutations as described in Section 2.2. An adaptive BLRM 
with EWOC will guide the dose-escalation to determine the MTD or RP2D. Before the MTD 
or RP2D can be declared for the study, at least 21 patients should have been treated, with at 
least six patients treated at the MTD or RP2D (Refer to Section 6.2.3.2). 
Patients enrolled in the Phase I part must continue to be evaluated according to the evaluation 
schedule noted in Table 7-1. 
Phase II part 
The Phase II part will start when the RP2D in tablet formulation has been identified. A 
minimum of 40 patients with advanced (stage IIIB) or metastatic (stage IV) NSCLC and 
documented EGFR activating mutation, who have never received any systemic antineoplastic 
therapy will be enrolled (Figure 4-1). Note: patients who have received no more than 1 cycle of 
systemic antineoplastic therapy in the advanced setting are allowed. 
The EGFR mutation status is determined by a local laboratory (pre-screening phase). The 
mutations L858R and exon 19 deletion account for approximately 90% of the EGFR activating 
mutations and confer sensitivity to the EGFR TKIs. Additionally the other rare mutations such 
as L861Q, G719S/A/C, and S768I also confer sensitivity to the EGFR TKIs and will also satisfy 
eligibility criteria. 
The EGFR mutation status may be determined from any available tumor tissue. A laboratory 
report showing evidence of EGFR activating mutation must be available in the source 
documents. 
Details of the sample size calculations leading to the patient numbers are provided in Section 
10.8. Patients enrolled in the Phase II part will follow the evaluation schedule noted in Table 7-
2.  


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Figure 4-1 
Study design, Phase II part  
 
The study includes different periods as illustrated in Figure 4-2 and Figure 4-3. Refer to Table 
7-1 and Table 7-2 for detailed information. 
Figure 4-2 
Study visit flow (Phase I part) 
 
Figure 4-3 
Study visit flow (Phase II part) 
 
In the Phase I part, patients may have tumor tissue and blood samples collected at screening 
and at disease progression to study the mechanisms of drug treatment resistance. For sites that 
are participating in a Novartis optional companion sample collection protocol to study treatment 
resistance, the collection of these samples is guided by the companion sample collection 
protocol and the related informed consent once approved and open. 
4.2 
Timing of interim analyses and design adaptations 
For the Phase I part, no formal interim analyses are planned. However, the dose-escalation 
design foresees that decisions based on the current data are taken before the end of the study. 
More precisely, after each cohort in the dose-escalation part, the next dose will be chosen 
depending on the observed data. Details of this procedure and the process for communication 
with investigators are provided in Section 6.2.3. 


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During the Phase II part there will be one interim futility analysis when approximately 20 
patients have completed at least 4 cycles of treatment or discontinued treatment prior to that 
time. 
Assessment of futility will be based on the calculated Bayesian probability of success (PoS). 
The Phase II will be stopped for futility if the PoS is less than 10% at the interim analysis. 
If applicable, enrollment of patients into the Phase II part will continue between the time the 
required data for patients in the interim analysis are observed and the time the results of the 
interim analysis are available.  
Detailed information on the statistical considerations for the interim analysis is provided in 
Section 10.7 and Section 10.8. 
In addition, data from patients in the Phase II part will be reviewed on an ongoing basis to 
monitor the safety and tolerability of the MTD/RP2D (Section 8.5). 
4.3 
Definition of end of the study 
The primary analysis will be performed when all patients enrolled have completed at least 6 
cycles of treatment or discontinued treatment prior to that time (if not sopped for futility at 
interim analysis). The primary analysis data will be summarized in the primary clinical study 
report (CSR) including Phase I and II data.  
Following the cut-off date for the analysis reported in the primary CSR, the study will remain 
open. , Ongoing patients will continue to receive study treatment and be followed as per the 
schedule of assessments, as long as patients derive benefit from EGF816 or until the end of 
study defined as the earliest occurrence of the following:  
• All patients have died or discontinued from the study  
• Another clinical study becomes available that can continue to provide EGF816  in this 
patient population of this study and all patients ongoing are eligible to be transferred to 
that clinical study 
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to patients who in the opinion of the Investigator 
are still deriving clinical benefit. 
Last patient last visit (LPLV) is defined as the date when the last visit is performed by the last 
patient still on study. The final analysis will occur at the end of the study. All available data 
from all patients up to LPLV will be summarized in a final CSR. 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible for an EOT visit, and the assessments for EOT as 
described in Section 7 should be performed for a discontinued or withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing IRBs and/or ECs of the early termination of the trial.  


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5 
Population 
5.1 
Patient Population 
In this study, EGF816 will be administered as a single agent in adult patients with locally 
advanced or metastatic NSCLC with specific EGFR mutations. Advanced NSCLC refers to 
patients with either locally advanced or metastatic NSCLC. Locally advanced NSCLC is 
defined as stage IIIB NSCLC not amenable to definitive multi-modality therapy including 
surgery. Metastatic NSCLC refers to stage IV NSCLC. 
For the Phase I part all patients must have advanced NSCLC harboring specific EGFR 
mutations, as described in Section 2.2. The EGFR mutation status may be determined by local 
or central laboratory testing.  
For the Phase II part, adult patients with locally advanced or metastatic NSCLC will be enrolled. 
The patients must not have received any prior systemic antineoplastic therapy in the advanced 
setting (NSCLC stage IIIB or IV). However, patients who have failed no more than 1 cycle of 
systemic antineoplastic therapy in the advanced setting are allowed. Note: Neo-adjuvant and 
adjuvant systemic therapies will be counted as 1 prior line of treatment if relapse occurred 
within 12 months from the end of the neo-adjuvant/adjuvant systemic therapy. 
The EGFR mutation status for the Phase II part will be determined by local laboratory testing 
as specified in the inclusion criteria below.  
Treatment failure is defined as documented disease progression or intolerance to treatment. 
Patients enrolled in the study are not permitted to participate in additional parallel 
investigational drug or device studies. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
For all patients (unless otherwise specified): 
1. Written informed consent must be obtained prior to any screening procedures 
2. Patient (male or female) ≥ 18 years of age 
[For Japan only: written consent is necessary both from the patient and his/her legal 
representative if he/she is under the age of 20 years.] 
3. Patients must have histologically or cytologically confirmed locally advanced (stage IIIB 
not amenable to definitive multi-modality therapy including surgery) or metastatic (stage 
IV) EGFR mutant NSCLC. 
4. Patients with controlled brain metastases may participate in the trial. If applicable, they must 
complete any planned radiation therapy and/or surgery >2 weeks prior to the first dose of 
study treatment and remain asymptomatic. Patients on steroids must have been on a stable 
low dose for 2 weeks prior to initiating study treatment. Patients must be neurologically 
stable, having no new neurologic deficits on clinical examination, and no new findings on 
central nervous system imaging. 
5. ECOG performance status: Phase I part: 0, 1, or 2; Phase II part: 0 or 1 


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6. Presence of at least one measurable lesion according to RECIST 1.1 per Investigator 
assessment. A previously irradiated site lesion may be counted as a target lesion only if 
there is clear sign of progression since the irradiation. (see Section 14.1 Appendix 1) 
7. Patients must be screened for HBV. Patients who are either HBsAg positive or HBV-DNA 
positive must be willing and able to take antiviral therapy 1-2 weeks prior to 1st dose of 
EGF816 treatment and continue on antiviral therapy for at least 4 weeks after the last dose 
of EGF816. Additional management of the patients would be provided by a physician with 
expertise in management of HBV, if needed. 
8. Patients must be screened for HCV. Patients must have negative hepatitis C antibody (HCV-
Ab) or positive HCV-Ab but undetectable level of HCV-RNA. Note: patients with 
detectable HCV-RNA are not eligible for the study. 
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests 
and other study procedures 
10. Requirements of EGFR mutation status and prior lines of treatment for Phase I 
patients: 
Patients must have locally advanced or metastatic NSCLC and meet one of the following 
criteria: 
• Treatment naive patients, who have locally advanced or metastatic NSCLC with EGFR 
activating mutation (e.g., L858R and/or ex19del), have not received any systemic 
antineoplastic therapy for advanced NSCLC and are eligible to receive EGFR TKI 
treatment. Note: patients who have received only one cycle of chemotherapy in the 
advanced setting are allowed. 
• Patients who have locally advanced or metastatic NSCLC with EGFR activating 
mutation AND an acquired T790M mutation (e.g., L858R and/or ex19del, T790M+) 
following progression on prior treatment with a 1st-generation EGFR TKI (e.g., 
erlotinib, gefitinib or icotinib) or 2nd-generation EGFR TKI (e.g., afatinib or 
dacomitinib). These patients may not have received more than 3 prior lines of 
antineoplastic therapy, including EGFR TKI, and may not have received any agent 
targeting EGFR T790M mutation (i.e. 3rd-generation EGFR TKI). EGFR mutation 
testing must be performed after progression on EGFR TKI. 
• Patients who have locally advanced or metastatic NSCLC with a “de novo” T790M 
mutation (i.e. no prior treatment with any agent known to inhibit EGFR including 
EGFR TKI). These patients may not have received more than 3 prior lines of 
antineoplastic therapy, and may not have received any prior agent known to inhibit 
EGFR, including EGFR TKIs. 
• Patients who have locally advanced or metastatic NSCLC harboring EGFR exon 20 
insertion or deletion.  These patients may not have received more than 3 prior lines of 
antineoplastic therapy, including EGFR TKIs. 
• Patients who have locally advanced or metastatic NSCLC with EGFR activating 
mutation AND without an acquired T790M mutation (e.g., L858R and/or ex19del, 
T790M-) following progression on a 1st-generation EGFR TKI (e.g., erlotinib, gefitinib 
or icotinib) or 2nd-generation EGFR TKI (e.g., afatinib or dacomitinib). These patients 
may not have received more than 3 prior lines of antineoplastic therapy, including 
EGFR TKIs, and may not have received any agent targeting EGFR T790M (i.e. 3rd-


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generation EGFR TKI). EGFR mutation testing must be performed after progression 
on EGFR TKI. 
• Patients who have locally advanced or metastatic NSCLC with EGFR activating 
mutation and an acquired T790M mutation (e.g., L858R or ex19del, T790M+) 
following progression on a prior treatment with a 1st/2nd-generation EGFR TKI, and 
have progressed on or are intolerant to a 3rd-generation EGFR TKI (e.g., AZD9291, 
CO-1686, or ASP8273).  These patients may not have received more than 3 prior lines 
of antineoplastic therapy, including EGFR TKIs. A laboratory report demonstrating 
evidence of EGFR T790M mutation in the tumor prior to treatment with a 3rd 
generation EGFR TKI must be available in the source documents. 
11. Requirements of EGFR mutation status and prior lines of treatment for Phase II 
patients: 
Patients must have advanced NSCLC with locally documented EGFR mutation L858R 
and/or ex19del (or other rare activating mutations that confer sensitivity to first and second 
generation EGFR inhibitors (e.g. L861Q, G719A/S/C, S768I)), and must be naïve from any 
systemic antineoplastic therapy in the advanced setting. Patients who have failed no more 
than 1 cycle of systemic antineoplastic therapy in the advanced setting are allowed. 
Treatment failure is defined as documented disease progression or intolerance to treatment. 
Note: Neo-adjuvant and adjuvant systemic therapies will be counted as 1 prior line of 
treatment if relapse occurred within 12 months from the end of the neo-adjuvant/adjuvant 
systemic therapy. 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
For All patients (unless otherwise specified): 
1. Patients with a history or presence of interstitial lung disease or interstitial pneumonitis, 
including clinically significant radiation pneumonitis (i.e. affecting activities of daily living 
or requiring therapeutic intervention) 
2. Patients with unstable brain metastases  
3. Presence or history of another malignancy 
Exception: Patients who have been disease-free for 3 years, or patients with a history of 
adequately treated in-situ carcinoma of the uterine cervix, basal or squamous cell carcinoma, 
non-melanomatous cancer of skin, history of stage IA melanoma that has been cured, are 
eligible. 
4. Undergone a bone marrow or solid organ transplant 
5. Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not 
mandatory) 
6. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at 
the time of study entry except for control of brain metastases, topical applications, inhaled 
sprays, eye drops or local injections 
7. Patients with clinically significant, uncontrolled heart disease, such as:  
• Unstable angina within 6 months prior to screening 
• Myocardial infarction within 6 months prior to screening 


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• Patients with a history of documented congestive heart failure (New York Heart 
Association functional classification III-IV) 
• Patients with uncontrolled hypertension defined as a Systolic Blood Pressure (SBP) ≥ 
160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-
hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is 
allowed prior to screening 
• Ventricular arrhythmias 
• Supraventricular and nodal arrhythmias not controlled with medication 
• Other cardiac arrhythmia not controlled with medication 
• Patients with a history of congenital long QT syndrome, history of Torsade de Pointes or 
patients with corrected QT (QTc) >470 msec using Fridericia correction (QTcF) on the 
screening ECG (using the mean QTcF value from triplicate ECGs) according to 
Investigator assessment  
8. Patients who have received thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting 
the study treatment or patients who have not recovered from radiotherapy-related toxicities. 
For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), 
radiotherapy ≤ 2 weeks prior to starting the study treatment or patients who have not 
recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 
weeks prior to starting study treatment 
9. Patients who have had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) 
within 4 weeks prior (2 weeks for resection of brain metastases) to starting study drug or 
who have not recovered from side effects of such procedure. Video-assisted thoracic surgery 
(VATS) and mediastinoscopy will not be counted as major surgery and patients can be 
enrolled in the study ≥1 week after the procedure. 
10. Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures. Any severe, acute, or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study treatment 
administration or that may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for the study 
11. Prior therapies 
• Patients who have been treated with chemotherapy or biologic therapy or other 
investigational agent ≤ 4 weeks prior to the first dose of study treatment 
• Unresolved toxicity greater than CTCAE grade 1 from prior anticancer therapy or 
radiotherapy (excluding neurotoxicity, alopecia, lymphopenia) 
• Note: exceptions to the above are possible, on a case by case basis, following discussion 
and mutual agreement between investigator and Novartis (applicable to the Phase I 
part only). 
12. Patients who have out of range laboratory values defined as 
• Absolute Neutrophil Count (ANC) <1.5 x 109/L (1.5 x 103/µL) 
• Hemoglobin (Hgb) <9 g/dL (90 g/L) 
• Platelets <75 x 109/L (75 x 103/µL) 


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• Total bilirubin >1.5 x upper limit of normal (ULN). For patients with Gilbert’s 
syndrome total bilirubin >3.0 x ULN 
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 x ULN 
for patients without hepatic metastasis 
• AST and/or ALT >5 x ULN for patients with hepatic metastasis 
• Alkaline phosphatase (ALP) >5 x ULN 
• Measured or calculated creatinine clearance <45 ml/min (0.75 mL/sec) using 
Cockcroft-Gault formula 
13. Patients who have the following laboratory values outside of the laboratory normal limits 
or cannot be corrected to within normal limits with supplements during screening: 
• Potassium 
• Magnesium 
• Phosphorus 
• Total calcium (corrected for serum albumin) 
14. Patients who are receiving treatment with medications that are known to be strong inhibitors 
or inducers of CYP3A4/5 and cannot be discontinued 1 week prior to the start of EGF816 
treatment and for the duration of the study.  
15. Participation in a prior investigational study within 4 weeks or within 5 half-lives of the 
investigational product, whichever is longer, prior to first dose of study treatment 
Note: exceptions to the above are possible, on a case by case basis, following discussion 
and mutual agreement between investigator and Novartis (applicable to the Phase I part 
only). 
16. Patients who have impairment of GI function or GI disease that may significantly alter the 
absorption of EGF816 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or 
malabsorption syndrome) 
17. Patients who are receiving treatment with any enzyme-inducing anticonvulsant that cannot 
be discontinued at least 1 week before first dose of study treatment, and for the duration of 
the study. Patients on non-enzyme-inducing anticonvulsants are eligible 
18. Pregnant or nursing (lactating) women  
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
the study and for 3 months after stopping the study treatment. Highly effective 
contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptomthermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment 
• Male Partner: male sterilization (at least 6 months prior to screening). For female 
subjects on the study the vasectomized male partner should be the sole partner for that 
subject. 


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• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
• In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of childbearing potential. 
20. Sexually active males unless they use a condom during intercourse while taking drug and 
for 3 months after stopping treatment; men should not father a child in this period. A condom 
is required to be used also by vasectomized men as well as during intercourse with a male 
partner in order to prevent delivery of the drug via seminal fluid. 
6 
Treatment 
6.1 
Study treatment 
The study treatment is EGF816. 
6.1.1 
Dosing regimen 
EGF816 will be administered orally once per day on a continuous dosing schedule. The starting 
dose for the Phase I part first cohort of patients will be 75 mg QD capsule.  
For the Phase II part, patients will be treated at the RP2D (150 mg QD) declared on 30-Aug-
2016 during Phase I part of the study.  
From protocol amendment # 03 dated 21 Aug 2014, an immediate release film-coated tablet 
was introduced during the dose-escalation phase I and patients were switched from capsules to 
tablets based on tablets stock availability. As of 07-Mar-2017, 44 patients from Phase I part 
were ongoing and were receiving capsule or tablet formulations.  
 
Upon the implementation of  protocol amendment # 07 dated 11-March-2020, all patients 
receiving tablets will begin to receive capsules, once the capsule formulation is released and 
available for dispensation, and will no longer receive tablets. 
The dose strength of both capsules and tablets can be found in Table 6-1. 
Table 6-1 
Dose and treatment schedule 
Study treatment 
Pharmaceutical form and 
route of administration 
Strength 
Frequency and/or 
Regimen 
EGF816 
Capsule for oral use 
25 mg, 50 mg, 100 mg  
Daily 
EGF816 
Tablet for oral use 
25 mg, 50 mg, 200 mg* 
Daily 


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Study treatment 
Pharmaceutical form and 
route of administration 
Strength 
Frequency and/or 
Regimen 
*200 mg Tablet formulation will be supplied to patients from Phase I and cannot be provided to 
patients in Phase II (RP2D is 150 mg QD) 
EGF816 (either as capsule or tablet) should be taken as follows: 
• Patients should be instructed to take their dose at approximately the same time of day. 
• On days when blood for PK samples need to be collected, the patient should take the dose 
during the clinic visit after the pre-dose PK samples and prior to the post-dose PK samples, 
when instructed by the site staff. 
• Each dose should be taken with a glass of water and swallowed over a short period of time. 
• Patients should be instructed to swallow capsules or tablets whole and not to chew or open 
them. 
• Since EGF816 is preliminary BCS class 1 (Section 1.2.1.1.1), EGF816 can be taken with or 
without food. On days when blood PK samples are collected, the time of the meal before 
and after the dose need to be recorded on the eCRF. 
• Grapefruit or grapefruit juice, seville orange (and juice), pummelos, pomegranate (and juice) 
star citrus fruits and hybrids of these mentioned fruits must be avoided during the treatment 
period of the study. 
• If vomiting occurs, no attempt should be made to replace the vomited dose before the next 
scheduled dose. 
• On days of PK/PD sampling, every effort must be made to capture the time of any vomiting 
within 4 hours of drug administration. 
• If the patient forgets to take his/her daily dose, then he/she should take EGF816 within 6 
hours after the scheduled time. If more than 6 hours have passed, then that day’s dose should 
be omitted and the patient should continue treatment with the next scheduled dose. 
• Patients should inform the investigational site staff of any missed or delayed doses. 
• During the whole duration of the treatment with EGF816, the patient is recommended to 
use precautionary measures against sunlight exposure (refer to Section 6.3.3 and Table 6-9) 
6.1.2 
Treatment duration 
Treatment with EGF816 will continue until: 
• Adverse event (based on the recommendations in Table 6-5) 
• Death 
• Progressive disease 
• Pregnancy 
• Protocol deviation 
• Study terminated by sponsor 
• Technical problems 
• Lost to follow-up 
• Physician decision 
• Subject/guardian decision 


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Patients who permanently discontinue the study treatment during the treatment phase will 
continue tumor assessments every 8 weeks until: 
• the patient has disease progression or 
• the study is terminated by the sponsor, or 
• withdrawal of consent for further assessments, or 
• the patient is lost to follow-up or  
• the patient dies.  
Patient may continue treatment with the study treatment until patient experiences unacceptable 
toxicity, disease progression and/or treatment is discontinued at the discretion of the 
investigator or withdrawal of consent. 
6.1.2.1 
Treatment beyond disease progression  
Patients may derive benefit from continuing study treatment despite initial evidence of disease 
progression therefore patients treated with EGF816 will be permitted to continue study 
treatment beyond initial disease progression as per RECIST 1.1 criteria provided they meet the 
following criteria: 
• Benefit assessed by the investigator (s) 
• No rapid disease progression 
• Tolerance of study treatment 
The judgment of the investigator should be documented in the Case Report Form as an 
Investigator comment and the continued evidence of clinical benefit should be updated on a 
regular basis.In addition, treatment beyond disease progression should not jeopardize critical 
interventions to treat/prevent severe complications, or prevent patients from receiving adequate 
care.  
Patients who meet above criteria and continue treatment beyond initial disease progression will 
continue all study procedures as outlined in Section 7. In case of clinical deterioration or 
suspicion of disease progression, a follow-up imaging assessment should be performed 
promptly rather than waiting for the next scheduled assessment. Patients with evidence of 
further disease progression on an imaging assessment or who are no longer deriving clinical 
benefit will be discontinued. 
6.2 
Dose-escalation guidelines  
6.2.1 
Starting dose rationale 
The starting dose for EGF816, for patients enrolled in the Phase I part of the trial, is set at 75 
mg administered orally on a continuous, once daily schedule. The selection of the starting dose 
follows the ICH S9 guidelines for choosing a starting dose for a first-in-human trial conducted 
in patients with cancer. 
For selection of the starting dose in the first in human clinical study, standard criteria for an 
anticancer drug were applied. In the 4-week GLP rat study, the 75 mg/kg dose was considered 
to approximate the severely toxic dose in 10% of animal (STD10). Expressing 75 mg/kg in the 
rat based on the body surface area is equivalent to 450 mg/m2. Applying a safety factor of 10, 
the starting dose in humans would be 1/10th of the STD10 in rats or 1/10th of 450 mg/m2 = 45.0 


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mg/m2. Since 1/10th of the STD10 in rat is below the highest non-severely toxic dose (HNSTD) 
in the dog (20 mg/kg or 400 mg/m2), this dose is expected to be well-tolerated by the dog. 
Therefore, the rat is considered an appropriate species for evaluating EGF816 toxicity and the 
rat STD10 was used as the basis for the starting dose calculation. Thus, based on an average 
body surface area (BSA) of 1.73m2, the recommended safe starting dose of EGF816 is 77.8 
mg/patient (~75 mg/patient/day). 
Formulation change from capsule to tablet (based on protocol amendment 03) 
An immediate release film-coated tablet will be introduced during the dose-escalation phase. 
EGF816 has a high solubility across the pH range of 1 to 6.8. In a Caco-2 cell trans-well study, 
EGF816 showed high permeability at the concentrations relevant to calculated intestinal lumen 
concentrations. In addition, EGF816 was almost completely absorbed as demonstrated in the 
rat radiolabel ADME study. The oral bioavailability of 55% observed in rat was due to the first-
pass metabolism. Therefore, based on available data EGF816 is considered a preliminary BCS 
class 1 compound. The dissolution profile of the capsule formulation was categorized as very 
rapidly dissolving with > 85% of drug in solution within 15 minutes at pH of 1. The dissolution 
profile of the tablet formulation was comparable or slightly slower than those for capsule. 
Therefore, the exposure of EGF816 following the same dose of tablet administration is 
predicted to be comparable or lower than that for the capsule formulation. 
Based on this rationale, EGF816 tablet will be introduced in this study at the highest dose level 
investigated with EGF816 capsule that has been evaluated in at least 3 patients and shown to 
satisfy the EWOC principle. In the situation that MTD/RP2D has been reached for capsule 
formulation, the EGF816 tablet will be introduced at the highest previously tested dose that is 
lower than the capsule MTD/RP2D, and the MTD/RP2D with the tablet formulation will be 
established separately. Dose-escalation for the tablet formulation will continue following the 
procedure specified in Section 6.2.3.  
EGF816 will be supplied by Novartis.  EGF816 25 mg, 50 mg, 100 mg capsules and 25 mg, 50 
mg and 200 mg tablets will be packaged in high-density polyethylene (HDPE) bottles.  Similar 
exposures were observed in the phase I part between capsules and tablets at 150 mg QD (refer 
to latest Investigator’s Brochure Edition). 
6.2.2 
Provisional dose levels for Phase I part (dose-escalation) 
Table 6-2 describes the starting dose and the dose levels that may be evaluated during this trial. 
Dose escalation will continue until MTD is reached and/or RP2D is determined. At all decision 
time points, the adaptive BLRM permits alterations in the dose increments based on the 
observed DLTs. 


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Table 6-2 
Provisional dose levels for Phase I part (dose-escalation) 
Dose level 
Proposed daily dose* 
Increment from previous dose 
-1** 
50 mg 
- 
1 (starting dose) 
75 mg 
(starting dose) 
2 
100 mg 
33% 
3 
150 mg 
50% 
4 
300 mg 
100% 
5 
450 mg 
50% 
6 
600 mg 
33% 
7 
800 mg 
33% 
8 
1000 mg 
25% 
*It is possible for additional and/or intermediate dose levels to be added during the course of the 
study. Dose levels may also be skipped if the safety data and BLRM analyses support a higher 
increase limited to at most 100% increase in dose level (e.g. a move from 300 mg to 600 mg). 
Cohorts may be added at any time (either during Phase I and/or during Phase II part) and at any 
dose level below either the estimated MTD or the RP2D for which safety data exists in order to 
better understand safety, PK or PD 
**Dose level −1 represents a treatment dose for patients requiring a dose reduction from the starting 
dose level.  
6.2.3 
Guidance for dose escalation and determination of MTD/RP2D 
6.2.3.1 
Definition and estimation of MTD/RP2D 
The MTD is the highest drug dosage that is unlikely (<25% posterior probability) to cause DLT 
in more than 33% of the treated patients in the first cycle of EGF816 treatment. 
A two-parameter BLRM employing the EWOC principle (Neuenschwander 2008; Babb 1998) 
will be used during the dose escalation to guide dose level selection and to estimate the MTD. 
Dose escalation will continue until the MTD is reached or until Novartis and Investigators reach 
consensus that, based on a review of the totality of the clinical data (e.g., DLT, lower grade AE, 
PK,
, preliminary antitumor activity etc.) there is no benefit to continue escalation and a 
lower RP2D is identified (e.g., when PK modeling predicts that further escalation will not result 
in higher drug exposures). 
Estimation of the MTD during the Phase I dose-escalation part of the study will be based upon 
the estimation of the probability of DLT in cycle 1 in patients in the Dose-Determining Set 
(DDS). The corresponding statistical methodology is described in Section 10.4.2. 
MTD/RP2D for each drug formulation or dosing schedule may be established when appropriate. 
6.2.3.2 
Dose cohort modification for Phase I part (dose-escalation) 
For the purposes of dose-escalation decisions, each cohort will consist of 1 to 6 newly enrolled 
evaluable patients who will be treated at the specified dose level. The first cohort will be treated 
with the starting dose of 75 mg QD. When two patients (who may be in different cohorts) have 
experienced a toxicity of CTCAE grade 2 for which relationship to study drug cannot be ruled 
out; or when any single patient experiences a DLT or AE of CTCAE grade 3 or greater during 
Cycle 1, the cohort size will be changed to between 3 and 6 evaluable patients for the current 
and subsequent cohorts.  


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Patients must complete a minimum of 1 cycle of treatment with the minimum safety evaluation 
and drug exposure or have had a DLT within the first cycle of treatment to be considered 
evaluable for dose-escalation decisions. Dose-escalation decisions will occur when the cohort 
of patients has met these criteria. 
Dose-escalation decisions will be made by Investigators and Novartis study personnel. 
Decisions will be based on a synthesis of all relevant data available from all dose levels 
evaluated in the ongoing study including safety information (DLTs, all CTCAE Grade ≥ 2 
toxicity data during Cycle 1), PK, and PD data from evaluable patients. The recommended dose 
for the next cohort of subjects will be guided by the BLRM with EWOC principle (Section 2.2). 
The adaptive Bayesian methodology provides an estimate of all dose levels of EGF816 that do 
not exceed the MTD and incorporates all DLT information at all dose levels for this estimation. 
In general, the next dose will have the highest chance that the DLT rate will fall in the target 
interval [16-33%) and will always satisfy the EWOC principle (Section 10.4.2). In all cases, the 
dose for the next cohort will not exceed a 100% increase from the previous dose. Smaller 
increases in dose may be recommended by the Investigators and Sponsor upon consideration of 
all of the available clinical data. If needed to better define the dose-toxicity relationship 
additional patients may be enrolled to the current dose level, to a preceding dose level, or to an 
intermediate dose level before proceeding with further dose escalation. 
If 2 patients in a previously untested dose level experience a DLT, enrollment to that cohort 
will stop, the BLRM will be updated and the next cohort will be opened at the next lower dose 
level or an intermediate dose level (see Section 14.2 Appendix 2) that satisfies the EWOC 
criteria. However, if 2 patients in a new cohort at a previously tested dose level experience a 
DLT (e.g., a total of 8 patients are treated on this dose level with 2 DLT observed), further 
enrollment to that cohort will stop, the BLRM will be updated with this new information and 
re-evaluation of the available safety, PK, and PD data will occur. By incorporating information 
gained at the preceding dose cohorts, additional patients may be enrolled into the current dose 
cohort only if the dose still meets the EWOC criteria and as agreed by Investigators and Novartis 
personnel. Alternatively, if recruitment to the same cohort may not resume, a new cohort of 
patients may be recruited to a lower dose as agreed by Investigators and Novartis personnel and 
if the BLRM predicts that the risk for this lower dose to exceed the MTD remains below 25% 
(EWOC). Re-escalation may then occur if data in subsequent cohorts supports this (EWOC 
criteria are satisfied) and Investigators and Novartis personnel agree. 
Dose escalation will continue until identification of the MTD or a suitable lower dose for Phase 
II part. This will occur when the following conditions are met: 
1. at least 6 patients have been treated at this dose 
2. this dose satisfies one of the following conditions: 
a. the posterior probability of targeted toxicity at this dose exceeds 50% and is the highest 
among potential doses, or 
b. minimum of 21 patients have already been treated on the trial. 
3. it is the dose recommended for patients, either per the model or by review of all clinical data 
by Novartis and Investigators in a dose-escalation teleconference. 
Note: if significant activity is seen early in the dose escalation, then a recommended dose may 
be identified and the phase II groups may be initiated without determination of the MTD; 
therefore fewer than 21 patients may be required. 


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To better understand the safety, tolerability, PK, PD (paired tumor biopsy) or preliminary 
activity of EGF816, additional cohorts of one to six patients may be enrolled at preceding dose 
levels, or to intermediate dose levels before or while proceeding with further dose escalation. 
If a decision is made to escalate to a higher dose level but one or more additional patient(s) 
treated at the preceding dose level experiences a DLT during the first cycle of treatment, then 
the BLRM will be updated with this new information before any additional patients are enrolled 
at that higher dose level. Subjects ongoing will continue treatment at their assigned dose levels. 
Change of drug formulation: 
By protocol amendment 07, the dose escalation decisions were already made and no additional 
patients were included for BLRM, hence the new change in formulation from tablet to capsule 
are not expected to impact this part of the study.  
Change of schedule:  
In the event of a change in dosing schedule, then a new BLRM would have been set up. This 
new BLRM would have incorporated down-weighted existing dose-escalation data in the prior 
distribution and a starting dose would have been identified at that time. Subsequent dosing 
decisions for the new schedule would have followed the same rules defined within the above 
paragraphs of this section.  
6.2.3.3 
Implementation of dose-escalation decisions 
To implement dose-escalation decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs), the recommendations from the BLRM, 
and the available PK and PD information will all be evaluated by the Investigators and Novartis 
study personnel (including the study physician and statistician) during a dose decision meeting 
by teleconference. Drug administration at the next higher dose level may not proceed until the 
investigator receives written confirmation from Novartis indicating that the results of the 
previous dose level were evaluated and that it is permissible to proceed to a higher dose level. 
6.2.3.4 
Intra-patient dose escalation for Phase I part (dose-escalation) 
Intra-patient dose escalation is not permitted during the first 4 cycles of treatment. After the 4th 
cycle is completed, individual patients may be considered for treatment at a dose of EGF816 
higher than the dose to which they were initially assigned. In order for a patient to be treated at 
a higher dose of EGF816, he or she must have received the lower dose for at least four cycles 
of therapy without a toxicity ≥ CTCAE grade 2 that is at least possibly related to the study drug. 
Moreover, the new, higher dose with which the patient is to be treated must be a dose that has 
completed evaluation in a dose-escalation meeting and that has not exceeded the MTD 
estimated by the BLRM. 
Any further increases after the initial intra-patient dose escalation are subject to the same rules 
as for the initial intra-patient escalation except that the patient must have received a minimum 
of 2 cycles of therapy at the prior current dose before escalation may occur. Consultation with 
Novartis must occur prior to any intra-patient dose-escalation decision. These changes must be 
recorded on the Dosage Administration Record eCRF. 
. 


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6.2.4 
Definitions of dose-limiting toxicities (DLTs) for Phase I part (dose-
escalation) 
A dose-limiting toxicity (DLT) is defined in the Phase I part as an adverse event or abnormal 
laboratory value assessed as unrelated to disease, progressive disease, inter-current illness, or 
concomitant medications that occurs within the first 28 days of treatment with EGF816 and 
meets any of the criteria included in Table 6-3. National Cancer Institute Common Terminology 
Criteria for Adverse events (NCI CTCAE) version 4.03 will be used for all grading. For the 
purpose of dose-escalation decisions, DLTs will be considered and included in the BLRM. 
The investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, 
CTCAE grade ≥ 2 adverse events will be reviewed for all patients at the current dose level. 
Table 6-3 
Criteria for defining dose-limiting toxicities in the Phase I part 
Toxicity 
Any of the following criteria: 
Hematology 
Any hematologic toxicity = grade 3, lasting for >7 consecutive days 
Any hematologic toxicity ≥ grade 4 (of any duration) 
Febrile neutropenia (ANC  1.0 x 109/L or 1000/mm3 with a single 
temperature of >38.3 °C (101 °F) or a sustained temperature of ≥38 °C 
(100.4 °F) for more than one hour. 
Renal 
Serum creatinine ≥ grade 3  (> 3.0 - 6.0 x ULN or >3.0 x baseline) 
Hepatic 
total bilirubin ≥ grade 3 (> 3 x ULN)  
AST or ALT = grade 3 (>5.0-20.0 x ULN) for ≥ 7 day 
AST or ALT = grade 4 (>20.0 x ULN) 
AST or ALT grade 3 and ≥ grade 2 bilirubin 
Neurologic 
Any neurological abnormality or toxicity ≥ grade 2 
Diarrhea 
≥ grade 3 despite optimal treatment 
Skin and 
subcutaneous tissue 
disorders 
≥ grade 3 despite 7 days optimal treatment 
Other adverse events 
Any adverse event ≥ grade 3. 
Single event or multiple occurrences of the same event that lead to a 
dosing delay of > 7 days in cycle 1, may be considered to be DLTs by the 
Investigators and Novartis, even if not CTCAE grade 3 or higher 
CTCAE version 4.03 will be used for all grading.  
Patients may receive supportive care (e.g. transfusion of red blood cells) as per local institutional 
guidelines, as long as causality can clearly be established that supportive care is to treat disease 
related events and not related to investigational agent 
6.3 
Dose modifications for toxicities 
6.3.1 
Dose modification and dose delay 
If a patient requires a dose interruption of  >21 days from the intended day of the next scheduled 
dose due to EGF816-related toxicity, then the patient must be discontinued from the study 
treatment unless described otherwise (see Table 6-7 and Table 6-8 for exception).   


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For patients who do not tolerate the protocol-specified dosing schedule due to drug related 
toxicities, dose interruptions and/or reductions are recommended in order to allow patients to 
continue the study treatment. 
Table 6-5 provides recommendations for dose modification and dose interruption (i.e., 
interruption and re-initiation criteria for EGF816 treatment). 
Each patient is allowed a maximum of 2 dose reductions. In addition, a patient must discontinue 
treatment with EGF816, if after treatment is resumed at a lower dose, the toxicity recurs with 
the same or worse severity. Exceptions can be made on a case by case basis after discussion 
between Novartis Clinical team and Investigator (applicable to the Phase I part). 
All dose interruptions or modifications must be recorded on the Dosage Administration Record 
CRF. 
In case of study treatment interruption, visit schedule should still be followed and assessments 
performed as per Table 7-1 (Phase I part) and Table 7-2 (Phase II part). 
Refer to Table 6-4 for recommended dose reduction steps for the Phase I and Phase II part of 
the study. 
Table 6-4 
Recommended dose reduction steps for the Phase I and II parts  
Dose level 
Reduction from 
initial dose for 
phase I* 
Proposed daily dose for phase II 
0 
0% (current dose) 
RP2D = 150 mg 
-1 
25%-33% reduction 
from current dose 
100 mg  
-2 
50% reduction from 
current dose 
75 mg  
*Note: Since phase I part is exploring dose escalation, the dose reductions in phase I are given as 
percent of initial dose rather than an absolute number because individual patients may be started on 
different initial doses. 
Table 6-5 
Criteria for dose reduction/interruption and re-initiation of EGF816 
treatment for adverse drug reactions 
Dose modifications for EGF816 
Worst toxicity 
CTCAEa Grade (value) during a 
cycle of therapy 
 
Investigations (Hematologic) 
Neutropenia (ANC) 
Grade 1 (ANC <LLN - 1500/mm3) 
Recommendation: maintain dose level 
Grade 2 (ANC <1500 - 1000/mm3) 
Recommendation: maintain dose level 
Grade 3 (ANC <1000 - 500/mm3) 
Recommendation: omit dose  until resolved ≤ Grade 2, then maintain 
dose level  
Grade 4 (ANC <500/mm3) 
Recommendation: omit dose until resolved to ≤ Grade 2, then ↓ 1 dose 
level 


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Dose modifications for EGF816 
Worst toxicity 
CTCAEa Grade (value) during a 
cycle of therapy 
 
Febrile neutropenia (ANC <1.0 x 
109/L, fever ≥ 38.5°C) 
Recommendation: omit dose until resolved, then ↓ 1 dose level 
Thrombocytopenia 
Grade 1 (PLT <LLN - 75,000/mm3) 
May maintain dose level 
Grade 2 (PLT <75,000 - 50,000/mm3) 
May maintain dose level 
Grade 3 (PLT <50,000 - 25,000/mm3) 
Recommendation: omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in >7 days, then ↓ 1 dose level  
Grade 4 (PLT <25,000/mm3) 
Recommendation: omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level 
Investigations (Renal) 
Serum creatinine 
Grade 1 (>ULN - 1.5 x ULN)- 
May maintain dose level 
Grade 2 (>1.5 – 3,.0 x ULN) 
Recommendation: omit dose until resolved to ≤ Grade 1 or baseline, 
then maintain dose level 
Grade 3 (>3.0 – 6.0 x ULN  
Recommendation: omit dose and discontinue patient from study drug 
treatment 
Grade 4 (>6.0 x ULN) 
Recommendation: omit dose and discontinue patient from study drug 
treatment 
Investigations (Hepatic)b 
Isolated Total Bilirubin 
(for patients with Gilbert Syndrome these dose modifications apply to changes in direct [conjugated] bilirubin 
only) 
>ULN -1.5 x ULN 
Recommendation: maintain dose level  
>1.5 - 3.0 x ULN  
 
Recommendation: omit dose. Monitor LFTsc weekly, or more frequently 
if clinically indicated until resolved to ≤ 1.5 x ULN  ,then: 
If resolved in ≤14 days, then maintain dose level 
If resolved in >14 days, then  1 dose level 
>3.0 - 10.0 x ULNg  
Recommendation: omit dose. Monitor LFTsc weekly, or more frequently 
if clinically indicated until resolved to ≤ 1.5 x ULN, then: 
If resolved in ≤14 days, then  1 dose level 
If resolved in 14 days, then discontinue patient from study drug 
treatment. The patient should be monitored weekly (including LFTsb), 
or more frequently if clinically indicated, until total bilirubin has resolved 
to baseline or stabilization over 4 weeks.  
>10.0 x ULNg 
Recommendation: Discontinue patient from study drug treatment 
The patient should be monitored weekly (including LFTsb), or more 
frequently if clinically indicated, until total bilirubin have resolved to 
baseline or stabilized over 4 weeks. 


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Dose modifications for EGF816 
Worst toxicity 
CTCAEa Grade (value) during a 
cycle of therapy 
 
Isolated AST or ALT 
>ULN - 3.0 x ULN 
Recommendation: maintain dose level  
>3.0 - 5.0 x ULN  
For patients with baseline value ≤ 3.0 
x ULN 
Recommendation: maintain dose level.  Repeat LFTsb as soon as 
possible, preferably within 48- 72 hours from awareness of the 
abnormal results; if abnormal lab values are confirmed upon the repeat 
test, then monitor LFTsb weekly, or more frequently if clinically 
indicated, until resolved to ≤ 3.0 x ULN 
For patients with baseline value > 3.0 
-5.0 x ULN 
Maintain dose level  
>5.0 - 10.0 x ULN 
For patients with baseline value ≤ 3.0 
x ULN  
Recommendation: omit dose. Repeat LFTsb as soon as possible, 
preferably within 48-72 hours from awareness of the abnormal results; 
monitor LFTsb weekly, or more frequently if clinically indicated, until 
resolved to ≤ 3.0 x ULN Then  
If resolved in ≤ 14 days, maintain dose level  
If resolved in > 14 days, ↓ 1 dose level  
For patients with baseline value > 3.0 
-5.0 x ULN 
 
Maintain dose level. Repeat LFTsb as soon as possible, preferably 
within 48-72 hours from awareness of the abnormal results; if abnormal 
lab values are confirmed upon the repeat test, then monitor LFTsb, 
weekly, or more frequently if clinically indicated, until resolved to ≤ 5.0 
x ULN  
If AST or ALT > 5 x ULN in patients 
with baseline AST or ALT ≤ 3 x ULN, 
or if AST or ALT > 8 x ULN in patients 
with baseline AST or ALT > 3 x ULN 
but ≤ 5 x ULN 
Immediate testing for viral hepatitis infection or reactivation should be 
performed, see Section 6.3.4. Patients who have HBV-DNA or HCV-
RNA monitoring during the study should be re-tested immediately 
> 10.0 - 20.0 x ULN  
Recommendation: Omit dose. Repeat LFTsb as soon as possible, 
preferably within 48-72 hours from awareness of the abnormal results; 
monitor LFTsb weekly, or more frequently if clinically indicated, until 
resolved to ≤ Grade 1 (or to baseline), then↓ 1 dose level. 
> 20.0 x ULN  
For patients deriving clinical benefit 
upon investigator’s judgement  
Recommendation: omit dose. Repeat LFTsb as soon as possible, 
preferably within 48-72 hours from awareness of the abnormal results; 
monitor LFTsb weekly, or more frequently if clinically indicated, until 
resolved to ≤ 3 x ULN (or ≤ 5 x ULN for patients with baseline value > 
3.0 -5.0 x ULN), then resume treatment at ↓ 1 dose level. Only 1 dose 
reduction is allowed; if reoccurs at > 5 x ULN, discontinue patient from 
study drug treatment 
For all other patients  
 
Discontinue patient from study drug treatment  
Repeat LFTsb as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to baseline or stabilization 


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Dose modifications for EGF816 
Worst toxicity 
CTCAEa Grade (value) during a 
cycle of therapy 
 
over 4 weeks. If AST or ALT>20.0 x ULN immediate testing for viral 
hepatitis infection or reactivation should be performed, see Section 
6.3.4. Patients who have HBV-DNA or HCV-RNA monitoring during the 
study should be re-tested immediately. 
Combinedd elevation of AST or ALT and concurrent Total bilirubinf 
For patients with normal baseline ALT 
or AST or total bilirubin value: 
AST or ALT >3.0xULN combined  with 
total bilirubin >2.0 x ULN without 
evidence of cholestasise  
 
OR  
For patients with elevated baseline 
AST or ALT or  total bilirubin value: 
[AST or ALT>2x baseline AND > 3.0 
xULN] OR [AST or ALT > 8.0 x ULN], 
whichever is lower, combined with 
[total bilirubin >2x baseline AND >2.0 
xULN] 
Mandatory: permanently discontinue study treatment Repeat  as soon 
as possible, preferably within 48 hours from awareness of the abnormal 
results, then with weekly monitoring of LFTsb), or more frequently if 
clinically indicated, until AST, ALT, or bilirubin have resolved to baseline 
or stabilization over 4 weeks. Testing for viral hepatitis infection or 
reactivation should be performed, see Section 6.3.4.  
Investigation (metabolic)h 
Asymptomatic amylase and/or lipase elevation 
Grade 1 (>ULN - 1.5 x ULN) 
May maintain dose level 
Grade 2 (>1.5 - 2.0 x ULN) 
May maintain dose level 
Grade 3 (>2.0 - 5.0 x ULN) 
Recommendation: omit dose until resolved to Grade ≤ 2, then: 
If resolved in ≤ 14 days, then maintain dose level 
If resolved in >14 days, then ↓ 1 dose level 
Grade 4 (>5.0 x ULN) 
Recommendation: Omit dose and discontinue patient from study drug 
treatment 
Note: withhold EGF816 for acute onset of new or progressive unexplained abdominal symptoms, such as severe 
pain or vomiting; perform diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic 
pathology. 
HBV and HCV reactivation 
Refer to Table 6-6, Table 6-7 and Table 6-8, and Section 6.3.4 for details. 
Cardiac Investigations 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 1 (QTc 450-480 ms) 
May maintain dose level 
Grade 2 (QTc 481-500 ms) 
May maintain dose level 
Grade 3 (QTc ≥ 501 ms on at least two 
separate ECGs) 
Recommendation: omit dose until QTC is less than 481 ms and then  
1 dose level 
- Perform an analysis of serum potassium, and if below lower limit of 
normal, correct with supplements to within normal limits.- Repeat ECG 


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Worst toxicity 
CTCAEa Grade (value) during a 
cycle of therapy 
 
in 24 hours, or less, as clinically indicated; continue monitoring as 
clinically indicated until QTc <481 ms 
- Repeat ECGs 7 days after dose resumption for all patients who had 
therapy interrupted due to QTc ≥ 501 ms. 
Grade 4 (QTcF ≥ 501 or > 60 ms 
change from baseline and Torsades 
de pointes or polymorphic ventricular 
tachycardia or signs/symptoms of 
serious arrhythmia) 
Recommendation : discontinue  patient from study treatment 
Bradycardia 
Grade 1 or 2 
 
Recommendation: omit dose until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm 
Evaluate concomitant medications known to cause bradycardia and 
adjust the dose of EGF816  
Grade 3 
Grade 
4 
(in 
patients 
taking 
a 
concomitant medication also known to 
cause bradycardia or a medication 
known to cause hypotension) 
Recommendation: omit dose until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm 
If the concomitant medication can be adjusted or discontinued, resume 
EGF816 at ↓ 1 dose level with frequent monitoring 
Grade 4 (in patients who are not taking 
a concomitant medication also known 
to cause bradycardia or known to 
cause hypotension) 
Recommendation: permanently discontinue EGF816 
Vascular disorders 
Hypertension 
CTCAE Grade 3 
Recommendation: omit dose until resolved ≤ Grade 1, then ↓ 1 dose 
level 
CTCAE Grade 4 
Recommendation: omit dose and discontinue patient from study drug 
treatment 
Gastro intestinal 
Diarrheae 
Grade 1 (despite maximal anti-
diarrheal medication) 
Recommendation: maintain dose level but adjust anti-diarrhea 
treatment 
Grade 2 (despite maximal anti-
diarrheal medication) 
Recommendation: omit dose until resolved to ≤ Grade 1, then maintain 
dose level. 
If diarrhea returns as ≥ Grade 2, then omit dose until resolved to ≤ 
Grade 1, then ↓ 1 dose level 
Grade 3 (despite maximal anti-
diarrheal medication) 
Recommendation: omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level 
Grade 4 (despite maximal anti-
diarrheal medication) 
Recommendation: omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level 
Nausea 
Grade 1 or 2 
Recommendation: maintain dose level but adjust anti-emetic treatment 


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Protocol No. CEGF816X2101 
 
 
Dose modifications for EGF816 
Worst toxicity 
CTCAEa Grade (value) during a 
cycle of therapy 
 
Grade 3 (despite standard anti-
emetics) 
Recommendation: omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level 
Vomiting 
Grade 1 (despite standard anti-
emetics)  
Recommendation: maintain dose level but adjust anti-emetic treatment 
Grade 2 (despite standard anti-
emetics) 
Recommendation: omit dose until resolved to ≤ Grade 1, then maintain 
dose level. 
If vomiting returns as ≥ Grade 2, then suspend dose until resolved to ≤ 
Grade 1, then ↓ 1 dose level 
Grade 3 (despite standard anti-
emetics) 
Recommendation: omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level 
Grade 4 (despite standard anti-
emetics) 
Recommendation: omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level 
Dose modifications apply to patients who experience nausea and/or vomiting despite appropriate antiemetic 
medication. This medication should be started at the first sign of nausea and/or vomiting. 
Skin and subcutaneous tissue disorders 
Rash/photosensitivity 
Refer to Table 6-9, Table 6-10 , and Table 6-11 for management and dose modification for rash/skin toxicities 
Pneumonitis/Interstitial lung disease 
Refer to Table 6-12 for management and dose modification for non-infectious pneumonitis/interstitial lung 
disease 
Fatigue/ Asthenia (General disorders and administration site conditions) 
Grade 1 or 2 
May maintain dose level 
Grade 3 
Recommendation: omit dose until resolved to ≤ grade 1, then : 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then↓ 1 dose level 
Metabolic 
Any Grade hypophosphatemia 
Treatment with phosphate supplements as clinically indicated and 
maintain dose level 
Persistent hyperglycemia (glucose > 
250 mg/dL) despite optimal anti-
hyperglycemic therapy 
Omit dose until hyperglycemia is adequately controlled then resume 
EGF816 at ↓ 1 dose level 
If adequate hyperglycemic control cannot be achieved with optimal 
medical management permanently discontinue patient from EGF816 
Other adverse events 
Grade 1 or 2 
May maintain dose level 
Grade 3 
Recommendation: omit dose until resolved to ≤ grade 1, then↓ 1 dose 
level 
Grade 4 
Recommendation: omit dose and then discontinue from study 
treatment.  


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Protocol No. CEGF816X2101 
 
 
Dose modifications for EGF816 
Worst toxicity 
CTCAEa Grade (value) during a 
cycle of therapy 
 
Note:  
Recommendation: Omit dose for ≥ grade 3 vomiting or grade 3 nausea 
only if the vomiting or nausea cannot be controlled with optimal 
antiemetic (as per local practice) 
All dose modifications should be based on the worst preceding toxicity. 
a Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 
b If Grade 3 or 4 hyper-bilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis as 
the etiology has been ruled out as per institutional guidelines (e.g., Review of peripheral blood smear and 
haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion of the investigator. 
c LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin >2.0 x ULN), alkaline phosphatase 
(fractionated if alkaline phosphatase > 2.0 x ULN) and GGT. For isolated elevations of any grade of alkaline 
phosphatase and/or gamma-glutamyl transpeptidase (GGT), maintain dose level. 
d “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold 
e “Cholestasis” defined as: ALP elevation  (>2xULN and R value< 2) in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. 
It  denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic or hepatocellular liver injury 
f If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter).  After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose 
or at one dose lower if meeting a criterion for dose reduction 
g Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and haptoglobin 
determination), then ↓ 1 dose level and continue treatment at the discretion of the investigator. 
h A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 1 
week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase. If asymptomatic Grade 2 elevations of 
lipase and/or amylase occur again at the reduced dose, patients will be discontinued permanently from study 
treatment. 
iAntidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea.  
6.3.2 
Guidelines for screening, monitoring and management of HBV / HCV 
reactivation 
HBV screening tests, on study monitoring, and management of HBV reactivation 
1. All patients must be screened with HBV serologic markers: HBsAg, HBsAb, and HBcAb. 
2. If HBsAg and/or HBcAb are positive, test for HBV-DNA.  
3. Refer to Table 6-6 for actions to be taken based on screening HBV results. 
4. If a patient is HBsAg positive or HBV-DNA positive BUT is not on antiviral therapy:  
a. Consult a physician with expertise in managing HBV  


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b. Initiate antiviral therapy with entecavir 0.5mg QD 1-2 weeks prior to 1st dose of 
EGF816 treatment. Note: ongoing patients prior to initiation of Amendment 5 follow 
the Urgent Safety Measure. 
c. If a patient cannot take entecavir or if entecavir is not available at your institution, 
contact Novartis to select an appropriate antiviral therapy.  
d. If antiviral therapy cannot be given, the patient is not eligible for EGF816 dosing.  
e. During the study, monitor HBV-DNA every 4 weeks (or more frequently if clinically 
indicated). (Refer to Table 6-7 if there is evidence of viral reactivation on study) 
f. Antiviral therapy should continue for at least 4 weeks after the last dose of EGF816. 
5. Patients who are HBsAg positive or HBV-DNA positive at screening and already have been 
receiving antiviral therapy are eligible provided the patient remains on antiviral treatment.   
a. Identify a consulting physician with expertise in managing HBV who can provide 
treatment guidance, if required, while the patient is on study.  
b. HBV-DNA should be monitored every 4 weeks (or more frequently if clinically 
indicated). 
c. Antiviral therapy should continue for at least 4 weeks after the last dose of EGF816.  
6. Refer to Table 6-7 for guidelines of management for HBV reactivation.  
Table 6-6 
Actions to be taken based on hepatitis B results screening 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and 
no 
prior HBV 
vaccination 
- 
or 
+ 
with 
prior 
HBV 
vaccination 
-  
or + with 
prior HBV 
vaccination 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Required 
actions 
* Consult a physician with expertise in managing 
HBV.  
After the consultation, antiviral therapy should be 
started 1-2 weeks prior to 1st dose of EGF816 
treatment. 
Recommended antiviral therapy is entecavir 
0.5mg QD. Contact Novartis if a patient cannot 
take entecavir or if entecavir is not available at 
your institution. 
Monitor HBV-DNA every 4 weeks (or more 
frequently if clinically indicated). 
Antiviral therapy should continue for at least 4 
weeks after the last dose of EGF816. 
No antiviral therapy. 
Monitor HBV-DNA every 4 
weeks. 
No antiviral 
therapy. 
HBV-DNA 
screening 
not 
required 
unless 
HBsAg 
and/or 
HBcAb are 
positive  


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Table 6-7 
Guidelines for management of HBV reactivation 
HBV reactivation (with or without clinical signs and symptoms)* 
Screening 
test results 
Monitoring test results 
that 
define 
HBV 
reactivation 
Actions to be taken 
Positive 
HBV-DNA 
OR 
Positive 
HBsAg 
Increase of 1 log in HBV-
DNA relative to screening 
HBV-DNA value  
OR 
new 
appearance 
of 
measurable HBV-DNA 
Interrupt EGF816 treatment. Assess patient compliance with 
antiviral therapy. Consult a physician with expertise in managing 
HBV and consider changing antiviral therapy. 
While patient is on antiviral therapy, continue interruption of 
EGF816 administration until resolution to: 
• 
≤ screening HBV-DNA levels and 
• 
≤ grade 1 ALT (or baseline ALT, if > grade 1) if ALT elevation 
was observed 
If resolution occurs within ≤ 21 days EGF816 should be re-
started 
at 
the 
same 
dose 
level 
unless 
dose 
reduction/interruption is indicated due to any other reason. 
Antiviral therapy should continue for at least 4 weeks after the 
last dose of EGF816 and is to be further maintained under the 
surveillance of a physician with expertise in the management 
of hepatitis B in compliance with international (Terrault NA et 
al 2018) and local guidelines. 
If resolution occurs > 21 days Contact Novartis for approval of 
restarting of EGF816. 
• 
If restarting of EGF816 is approved: follow the same guidelines 
as above. 
• 
If restarting of EGF816 is NOT approved: discontinue EGF816 
treatment. Continue antiviral therapy for at least 4 weeks after 
the last dose of EGF816, antiviral treatment is to be further 
maintained under the surveillance of a physician with expertise 
in the management of hepatitis B in compliance with 
international (Terrault NA et al 2018) and local guidelines. 
Monitor HBV-DNA every 4 weeks (or more frequently if 
clinically indicated). 


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HBV reactivation (with or without clinical signs and symptoms)* 
Screening 
test results 
Monitoring test results 
that 
define 
HBV 
reactivation 
Actions to be taken 
Negative 
HBV-DNA 
AND 
Negative 
HBsAg 
New 
appearance 
of 
measurable HBV-DNA  
Interrupt EGF816 treatment. Consult a physician with expertise in 
managing HBV. After the consultation, start antiviral therapy. 
While patient is on antiviral therapy, continue interruption of 
EGF816 administration until resolution to: 
• 
≤ baseline HBV-DNA levels and 
• 
≤ grade 1 ALT (or baseline ALT, if > grade 1) if ALT elevation 
was observed. 
If resolution occurs within ≤ 21 days EGF816 should be re-
started 
at 
the 
same 
dose 
level 
unless 
dose 
reduction/interruption is indicated due to any other reason. 
Antiviral therapy should continue for at least 4 weeks after the 
last dose of EGF816 and is to be further maintained under the 
surveillance of a physician with expertise in the management 
of hepatitis B in compliance with international (Terrault NA et 
al 2018) and local guidelines. 
If resolution occurs > 21 days Contact Novartis for approval of 
restarting of EGF816. 
• 
If restarting of EGF816 is approved: follow the same guidelines 
as above.  
• 
If restarting of EGF816 is NOT approved: discontinue EGF816 
treatment. Continue antiviral therapy for at least 4 weeks after 
the last dose of EGF816. 
Monitor HBV-DNA every 4 weeks (or more frequently if 
clinically indicated). 
* All reactivations of HBV are to be recorded as serious adverse event (SAE). Date of viral reactivation is the 
date on which the defined lab results for reactivation were met (e.g. for a patient who was HBV-DNA positive on 
01-Jan-2015 and whose ALT reached > 5 × ULN on 01-Apr-2015, the date of viral reactivation is 01-Jan-2015). 
HCV screening tests, on study monitoring, and management of HCV 
reactivation  
1. Screen all new patients for HCV-Ab. If HCV-Ab is detected then check HCV-RNA.   
2. Only patients with negative HCV-Ab or with positive HCV-Ab but undetectable level of 
HCV-RNA are eligible to be dosed with EGF816 (assuming all other eligibility criteria are 
met). Patients with detectable HCV-RNA are not eligible to be enrolled in the study. 
3. The following two categories of patients should be monitored every 4 weeks (or more 
frequently if clinically indicated) with HCV RNA-PCR for HCV reactivation:  
a. Patients with detectable HCV-RNA at screening and were treated until HCV-RNA 
becomes undetectable (only applicable to patients enrolled prior to amendment 5) 
b. Patients with known history of HCV infection and undetectable HCV-RNA at 
screening  
4. Refer to Table 6-8 for definition of HCV reactivation and the management guidelines. 


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Table 6-8 
Guidelines for management of HCV reactivation 
HCV reactivation (with or without clinical signs and symptoms)1 
Screening test results 
Monitoring test results 
that 
define 
HCV 
reactivation 
Action to be taken 
Knowledge 
of 
past 
hepatitis C infection with 
no detectable HCV-RNA 
OR  
Detectable HCV-RNA at 
screening 
and 
was 
treated until HCV-RNA 
becomes undetectable 2 
New 
appearance 
of 
detectable HCV-RNA 
Interrupt EGF816 treatment. Consult a physician with 
expertise in managing HCV. After the consultation, start 
antiviral therapy. 
While patient is on antiviral therapy, continue interruption 
of EGF816 administration until resolution to: 
• 
no detectable HCV-RNA and 
• 
≤ grade 1 ALT (or baseline ALT, if > grade 1) if ALT 
elevation was observed. 
If resolution occurs within ≤ 21 days EGF816 should 
be re-started at the same dose level unless dose 
reduction/interruption is indicated due to any other 
reason.  
If resolution occurs > 21 days Contact Novartis for 
approval of restarting of EGF816. 
• 
If restarting of EGF816 is approved: follow the same 
guidelines as above.  
• 
If restarting of EGF816 is NOT approved: 
permanently discontinue the patient from EGF816 
treatment 
Monitor HCV-RNA every 4 weeks (or more 
frequently if clinically indicated) 
1. All reactivations of HCV are to be recorded as serious adverse event (SAE). Date of viral reactivation is the 
date on which the defined lab results for reactivation were met (e.g., for a patient whose HCV-RNA was 
detectable on 01-Jan-2015 and ALT reached > 5 x ULN on 22-Jan-2015, the date of viral reactivation is 01-
Jan-2015). 
2. Applicable to ongoing patients only 
On study monitoring of liver function test (LFT) for all patients 
LFTs should be monitored for all patients as per protocol, or more frequently if clinically 
indicated. 
At any time during the study, if ALT > 5 x ULN in patients with baseline ALT ≤ 3 x ULN, or 
if ALT > 8 x ULN in patients with baseline ALT > 3 x ULN but ≤ 5 x ULN: immediately 
1. Perform test(s) for viral hepatitis infection or reactivation: all patients should be screened 
with viral hepatitis panel (HAV-Ab-IgM, HBsAg, HBcAb-IgM, and HCV-Ab).  In addition 
a. Patients who have HBV-DNA monitoring during the study should be re-tested for 
HBV-DNA immediately; refer to Table 6-7 for definition and management of HBV 
reactivation. 
b. Patients who have HCV-RNA monitoring during the study should be re-tested for 
HCV-RNA immediately; refer to Table 6-8 for definition and management of HCV 
reactivation. 
2. If any of the above tests indicate: 
a. HBV reactivation: refer to Table 6-7 for management guidelines. 


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b. HCV reactivation: refer to Table 6-8 for management guidelines. 
c. New viral infection: immediately interrupt dosing, consult a physician with expertise 
in managing viral hepatitis and contact Novartis for further discussion. 
3. Perform other relevant tests/procedures as clinically indicated. 
4. Follow the dosing modification for ALT elevation according to guidelines in Table 6-5. 
6.3.3 
Guidelines for the management and dose modification of skin-related 
toxicities 
Rash, particularly maculopapular rash or rash pruritic, is an adverse event frequently observed 
following treatment with EGF816. Patients must be closely monitored for any signs/symptoms 
related to rash/skin toxicities. Recommended guidelines for management and dose modification 
of rash/skin toxicities are provided in Table 6-9 , Table 6-10 , and Table 6-11. 
Table 6-9 
Guidelines for prevention and symptomatic care of rash/skin toxicities 
Type of care 
Action 
Prevention/Prophylaxis 
Starting from Day 1 for all 
patients 
• 
Avoid unnecessary exposure to sunlight/ ultraviolet 
• 
Apply broad-spectrum sunscreen with SPF≥15 at least twice daily 
• 
Use thick, alcohol-free emollient cream (e.g. glycerine and cetomacrogol 
cream) on dry areas of the body at least twice daily 
Symptomatic care* 
• 
Pruritic lesions: cool compresses, topical steroids and oral antihistamine 
therapies 
• 
Desquamation: thick, alcohol-free emollient cream and mild soap 
• 
Paronychia: antiseptic bath and topical antibiotics; if no improvement, 
consult dermatologist 
• 
Infected lesions: appropriate topical or systemic antibiotics 
• 
Avoid exposure to sunlight/ultraviolet 
*Patients who develop rash/skin toxicities should be evaluated by a qualified physician and receive symptomatic 
and supportive care management. 
Table 6-10 
Management and dose modification for maculopapular rash1, 2 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
Macules/papules 
covering 
<10% 
BSA 
• 
Initiate appropriate symptomatic care (Refer 
to Table 6-9) 
• 
Initiate oral antihistamine treatment (e.g. 
levocetirizine 5mg qd, desloratadine 5mg 
qd, or fexofenadine 180 mg qd) maintained 
for 1 week after resolution of Grade 1 rash 
• 
Consider steroid use: 
• 
Low-dose oral steroid (e.g. 
prednisolone 5mg-10mg po qd for 3-5 
days) 
• 
If pruritus with inflammation signs like 
scaling, erythema and infiltration: 
Moderate potency topical steroid (e.g. 
0.1% momentasone or 0.1% 
betamethasone valerate cream) on 
affected areas 
• 
 
• 
Re-assess after 1 week until resolution 
Continue study drug at same dose level 


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CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 2 
Macules/papules 
covering 10-30% 
BSA 
• 
Initiate appropriate symptomatic care (Refer 
to Table 6-9) 
• 
Consult a dermatologist. 
• 
Initiate oral antihistamine treatment (e.g. 
levocetirizine 5mg qd, desloratadine 5mg 
qd, or fexofenadine 180 mg qd) maintained 
for 4 weeks after resolution 
• 
Steroid use: 
• 
consider initiating oral steroids (e.g. 
20mg-40mg po qd for 1-2 weeks) with 
taper 
• 
If pruritus with inflammation signs like 
scaling, erythema and infiltration: Potent or 
ultrapotent topical steroid (e.g. 0.025% 
desoximetasone 
ointment 
or 
0.05% 
clobetasol propionate cream) on affected 
areas 
• 
Re-assess after 1 week 
Continue study drug at same dose level 
If no recovery to Grade ≤ 1 within 2 
weeks, despite appropriate systemic 
treatment as per guidelines, interrupt 
EGF816 for 1 week.  
• 
If recovers to Grade ≤ 1, within 1 
week of dose interruption restart at 
same dose 
• 
If rash does not recover to Grade ≤ 
1 within 1 week of dose interruption, 
restart EGF816 at reduced dose -1 
only after rash has recovered to ≤ 
Grade 13 
Grade ≥3 
Macules/papules 
covering 
>30% 
BSA 
• 
Initiate appropriate symptomatic care (Refer 
to Table 6-9) 
• 
Consult dermatologist 
• 
Initiate oral antihistamine treatment (e.g. 
levocetirizine 5mg qd, desloratadine 5mg 
qd, or fexofenadine 180 mg qd) maintained 
for 4 weeks after resolution 
• 
Steroid Use: 
• 
Mid-dose oral steroid (e.g. 20-40mg po 
qd for 1-2 weeks) with taper  
• 
If pruritus with inflammation signs, (scaling, 
erythema 
and 
infiltration), 
potent 
or 
ultrapotent topical steroid (e.g. 0.025% 
desoximetasone 
ointment 
or 
0.05% 
clobetasol propionate cream) on affected 
areas 
• 
Re-assess every week until resolution 
Continue EGF816 at same dose level 
If no recovery to Grade ≤ 1 within 1 week, 
despite appropriate systemic treatment 
as per guidelines, interrupt for 1 week 
• 
*If recovers to Grade ≤ 1 within 1 
week of dose interruption, restart at 
same dose   
• 
*If rash does not recover to Grade ≤ 
1 within 1 week, restart EGF816 
reduced by 1 dose level only after 
rash has recovered to ≤ Grade 1 
1 Maculopapular rash (group term) includes the following preferred terms: rash erythematous, rash morbilliform, 
rash papular, rash maculo-papular, rash rubelliform, rash scarlatiniform, rash macular.  
2 For all grade 2 and 3 of maculopapular rash, consider skin biopsy for pathologic evaluation. Study drug may be 
resumed although steroids are still ongoing or being tapered. 
3 A maximum of 2 dose reductions is allowed. Patients, who require further dose decrease after 2 dose 
reductions, should be discontinued from study drug. Escalation by one level to previous dose level may be 
considered if no rash is evident after 4 weeks of uninterrupted study drug at the reduced dose level. Re-escalation 
can only be done once. 
* Guidelines to be followed even if EGF816 interrupted earlier 
Table 6-11 
Management and dose modification for other rashes including 
acneiform rash 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• 
Monitor for change in severity and consider 
symptomatic and/or topical treatment (Refer 
to Table 6-9) 
Continue study drug at same dose level 


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CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
• 
Re-assess every 2 weeks 
Grade 2 
• 
Initiate appropriate symptomatic care (Refer 
to Table 6-9)  
• 
Depending on the type of rash, a variety of 
agents can be used including mild to 
moderate strength steroid creams, , topical 
or systemic antibiotics, topical or systemic 
antihistamines. 
• 
Re-assess every 2 weeks 
Continue study drug at same dose level 
• 
If no recovery or worsened within 2 weeks, 
interrupt study drug until rash recovers to ≤ 
Grade 1 
• 
Once rash recovers to ≤ Grade 1, then 
restart study drug at one reduced dose level 
Grade ≥3 
• 
Initiate appropriate symptomatic care (Refer 
to Table 6-9) 
• 
Depending on the type of rash, a variety of 
agents can be used including mild to 
moderate strength steroid creams, low-dose 
oral steroids, etopical or systemic antibiotics, 
topical or systemic antihistamines. 
• 
Consult dermatologist 
• 
Re-assess every 2 weeks 
Interrupt study drug until rash recovers 
to ≤ Grade 1. 
Once rash recovers to ≤ Grade 1, restart study 
drug at one reduced dose level 
• 
If no recovery to ≤ Grade 2 within 3 
weeks, permanently discontinue study 
drug 
• 
Patients who develop more than 1 
episode of Grade ≥3 rash will be 
permanently discontinued from study 
treatment 
*A maximum of 2 dose reductions is allowed. Patients, who require further dose decrease after 2 dose reductions, 
should be discontinued from study drug. Escalation by one level to previous dose level may be considered if no 
rash is evident after 4 weeks of uninterrupted study drug at the reduced dose. Re-escalation can only be done 
once. 
6.3.4 
Guidelines for the management and dose modification of non-
infectious pneumonitis/interstitial lung disease 
Monitor patients for pulmonary symptoms indicative of pneumonitis/ILD. In addition, withhold 
study treatment for acute onset of new or progressive unexplained pulmonary symptoms, such 
as dyspnea, cough and fever and during diagnostic workup for pneumonitis/ILD to exclude 
alternative causes such as, but not limited to infections, lymphangitic carcinomatosis, 
cardiogenic edema, or pulmonary hemorrhage. Permanently discontinue study treatment if the 
diagnosis of ILD is confirmed and initiate appropriate treatment as necessary. 
Recommended guidelines for management of non-infectious pneumonitis/interstitial lung 
disease are provided in Table 6-12 . These general guidelines constitute guidance to the 
Investigator and may be supplemented by discussions with the Medical Monitor representing 
the Sponsor. 


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Table 6-12 
Management of non-infectious pneumonitis / interstitial lung disease 
CTCAE Grade 
Required investigations 
Management of 
pneumonitis 
Action and dose modification 
Grade 1 
Asymptomatic, 
radiographic 
findings only 
• Exclude infectious 
etiology. CT scan (high-
resolution with lung 
windows) recommended, 
with serial imaging to 
monitor for resolution or 
progression- re-image at 
least every 3 weeks 
• Monitor for symptoms 
every 2-3 days - Clinical 
evaluation and laboratory 
work-up for infection 
• Monitoring of oxygenation 
via pulse oximetry 
recommended 
• Consultation of 
pulmonologist 
recommended 
 
No specific therapy 
is required. 
Interrupt study treatment during 
diagnostic workup for 
pneumonitis/ILD. Exclude infections 
and other etiologies. 
If diagnosis of pneumonitis/ILD is 
confirmed, permanently discontinue 
study treatment. In absence of 
diagnosis of pneumonitis/ILD: 
restart study treatment at the same 
dose. If symptoms recur after 
resumption of study treatment, 
permanently discontinue study 
treatment 
Grade 2 
Symptomatic, not 
interfering with 
activity daily 
living (ADL) 
Exclude infectious etiology. 
CT scan (high resolution with 
lung windows). 
• 
Monitor symptoms 
daily, consider 
hospitalization 
• 
Clinical evaluation 
and laboratory work 
up for infection 
• 
Consult 
pulmonologist 
Consider pulmonary function 
testinga. 
. Consider a bronchoscopy 
with biopsy and /or 
bronchoalveolar lavage 
(BAL)c. 
Symptomatic therapy 
including corticosteroids if 
clinically indicated (1 to 2 
mg/kg/day prednisone or 
equivalent as clinically 
indicated)b  
Symptomatic only. 
Consider 
corticosteroidsb if 
symptoms are 
troublesome. 
Interrupt study treatment during 
diagnostic workup for 
pneumonitis/ILD and until 
improvement to ≤ Grade 1. Exclude 
infections and other etiologies. 
If diagnosis of pneumonitis/ILD is 
confirmed, permanently discontinue 
study treatment. In absence of 
diagnosis of pneumonitis/ILD: if 
symptoms resolve to ≤ Grade 1 in ≤ 
7 days restart the study treatment 
at one reduced dose level *. 
If symptoms fail to resolve within 7 
days or recur after resumption of 
study treatment at decreased dose, 
permanently discontinue study 
treatment. 


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CTCAE Grade 
Required investigations 
Management of 
pneumonitis 
Action and dose modification 
Grade 3 
Symptomatic, 
interfering with 
ADL; O2 
indicated 
 
AND 
 
Grade 4 Life-
threatening; 
ventilatory 
support indicated 
CT scan (high resolution with 
lung windows) 
Clinical evaluation and 
laboratory work-up for 
infection 
Consult pulmonologist 
Pulmonary function testinga. 
If < normal, repeat every 8 
weeks until ≥ normal 
Bronchoscopy with biopsy 
and/or BALc if possible 
 
Repeat every cycle until 
return to within normal limits. 
 
Treat with IV 
steroids 
(methylprednisolone 
125 mg) as 
indicated. When 
symptoms improve 
to ≤ Grade 1, a high 
dose oral steroid 
(prednisone 1 to 2 
mg/kg once per day 
or dexamethasone 
4 mg every 4 
hours)b. 
If IV steroids 
followed by high 
dose oral steroids 
does not reduce 
initial symptoms 
within 48 to 72 
hours, consider 
non-corticosteroid 
immunosuppressive 
medication. 
Oxygen therapy as 
indicated. 
Mandatory: permanently 
discontinue study drug. 
 
 
 
 
a PFT (Pulmonary function tests) to include: diffusing capacity corrected for hemoglobin (DLCO); spirometry; 
resting oxygen saturation 
Guideline for significant deterioration in lung function: Decrease in spirometry and/or DLCO of 30% and/or O2 
saturation ≤ 88% at rest on room air. 
b Duration and dose of course of corticosteroids will vary according to circumstances but should be as limited 
as possible. Consider tapering dosage at end. 
c If bronchoscopy is performed, bronchoalveolar lavage (BAL) should be done where possible to exclude 
alveolar hemorrhage, opportunistic infections, cell count + determination lymphocyte CD4/8 count where 
possible. 
6.3.5 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value, must be followed at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary. 
All patients must be followed up for adverse events and serious adverse events for 30 days 
following the last doses of EGF816 as part of the study requirements. 
6.3.5.1 
Follow-up on potential QTcF prolongation 
In case of QTcF >500 ms, (or QTcF prolongation >60 ms from baseline) 
• Assess the quality of the ECG recording and the QT value and repeat if needed 
• Interrupt study treatment 
• Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment. 


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• Review concomitant medication use for other causes for QT prolongation, and for drugs 
with the potential to increase the risk of drug exposure related QT prolongation 
• Check study drug dosing schedule and study treatment compliance 
• Consider collecting a time-matched PK sample, and record time and date of last study 
drugs intake. 
After confirming ECG reading at site, if QTcF > 500 ms 
• Interrupt study treatment  
• Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab 
• If QTcF confirmed > 500 ms: 
• Correct electrolytes, eliminate culprit concomitant treatments, and identify clinical 
conditions that could potentially prolong the QT 
• Consult with a cardiologist (or qualified specialist) 
• Increase cardiac monitoring as clinically indicated, until the QTcF returns to ≤ 480 
ms. 
• After resolution to ≤480 ms, consider re-introducing study treatment at reduced dose, and 
increase ECG monitoring: 
• If QTcF remains ≤500 ms after dose reduction, continue planned ECG monitoring 
during subsequent study treatment 
• If QTcF recurs > 500 ms after dose reduction, recommendation: discontinue patient 
from trial 
6.3.5.2 
Follow up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below: 
• For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN  
• For patients with elevated AST or ALT or TBIL value at baseline: (AST or ALT > 2 x 
baseline AND > 3.0 x ULN) OR (AST or ALT > 8.0 x ULN), combined with (TBIL > 2 x 
baseline AND > 2.0 x ULN)  
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.  
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).  
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 


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history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.  
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.  
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted.  
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is performed 
in the study.  
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented. 
6.3.6 
Anticipated risks and safety concerns of the study drug 
For the Phase I part, appropriate eligibility criteria and specific DLT definitions, as well as 
specific dose modification and stopping rules are included in this protocol. Prophylactic or 
supportive treatment for other expected toxicities, including management of other study-drug 
induced adverse events will be as per institutional guidelines. Refer to preclinical toxicity 
(Section 1.2.1.1.2) and or clinical data found in the [Investigator’s Brochure]. 
6.4 
Concomitant medications 
6.4.1 
Permitted concomitant therapy 
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g., such as anti-emetics, anti-diarrhea) and safety of the patient are allowed. Anticoagulation 
treatment is also allowed if INR has been established within the therapeutic range prior to study 
entry.  PT and PTT ≥ 1.5x ULN are permitted in these cases. 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment. All medications (other than study treatment) and 
significant non-drug therapies (including physical therapy, herbal/natural medications and 
blood transfusions) administered within 28 days prior to the administration of study treatment 
and during the study must be listed on the Prior and Concomitant Medications or the Surgical 
and Medical procedures eCRF. 
After discussion with Novartis, patients who develop progressive disease limited to the bone or 
central nervous system (CNS) may undergo radiotherapy to the bone or CNS and surgical 
resection of CNS metastases, and remain on study.  EGF816 should be held for at least 5 days 
prior to radiotherapy or surgery.  EGF816 may be resumed >3 days after completing 
radiotherapy or surgery if all procedure-related toxicities have resolved to ≤ Grade 1. 


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The exception to this is palliative bone radiation, which is permitted throughout the study. 
However, study treatment should be interrupted on the day of radiotherapy.  
The use of bisphosphonates is allowed regardless of indication provided patients have been on 
stable doses optimally for at least 4 weeks prior to the start of treatment. Patients requiring 
initiation of bisphosphonate treatment during the course of the study should be assessed by 
appropriate image modalities to exclude disease progression; if disease progression is 
documented, the patient should discontinue study treatment.  
No drug-drug interaction is expected between EGF816 and bisphosphonates as the drugs are 
eliminated through different elimination pathways. Bisphosphonates are not inhibitors of 
human CYP450 enzymes involved in the metabolism of EGF816 and do not undergo 
metabolism in vivo. 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
Based on the in vitro studies, EGF816 is primarily metabolized by CYP3A4. Moderate 
inhibitors and inducers of CYP3A4 should be used with caution.  
EGF816 is a P-gp substrate. Co-administration of EGF816 with P-gp inhibitors may increase 
systemic exposure and/or alter tissue uptake of EGF816. EGF816 is a moderate inhibitor of 
BCRP with IC50 value of 4 µM. The exposure of BCRP substrate may increase when co-
administered with EGF816. EGF816 is an inhibitor of the human multidrug and toxin extrusion 
transporter 1 and 2-K (MATE1 and MATE2-K) with an IC50 of 0.70 and 4.6 µM respectively. 
As a result EGF816 has potential to increase the exposure of co-medications whose clearance 
is significantly mediated by MATE. In the absence of data confirming whether such an 
interaction occurs in patients, caution should be exercised when potent P-gp inhibitors and 
MATE or BCRP substrates are concurrently used. 
The patient and the Investigator should be aware of potential signs of overdose of the 
concomitant medication. In the event of suspected toxicity, administration of either EGF816 or 
concomitant drugs should be discontinued according to Investigator judgment. 
Refer to Section 14.3 Appendix 3 for permitted medications that require caution when 
concomitantly used with EGF816. 
6.4.3 
Prohibited concomitant therapy 
Concomitant antineoplastic therapy (including radiotherapy and surgery) or other 
investigational treatment is prohibited except as described in Section 6.4.1. 
EGF816 is primarily metabolized by CYP3A4, therefore strong inhibitors and strong inducers 
of CYP3A4 should not be used concomitantly with EGF816.  
Live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow 
fever, varicella, and TY21a typhoid vaccines) should not be administered while a patient is 
dosed with EGF816 and for 30 days after the last dose of EGF816. 
Refer to Section 14.4 Appendix 4 for a list of prohibited medications. If a patient must use a 
drug in Section 14.4 Appendix 4, the patient must be discontinued from the study. 


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6.5 
Patient numbering, treatment assignment or randomization 
This is a non-randomized trial and Integrated Response Technology (IRT) will only be used for 
patient registration and study medication management in the Phase II part. 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for molecular pre-screening or screening, as applicable and is 
retained as the primary identifier for the patient throughout his/her entire participation in the 
trial. The Subject No. consists of the Center Number (Center No.) (as assigned by Novartis to 
the investigative site) with a sequential patient number suffixed to it, so that each subject is 
numbered uniquely across the entire database. Upon signing the molecular pre-screening or 
screening informed consent form, as applicable, the patient is assigned to the next sequential 
Subject No. available to the investigator through the Oracle Clinical RDC interface. 
For the Phase II part, at the molecular pre-screening visit, the investigator or designated staff 
will contact the Interactive Response Technology (IRT) to provide the requested information 
for patient registration. Once assigned, the Subject No. must not be reused for any other subject 
and the Subject No. for that individual must not be changed, even if the patient is re-screened. 
If the patient fails to start treatment for any reason, the reason will be entered into the Screening 
Disposition page. IRT must be notified within 2 days that the patient was not enrolled. 
6.5.2 
Treatment assignment 
This is a non-randomized trial. For the Phase I part, the assignment of a patient to a particular 
group will be coordinated by the sponsor.  
For the Phase II part, an IRT will be used to track patient enrollment, document key eligibility 
criteria, and track individual assignment of EGF816 drug supplies. The IRT will dispense the 
selected EGF816 dose to each patient participating in this trial. 
For each allocated patient, and prior to dosing, all patients who fulfill all inclusion/exclusion 
criteria will be assigned via IRT an inclusion number. The IRT will also specify medication 
number of  the first bottles of EGF816 study drug to be dispensed to the patient. IRT must be 
notified within 2 days that the patient was not enrolled. 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take 
EGF816 as per protocol. EGF816 will be dispensed to the patient by authorized site personnel 
only. Dose strength and treatment schedule are described in Table 6-1. All dosages prescribed 
to the patient and all dose changes during the study must be recorded on the Dosage 
Administration Record CRF. Study treatment including instructions for administration is 
dispensed by study personnel. Patients will be provided with adequate supply of EGF816. 
6.6.1 
Study drug packaging and labeling 
The study medication packaging has a 2-part label (base plus tear-off label). Immediately before 
dispensing the package to the patient, site personnel will detach the outer part of the label from 
the package and affix it to the source document (Drug Label Form) for that patient’s unique 
patient number. 


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In Phase I, responsible site personnel will add the patient number on the label. 
For the Phase II part, a unique medication number will also be printed on each part of this label. 
Responsible site personnel will identify the study treatment package(s) to dispense to the patient 
by using the IRT and obtaining the medication number(s) for the Phase II part. Site personnel 
will add the patient number on the label.  
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and the medication number but no 
information about the patient. 
6.6.2 
Drug supply and storage 
Study treatment must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the [Investigator’s Brochure]. 
Table 6-13 
Supply and storage of study treatment 
Study treatments 
Supply 
Storage 
EGF816 
Centrally supplied by Novartis 
Refer to study treatment label 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate 
Study treatment destruction at the investigational site will only be permitted if authorized by 
Novartis in a prior agreement and if permitted by local regulations. 


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7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 and Table 7-2 list all of the assessments for the Phase I part and Phase II part, 
respectively, and indicate with an “X”, the visits when they are performed. All data obtained 
from these assessments must be supported in the patient’s source documentation. The tables 
indicate which assessments produce data to be entered into database (D) or remain in source 
documents only (S) (“Category” column). 
No CRF will be used as a source document. 
Visit and schedule windows 
Written informed consent must be obtained before any study specific assessments are 
performed, including those at molecular screening and screening. Screening/baseline 
evaluations (including baseline radiological assessment/s) must be performed ≤ 28 days of 
Cycle 1 Day 1.  
For the Phase I part, laboratory assessments performed as part of the screening evaluations and 
within 72 hours of the first dose of study treatment, are not required to be repeated on the first 
dosing day.  
For the Phase II part, laboratory assessments and height/weight performed as part of the 
screening evaluations and within 7 days of the first dose of the study treatment will not be 
required to be repeated on Cycle 1, Day 1. 
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. All safety assessments (e.g., hematology, chemistry, vitals, etc.) have a +/- 3 days 
window of the due date of the safety assessment. HBV/HCV results should be available prior 
to the first dose of EGF816 treatment. On days when PK is collected the window is only +/- 1 
day. PK sample of C1D1 (Cycle 1, Day 1) must be collected at the same day of first dose.  
Radiological assessments must be performed +/-7 days of the scheduled date of the assessment. 
If an off-schedule imaging assessment is performed, subsequent imaging assessments should 
be performed in accordance with the original imaging schedule. 
If a given visit is out of window, the next visit should be performed with reference to the day 
of the first dose of study treatment in order to get the patient back on schedule. 
All assessments required on Cycle 1, Day 1 must be done prior to the first dose of the study 
treatment unless otherwise specified. The investigator should check the pre-dose laboratory 
results prior to starting treatment. 
Note: Phase I patients will follow the visit schedule outlined in Table 7-1 while Phase II patients 
will follow the visit schedule outlined in Table 7-2. 


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Table 7-1 
Visit evaluation schedule (Phase I Part) 
Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Follow-Up 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
End of study 
treatment (EoT)
30-day Safety 
F/U 
Disease 
progression F/U
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16 
Day 22 
Day 1 
Day 2 
Day 8 
Day 15 
Day 22 
Day 1  
Day 15 
 
 
 
Obtain Molecular 
Pre-screening 
Informed Consent 
(if applicable) 
D 
7.1.1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain Main 
Informed Consent 
D 
7.1.2  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.2.2  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusio
n criteria 
D 
5  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current medical 
conditions at entry 
D 
7.1.2.2  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and 
extent of cancer 
D 
7.1.2.2  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
antineoplastic 
therapies 
D 
7.1.2.2  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
D 
7.1.2.2  
 
X 
Continuously for concomitant medications 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Follow-Up 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
End of study 
treatment (EoT)
30-day Safety 
F/U 
Disease 
progression F/U
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16 
Day 22 
Day 1 
Day 2 
Day 8 
Day 15 
Day 22 
Day 1  
Day 15 
 
 
 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
D 
7.1.2.2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Tumor 
progression status 
D 
7.1.2.2  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
S 
7.2.2.1  
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
Vital signs  
D 
7.2.2.2  
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
Height  
D 
7.2.2.3  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
D 
7.2.2.3  
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
Performance 
status 
D 
7.2.2.4  
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
Laboratory 
assessments 
D 
7.2.2.5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
D 
7.2.2.5.1  
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
Chemistry 
D 
7.2.2.5.2  
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
Coagulation 
D 
7.2.2.5.3  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
D 
7.2.2.5.4  
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
HBV testing 
D 
6.3.3  
7.2.2.5.5 
 
X 
In cases of positive HBV testing, monitor HBV-DNA every 4 weeks, per Table 6-6 and Table 6-7 (or 
more frequently if clinically indicated). 
 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Follow-Up 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
End of study 
treatment (EoT)
30-day Safety 
F/U 
Disease 
progression F/U
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16 
Day 22 
Day 1 
Day 2 
Day 8 
Day 15 
Day 22 
Day 1  
Day 15 
 
 
 
HCV testing 
D 
6.3.3  
7.2.2.5.5  
 
X 
In cases of positive HCV-Ab, monitor HCV-RNA every 4 weeks, per Table 6-8 (or more frequently if 
clinically indicated). 
 
Pregnancy test 
D 
7.2.2.5.6 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
Imaging 
Tumor evaluation 
D 
7.2.1  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xa 
 
Xa 
 
X 
Chest X-raye 
D 
7.2.5.1  
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
ECG 
D 
7.2.2.6.1  
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
D 
8  
SA
E 
only 
Continuously 
X 
 
 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of 
archival tumor 
sample  
D 
7.1.1  
7.2.4  
Xb 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of 
newly obtained 
tumor from 
biopsy/resection 
D 
7.1.1 
7.2.4 
Xb 
Xb 
 
 
 
 
 
 
 
 
 
 
 
Xb 
 
Xb  
 
 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Follow-Up 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
End of study 
treatment (EoT)
30-day Safety 
F/U 
Disease 
progression F/U
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16 
Day 22 
Day 1 
Day 2 
Day 8 
Day 15 
Day 22 
Day 1  
Day 15 
 
 
 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Follow-Up 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
End of study 
treatment (EoT)
30-day Safety 
F/U 
Disease 
progression F/U
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16 
Day 22 
Day 1 
Day 2 
Day 8 
Day 15 
Day 22 
Day 1  
Day 15 
 
 
 
End of Phase 
Disposition 
D 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Safety follow-up 
S 
7.1.5.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Study Drug 
administration  
D 
6.1.1  
 
 
Continuously 
 
 
 
PK sampling  
D 
7.2.3.1  
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
Xd 
 
 
 
 
a.Tumor assessment every 8 weeks from the start of cycle 3 until progression of disease as per Table 7-3; EOT scan not required if previous scan was done ≤ 28 days 
b Refer to Section 7.1.1 and Section 7.2.4. For subsequent cycles, newly obtained samples will be collected at C4D1, C6D1 (optional) and C8D1 (optional) and EOT 
(optional). 
d Cycle 3 and cycle 4 only  
e [For Japan only, refer to Section 7.2.5] [For Japan only, percutaneous oxygen saturation (SpO2) will be measured every time physical examination is performed. In 
addition, SpO2 and vital signs will be measured on Days 2-7 in Cycle 1.] 
* Collect at screening or anytime thereafter 
**Sample will not be collected if a newly obtained tumor sample has already been collected at screening for the purpose of DNA sequencing 
***Mandatory if participating in the Companion Sample Collection Protocol. Refer to Companion Sample Collection Protocol for further information 


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Table 7-2 
Visit evaluation schedule (Phase II part) 
Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post-treatment 
Follow-up Phase 
Survival 
Follow-
up 
Phase 
Molecular 
Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
End of study treatment 
(EOT) Visit (within 7d of 
last dose) 
30-day Safety 
F/U 
Disease progression 
F/U (every 8 wks) 
Study Phase 
Completion 
Survival (every 3 
months) 
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16K 
Day 22 K 
Day 1 
Day 2 
Day 8 K 
Day 15 K 
Day 22 K 
Day 1 
Day 15 K 
Pre-Screening 
Obtain 
Molecular Pre-
screening ICF  
D 
7.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT 
Registration  
D 
6.5.1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
EGFR mutation 
status by local 
testing 
D 
7.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main Screening 
Obtain Main 
ICF 
D 
7.1.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient history 
Demography 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclus
ion criteria 
D 
5.2, 5.3  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
S 
7.1.2.1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant 
medical 
history/current 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post-treatment 
Follow-up Phase 
Survival 
Follow-
up 
Phase 
Molecular 
Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
End of study treatment 
(EOT) Visit (within 7d of 
last dose) 
30-day Safety 
F/U 
Disease progression 
F/U (every 8 wks) 
Study Phase 
Completion 
Survival (every 3 
months) 
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16K 
Day 22 K 
Day 1 
Day 2 
Day 8 K 
Day 15 K 
Day 22 K 
Day 1 
Day 15 K 
medical 
conditions at 
entry 
Diagnosis and 
extent of cancer 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
antineoplastic 
therapies 
(meds, surgery, 
radiation) 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomita
nt medications 
(including OTC 
meds), 
procedures and 
significant non-
drug therapies 
D 
7.1.2.2 
 
X 
Continuously for concomitant medications 
 
Tumor 
progression 
status 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post-treatment 
Follow-up Phase 
Survival 
Follow-
up 
Phase 
Molecular 
Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
End of study treatment 
(EOT) Visit (within 7d of 
last dose) 
30-day Safety 
F/U 
Disease progression 
F/U (every 8 wks) 
Study Phase 
Completion 
Survival (every 3 
months) 
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16K 
Day 22 K 
Day 1 
Day 2 
Day 8 K 
Day 15 K 
Day 22 K 
Day 1 
Day 15 K 
Physical examination 
Complete 
physical 
examination, 
including 
neurological 
exams 
S 
7.2.2.1 
 
X 
Clinically indicated 
 
 
 
 
Targeted 
physical 
examination 
S 
7.2.2.1 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Vital signs  
D 
7.2.2.2 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Height  
D 
7.2.2.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
D 
7.2.2.3 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
ECOG 
Performance 
status 
D 
7.2.2.4 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Chest X-rayc 
D 
7.2.5.1 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Laboratory 
assessments 
D 
7.2.2.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
D 
7.2.2.5.1 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
Chemistry 
D 
7.2.2.5.2 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
Coagulation 
D 
7.2.2.5.3  
 
X 
As clinically indicated 
 
 
 
 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post-treatment 
Follow-up Phase 
Survival 
Follow-
up 
Phase 
Molecular 
Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
End of study treatment 
(EOT) Visit (within 7d of 
last dose) 
30-day Safety 
F/U 
Disease progression 
F/U (every 8 wks) 
Study Phase 
Completion 
Survival (every 3 
months) 
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16K 
Day 22 K 
Day 1 
Day 2 
Day 8 K 
Day 15 K 
Day 22 K 
Day 1 
Day 15 K 
Urinalysis 
D 
7.2.2.5.4  
 
X 
As clinically indicated 
 
 
 
 
HBV testing 
D 
6.3.3  
7.2.2.5.5  
 
X 
In cases of positive HBV testing, monitor HBV-DNA every 4 weeks, per Table 6-66 
and Table 6-7 (or more frequently if clinically indicated). 
 
 
 
HCV testing 
D 
6.3.3  
7.2.2.5.5  
 
X 
In cases of positive HCV-Ab, monitor HCV-RNA every 4 weeks, per Table 6-8 (or 
more frequently if clinically indicated). 
 
 
 
Serum 
pregnancy test  
D 
7.2.2.5.6 
6  
 
X 
(within 
72 hr) 
Xj 
 
X 
 
 
 
 
Urine 
pregnancy test 
D 
7.2.2.5.6  
 
 
 
As clinically indicated 
 
 
 
 
 
Tumor assessments RECIST 1.1 
CT/MRI of 
chest, 
abdomen, 
pelvis 
D 
7.2.1 
 
X 
Treatment period: 
C3D1 and every 8 weeks (±7 days)  
End of treatment (EOT):  
Scans not required if previous CAP scans were performed within ≤28 days)  
Disease Progression Follow Up: 
Every 8 weeks (±7 days) 
 
 
Whole body 
bone scan 
D 
7.2.1 
 
X 
Only if clinically indicated 
 
 
 
 
CT/MRI of brain 
D 
7.2.1 
 
X 
C3D1 and every 8 wks (if positive at baseline) or if clinically indicated 
 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post-treatment 
Follow-up Phase 
Survival 
Follow-
up 
Phase 
Molecular 
Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
End of study treatment 
(EOT) Visit (within 7d of 
last dose) 
30-day Safety 
F/U 
Disease progression 
F/U (every 8 wks) 
Study Phase 
Completion 
Survival (every 3 
months) 
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16K 
Day 22 K 
Day 1 
Day 2 
Day 8 K 
Day 15 K 
Day 22 K 
Day 1 
Day 15 K 
CT/MRI of other 
metastatic sites 
(e.g., neck, 
etc.) 
D 
7.2.1 
 
Xf 
C3D1 and every 8 wks (if positive at baseline) or if clinically indicated 
 
Localized bone 
CT scan, MRI 
or X-ray (for 
any lesions 
identified on the 
whole body 
bone scan that 
are not visible 
on the 
chest/abdomen/
pelvis CT scan 
or MRI) 
D 
7.2.1 
 
Xg 
C3D1 and every 8 wks (if positive at baseline) or if clinically indicated 
 
Photography 
(for skin 
lesions) 
D 
7.2.1 
 
Xh 
C3D1 and every 8 wks (if positive at baseline) or if clinically indicated 
 
Safety assessments 
Adverse events 
D 
8  
SA
E 
only 
Continuously 
 
 
X 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post-treatment 
Follow-up Phase 
Survival 
Follow-
up 
Phase 
Molecular 
Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
End of study treatment 
(EOT) Visit (within 7d of 
last dose) 
30-day Safety 
F/U 
Disease progression 
F/U (every 8 wks) 
Study Phase 
Completion 
Survival (every 3 
months) 
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16K 
Day 22 K 
Day 1 
Day 2 
Day 8 K 
Day 15 K 
Day 22 K 
Day 1 
Day 15 K 
Study drug administration 
EGF816 dosing 
D 
6.1  
 
 
Continuously 
 
 
 
 
Biomarkers assessments 
Collection of 
archival tumor 
sample  
D 
7.2.4 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post-treatment 
Follow-up Phase 
Survival 
Follow-
up 
Phase 
Molecular 
Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
End of study treatment 
(EOT) Visit (within 7d of 
last dose) 
30-day Safety 
F/U 
Disease progression 
F/U (every 8 wks) 
Study Phase 
Completion 
Survival (every 3 
months) 
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16K 
Day 22 K 
Day 1 
Day 2 
Day 8 K 
Day 15 K 
Day 22 K 
Day 1 
Day 15 K 
Pharmacokinetics and ECG assessments 
Extensive ECG 
collection 
D 
7.2.2.6.1 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
 
 
Xb 
 
X 
 
 
 
 
PK sampling  
D 
7.2.3.1 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
Xb 
 
 
 
 
 
 
Post-treatment follow-up 
Antineoplastic 
therapies 
(medications, 
surgeries, 
radiotherapies) 
since 
discontinuation 
of study drug 
D 
7.1.2.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (continuous until the last follow-up visit) 
End of Phase 
Disposition  
D 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Safety follow-up 
S 
7.1.5.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Survival  
D 
7.1.5.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Visit Name 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post-treatment 
Follow-up Phase 
Survival 
Follow-
up 
Phase 
Molecular 
Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
End of study treatment 
(EOT) Visit (within 7d of 
last dose) 
30-day Safety 
F/U 
Disease progression 
F/U (every 8 wks) 
Study Phase 
Completion 
Survival (every 3 
months) 
Day -28 
to 1 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16K 
Day 22 K 
Day 1 
Day 2 
Day 8 K 
Day 15 K 
Day 22 K 
Day 1 
Day 15 K 
a Tumor assessment every 8 weeks from the start of cycle 3 until progression of disease 
b Cycle 3 and cycle 4 only 
c [For Japan only, refer to Section 7.2.5][For Japan only, percutaneous oxygen saturation (SpO2) will be measured every time physical examination is performed. In 
addition, SpO2 and vital signs will be measured on Days 2-7 in Cycle 1] 
d Patients who permanently discontinue the study treatment without having disease progression will continue tumor assessments every 8 weeks until disease 
progression. 
e Refer to Section 7.2.4.1.3  
f if other metastatic sites 
g only if lesions on whole body bone scan that are not visible on the CAP scans 
h only if skin lesions 
I Cycle 3 Day 1 and day 1 of every 3rd cycle thereafter 
J Serum pregnancy should be done at screening and/or at C1D1 before the start of EGF816 
K Visits not applicable for Phase II 
Abbreviations: ICF, informed consent form; C, cycle; CAP, chest/abdomen/pelvis; CT, computed tomography; D, entered into database; d, day; ECG, 
electrocardiogram; EOT, end of treatment; EOS, end of study; F/U, follow-up; MRI, magnetic resonance imaging; NSCLC, non-small cell lung cancer; PD, progressive 
disease; PK, pharmacokinetics; S, remains in source document only; Tx, treatment; wks, weeks; 
*Collect at baseline or anytime thereafter 
**Sample will not be collected if a fresh tumor sample has already been collected at baseline for the purpose of DNA sequencing 


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7.1.1 
Molecular pre-screening 
All patients entering the pre-screening phase must sign the molecular pre-screening informed 
consent form (ICF). 
In order to be considered eligible for the study, the following sample and testing requirements 
apply: 
For Enrollment in the Phase I part: 
Evidence of previously documented EGFR mutation status is acceptable. Alternatively, patients 
can participate in molecular pre-screening to assess whether or not their tumor harbors specific 
documented EGFR mutations by either local or central laboratory. Refer to Section 5.2 for 
specifics regarding the eligible EGFR mutations and required timing (if any) relative to prior 
treatment of the tumor sample tested. 
For enrollment in the Phase II part: 
NSCLC patients with EGFR activating mutation (e.g., L858R and/or ex19del), as determined 
by a local test.  
Existing local data and the results of local testing must be captured on the appropriate eCRF 
upon enrollment onto the study after the patient has signed the study’s Informed Consent. 
Patients in Phase II will be able to proceed with main informed consent form signature and 
study specific screening procedures if activating EGFR mutations (e.g. L858R and/or ex19del ) 
analysis results are documented.  
During the molecular pre-screening period, the Investigator or designee should start gathering 
all available supportive screening evaluations (e.g., demography, relevant medical 
history/current medical conditions, prior antineoplastic therapies etc.) in order to prepare for  a 
potential patient enrollment. 
Upon local confirmation of the presence of EGFR activating mutations, patients may advance 
to the screening period to complete the required study eligibility assessments. 
7.1.2 
Screening 
After the EGFR mutation status has been determined by a local laboratory, patients may begin 
the screening assessments to determine patient eligibility. All patients must sign and date the 
study IRB/IEC approved main ICF prior to performing any screening procedures based on the 
study inclusion and exclusion criteria.  
 
 
 
 
. 
Screening assessments must be completed within 28 days prior to the first dose of study 
treatment with the exception of pregnancy test, which must be performed within 72 hours before 
the first dose. Clinical and radiological tumor assessment by RECIST 1.1 (Section 14.1 


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Appendix 1) should be conducted preferably within 1 week (7 days) prior to the first dose of 
the study treatment; however tumor assessments up to 4 weeks (28 days) prior to the first dose 
will be acceptable. The tumor assessment made during the screening phase will provide the 
baseline tumor measurements, which will be used to determine future responses and/or 
progression. A complete list of screening evaluations is provided in the visit schedule evaluation 
tables (Table 7-1 and Table 7-2).  
Screening for hepatitis B 
Prior to study entry, all patients must be screened with HBV serologic markers: HBsAg, 
HBsAb, and HBcAb. Check HBV-DNA if HBsAg and/or HBcAb are positive. Refer to Table 
6-6 for actions to be taken based on screening HBV results.  
Screening for hepatitis C 
Screen all patients for HCV-Ab. If HCV-Ab is detected then check HCV-RNA. Only patients 
who are HCV-Ab negative or HCV- Ab positive with undetectable level of RNA are eligible to 
be enrolled.  Note: patients with detectable HCV-RNA will not be eligible for the study. Patients 
with HCV-Ab positive or history of hepatitis C infection should be monitored every 8 weeks 
(or more frequently if clinically indicated) with HCV-RNA. 
All screening evaluations will be performed within 28 days prior to Treatment Day 1. 
HBV/HCV tests will be performed by a local laboratory for the Phase I part and the Phase II 
part. HBV/HCV test results should be available prior to the first dose of EGF816 treatment.  
7.1.2.1 
Eligibility screening 
The main screening period commences as soon as the patient signs the main ICF and ends when 
the patient fails screening or starts treatment. Evaluations will be performed within 4 weeks (i.e. 
within 28 calendar days) prior to the first dose of study drug, unless otherwise noted. All 
screening assessments, including laboratory assessments, must be performed as described in the 
protocol (Table 7-1 and Table 7-2). Any imaging assessments already completed as patient’s 
standard of care within 28 days prior to start of treatment, including before signing the main 
study ICF, can be considered as the baseline images for this study.  Any imaging assessments 
obtained after first dose cannot be considered baseline images. 
 
 
 
Eligibility Check 
For patients enrolled in Phase II part of the study, once all screening procedures are completed, 
an eligibility checklist must be completed via IRT by the investigator or designee prior to 
receiving the first dose of study treatment. Please refer to and comply with the detailed 
guidelines in the IRT manual. 
After the eligibility has been checked and confirmed that the patient is eligible for the trial, then 
the patient can be enrolled into the study. 
A patient who has a laboratory test result or an ECG finding that does not satisfy the entrance 
criteria may have the test(s) repeated. These test(s) may be repeated as soon as the investigator 
believes the re-test result(s) is/are likely to be within the acceptable range to satisfy the entrance 


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criteria. If re-tests are performed during the 28-days screening period, the subject will not be 
required to sign another ICF, and the original patient ID number assigned by the investigator 
will be used. In the event that the laboratory test(s) cannot be performed during the original 
screening period of 28 days, or the re-test(s) do not meet the entrance criteria, or other eligibility 
criteria have changed and are not met anymore, the patient is considered a screen failure, and 
must be discontinued from the study. Patients who met all eligibility criteria but fail to be started 
on treatment as scheduled may also be re-screened, provided the patient was not registered 
previously in the CRF as having entered the Treatment Period. 
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed. 
All required screening activities must be performed when the patient is re-screened for 
participation in the study. An individual patient may only be re-screened once for the study. 
Once the number of patients screened and enrolled is likely to ensure target enrollment, the 
Sponsor may close the study to further screening. In this case, the patients who screen failed 
will not be permitted to re-screen. 
If a subject fails screening but is rescreened, the subject must be rescreened using the same 
subject number. 
All eligibility criteria must be re-checked, based on the most recent data available, and met prior 
to enrollment of the patient into the study. 
If the rescreening is successful, the following information should be collected in the CRF: 
• Date the study informed consent was first signed. 
• All assessments done during the first screening period. 
• All assessments repeated during the re-screening period (e.g. ECG, lab). 
• Updated information as per latest status during the re-screening period e.g. Medical history, 
diagnosis and extent of cancer. 
• Adverse events based on the date of re-consent. 
7.1.2.2 
Information to be collected on screening failures 
Patients who signed an ICF but failed to be started on treatment for any reason will be 
considered a screen failure. Both patients who signed a molecular pre-screening ICF but are 
considered ineligible after molecular pre-screening, as well as patients who are found not 
eligible after signing the main study consent will be considered as screening failures, and data 
will be handled in the same manner. The reason for not satisfying eligibility criteria and not 
being enrolled will be entered on the Screening Phase Disposition eCRF page. The following 
eCRF pages must be completed for screening failure patients: 
• Screening Phase Disposition 
• Demography 
• Informed consent 
• Inclusion/Exclusion Criteria 
• Withdrawal of consent (if applicable) 
• Death (if applicable) 


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No other data will be entered into the clinical database for patients who are screen failures, 
unless the patient experienced a Serious Adverse Event during the Screening Phase (see Section 
8 for SAE reporting details). For molecular pre-screening failures, only SAEs possibly related 
to a study procedure will be reported.  
If the patient fails to be enrolled, the IRT (for patients in Phase II only) must be notified within 
2 days of the screen fail that the patient was not enrolled. 
7.1.2.3 
Patient demographics and other baseline characteristics 
Data to be collected include: 
• EGFR mutation status 
• Demography (including: date of birth, age, patient initials if permitted, gender, 
childbearing potential, race and ethnicity, or as allowed by local regulations) 
• Relevant medical history 
• Phase assignment 
• Smoking history 
• NSCLC diagnosis and extent of disease, including: 
• Date of diagnosis and stage of NSCLC 
• Site of metastatic disease 
• Characteristics of disease 
• Prior antineoplastic therapies (medications, radiation, surgeries) 
• Prior and current concomitant medications, surgical and medical procedures 
• HBV and HCV status  
Note: all other medications taken within 28 days before the first dose of study treatment is 
administered must be recorded on the Prior and current concomitant medication eCRF page and 
updated on an ongoing basis if there is new change to the medication. 
7.1.3 
Treatment period 
Following completion of screening procedures and confirmation of patient eligibility, the 
patient will be enrolled via the IRT (for patients in Phase II only).   
The study treatment will begin on Cycle 1, Day 1 with the first administration of EGF816 and 
does not have fixed treatment duration. Information on drug exposure will be collected on the 
Dosage Administration Record eCRF. 
A treatment cycle is defined as 28 days (4 calendar weeks) for the purposes of scheduling 
procedures and evaluations. Please refer to Table 7-1 and Table 7-2 for details of the timing of 
required assessments and Section 7.1 for visit windows. 
7.1.4 
Discontinuation of Study Treatment 
Patients may voluntarily discontinue the study treatment for any reason at any time. If a patient 
decides to discontinue the study treatment, the investigator should make every effort (e.g. 
telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information in the patient’s chart and on the appropriate CRF pages. Patients may be considered 


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withdrawn if they state an intention to withdraw consent, fail to return for visits, or become lost 
to follow-up for any other reason.  
The investigator must discontinue study treatment for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being such as the emergence of the 
severe adverse events, significant laboratory abnormalities or pregnancy. Treatment may also be 
discontinued due to protocol deviations that result in a significant risk to the patient’s safety, 
deviations from the prescribed dose regimen such as missed doses or prolonged drug interruptions, 
or use of prohibited medications which are summarized in Appendix 4. 
Patients who discontinue study treatment should undergo an end of study visit and then enter the 
post-treatment follow-up phase. Patients who discontinue study treatment should not be 
considered withdrawn from the study. They should return for the assessments indicated in 
Section 7.2.1. In addition, before a new anti-neoplastic therapy is initiated for a patient, it is 
strongly recommended to perform a tumor assessment. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be made to 
contact them as specified in Section 7.1.7. 
The investigator must also contact the IRT (for patients in Phase II only) to register the patient’s 
discontinuation from study treatment.  
In some circumstances patients may be allowed to continue to receive study treatment beyond 
disease progression as per RECIST criteria (Section 6.1.2.1). These patients will continue 
assessments as outlined in Section 7, and will complete the EOT visit only after permanent 
discontinuation of study treatment. 
7.1.5 
Follow-up period 
7.1.5.1 
Follow-up for safety evaluations 
30-day follow-up 
All patients must have safety evaluations for 30 days after the last dose of study treatment.  
At the end of this period, the investigator should assess and discuss with the patient any AE 
observed/concomitant medication taken since discontinuation of study treatment. This can be 
done via a phone contact.  
Data collected should be added to the Adverse Events eCRF and the Concomitant Medications 
eCRF. Antineoplastic therapies will be captured on the 'Antineoplastic therapies since 
discontinuation of study treatment' eCRF page. 
Patients whose treatment is permanently discontinued due to an AE (clinical or based on 
abnormal laboratory value) must be followed until resolution or stabilization of the event, 
whichever comes first. In case of an abnormal laboratory value, blood tests should be repeated 
until resolution or stabilization. 
Post-treatment follow-up 
Patients who discontinue the study treatment (i.e. EGF816) without a radiological confirmation 
of disease progression (i.e. patients who discontinue due to clinical disease progression, or 
unacceptable toxicity, or physician or patient’s decision or patient’s withdrawal of consent) will 
continue to have follow-up tumor assessments according to the current tumor assessment 
schedule or as clinically indicated until  radiological confirmation of disease progression by 


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Investigator assessment (both Phase I and II parts), or withdrawal of consent for further tumor 
assessments, or loss to follow-up or death. The results of follow-up tumor assessments should 
be documented in patient’s source documents. Scans performed during the tumor follow-up 
period must be sent promptly to BIRC for an independent tumor assessment. Antineoplastic 
therapies since discontinuation of study treatment will continue to be collected. 
Survival follow-up 
As of amendment 4, all patients enrolled in the Phase II part will be followed for survival every 
3 months until death, lost to follow-up or withdrawal of consent for survival follow-up. Patient’s 
survival status may be collected via a phone call. Antineoplastic therapies will be captured on 
the 'Antineoplastic therapies since discontinuation of study treatment' eCRF page following the 
last dose of the study treatment. 
7.1.5.2 
Replacement policy 
Phase I part 
Patients will not be replaced on study. However, if a patient is considered as non-evaluable for 
the DDS, enrollment of a new patient to the current cohort will be considered if there is less 
than the required number of evaluable patients. Enrollment of new patients may be considered 
until at least the minimum number (1 or 3) or at most the maximum number (3 or 6) of evaluable 
patients is achieved within the cohort. Minimum and maximum numbers of evaluable patients 
per cohort are defined in Section 6.2.3. 
Phase II part 
Patients lost to follow-up or withdrawing consent from the study without disease progression 
will be considered as non-responders for the primary analysis and will not be replaced. 
7.1.6 
Withdrawal of Consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study any 
longer, and does not want any further visits or assessments, and does not want any further study 
related contact. 
Novartis will continue to retain and use all research results that have already been collected for the 
study evaluation. All biological samples that have already been collected may be retained and 
analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator should make every effort (e.g., telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. 
Study treatment must be discontinued and no further assessments should be conducted. 
Further attempts to contact the patient are not allowed unless safety findings require communication 
or follow up. 
7.1.7 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 


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the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g., dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor response will be assessed locally and centrally according to the Novartis guideline 
version 3.2 (Appendix 1) based on RECIST 1.1 (Eisenhauer et al 2009). Details of the central 
review process will be described in the independent review charter.  
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis.    
Information regarding prior interventions (e.g. radiotherapy), pre-existing radiographic findings 
that mimic metastatic disease at baseline/screening and prior interventions should be 
transmitted to the imaging CRO via the Baseline Clinical Form along with the baseline imaging 
data for review by the independent radiologist. Sites must ensure the data entered on the form 
is consistent with the data entered in the clinical database.  
Information regarding cytology results should be transmitted to the imaging CRO via the 
Cytology Form for all visits, when applicable, for review by the independent radiologist. Sites 
must ensure the data entered on the form is consistent with the data entered in the clinical 
database. 
The imaging assessment collection plans are presented in Table 7-3 and Table 7-4 for the Phase 
I part and Phase II part, respectively. 
Table 7-3 
Imaging collection plan (Phase I part) 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
CT or MRI 
with contrast 
enhancement 
(Chest and Abdomen) 
Mandated 
Mandated, every 8 weeks 
(±7 days) 
Whole body bone scan 
If clinically indicated 
Not applicable 
Brain CT or MRI 
Mandated 
If brain lesions at screening 
every 8 weeks (±7 days) 
Bone X-ray, CT or MRI 
(bone lesions only) 
If lesions on bone scan that are not 
visible on the chest and abdomen 
CT/MRI 
If bone lesions at screening 
every 8 weeks (±7 days) 
Skin color photography 
(skin lesions only) 
Mandated if skin lesions at screening 
If skin lesions at screening 
every 8 weeks (±7 days) 
CT or MRI of other tumor 
sites (e.g., pelvis) 
If clinically indicated 
If lesions identified at 
screening every 8 weeks (±7 
days) 
For the Phase I part, the imaging data will be retrospectively collected and stored for possible 
independent review by an imaging CRO designated by Novartis; tumor response will be 


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determined locally according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
(Section 14.1 Appendix 1). The local investigator’s assessment will be used for efficacy 
analysis and for treatment decision making.  
Table 7-4 
Imaging collection plan (Phase II part) 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Computed tomography (CT) or 
magnetic resonance imaging 
(MRI) of CAP (Chest, Abdomen, 
Pelvis) with contrast 
enhancement 
Mandated 
Every 8 weeks (±7 days) until PD 
determined by Investigator and BIRC 
assessments, End of treatment (EOT) 
scan not required if previous CAP 
scan was performed within ≤28 days) 
CT or MRI of other metastatic 
sites (e.g., neck, etc.), if 
applicable 
Only if other metastatic sites are 
suspected 
Mandated if patient has other 
metastatic sites at baseline (following 
the same schedule as CT/MRI of 
chest/abdomen/pelvis) or otherwise, 
only if clinically indicated 
Whole Body Bone Scan [e.g. Tc-
99 bone scan, whole body bone 
MRI, Fluorodeoxyglucose 
positron emission tomography 
(FDG-PET) or sodium fluoride 
positron emission tomography 
(NaF PET)] 
Mandated 
If clinically indicated” (Refer to Section 
7.2.1.1).  
Brain CT or MRI 
Mandated 
If brain lesions at screening 
every 8 weeks (±7 days) 
Bone X-ray, CT or MRI (bone 
lesions only) 
If lesions on bone scan that are 
not visible on the chest and 
abdomen CT/MRI 
Every 8 weeks (±7 days) 
Skin color photography (skin 
lesions only) 
Mandated if skin lesion(s) is/are 
selected as target lesion(s) at 
baseline 
Every 8 weeks (±7 days) 
For the Phase II part, imaging data will be centrally collected, checked for quality, and read by 
BIRC according to the Novartis guideline (Section 14.1 - Appendix 1) based on RECIST 1.1. 
7.2.1.1 
Baseline imaging assessment 
Baseline imaging assessments will be performed within 28 days prior to the first dose of study 
treatment (prior to Cycle 1 Day 1). 
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after first 
dose cannot be considered baseline images.  
Imaging requirements at baseline 
• Patients must have measurable disease as RECIST 1.1 (Section 14.1 - Appendix 1). 
Measurable (“target”) lesions include lytic or mixed (lytic + blastic) bone lesions with an 
identifiable soft tissue component that meets the measurability criteria per RECIST 1.1 
(Appendix 1). 
• Patients with only non-measurable lesions are not eligible. 


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• If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
• Any potentially measurable lesion that has been previously treated with radiotherapy should 
be considered as a non-measurable (“non-target”) lesion. However, if a lesion previously 
treated with radiotherapy has clearly progressed since the radiotherapy, it can be considered 
as a measurable lesion. 
All measurable lesions up to a maximum of 5 nodal and/or non-nodal lesions in total (and a 
maximum of 2 lesions per organ), representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline. 
Tumor assessments required at baseline 
The following assessments will be performed: 
• Computed Tomography (CT) with IV contrast or Magnetic Resonance Imaging (MRI) of 
chest, abdomen and pelvis. 
• The preferred radiologic technique is CT with intravenous (IV) contrast. If a patient is 
known to have a contraindication to CT contrast media or develops a contraindication 
during the trial, a non-contrast CT of the chest (MRI is not recommended due to 
respiratory artifacts) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed. 
• Brain CT or MRI with IV contrast, if clinically indicated  
• If brain lesions are documented at screening, scans need to be continued following the 
same schedule as CT/MRI of chest, abdomen and pelvis. The same methodology as at 
screening should be used. Contrast enhanced brain MRI is preferred, however, if MRI 
contrast is contraindicated, then MRI without contrast or CT with/without contrast is 
acceptable. 
• A whole body bone scan according to institutional guidelines [e.g. Tc-99 bone scan, whole 
body bone MRI, Fluorodeoxyglucose positron emission tomography (FDG-PET) or sodium 
fluoride positron emission tomography (NaF PET)] required at screening and if clinically 
indicated on study.  
• Whole body bone scans is needed for Phase I if clinically indicated at screening and not 
required on study. 
• Whole body bone scans is required for the Phase II if clinically indicated on study. If 
indicated, the same methodology as at screening should be used. 
• Localized bone CT, MRI or X-rays for any lesions identified on the  whole body bone scan, 
that are not visible on the chest, pelvis and abdomen CT or MRI. 
• If skeletal lesions are documented at baseline, scans need to be continued following the 
same schedule as CT/MRI of chest and abdomen. The same methodology as at screening 
should be used. 
• CT or MRI of other metastatic sites not captured by any of the above listed images (e.g., 
neck) if clinically indicated. 
• If additional sites of disease are documented at screening, scans need to be continued 
following the same schedule as CT/MRI of chest, abdomen and pelvis. The same 
methodology as at screening should be used. 
• Color photography for any skin lesions present, if clinically indicated. 


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• Color photography should be continued following the same schedule as CT/MRI of 
chest, abdomen and pelvis acquired using a digital camera in clear focus, including a 
scale/ruler, in such a way that the size of the lesion(s) can be determined from the 
photograph. 
Note: chest X-ray and ultrasound must not be used to measure tumor lesions. 
7.2.1.2 
Post-baseline imaging assessments  
Imaging assessments as described in Table 7-3 (Phase I) and Table 7-4 (Phase II) should be 
performed at the timepoints specified using the same imaging modality used at baseline, 
irrespective of study treatment interruption or actual dosing (see Table 7-1 and Table 7-2). 
Imaging assessments for response evaluation will be performed every 8 weeks (±7 days) until 
disease progression, death, lost to follow-up or withdrawal of consent. Imaging assessments 
should be scheduled using the first dose date as the reference date (not the date of the previous 
tumor assessment), and should be respected regardless of whether treatment with study 
treatment is temporarily withheld or unscheduled assessments performed.  
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a patient, if necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment. 
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same local 
radiologist/physician throughout the study so that the comparison is consistent. If an off-
schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule. 
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of IV contrast media. At the discretion of the 
Investigators, FDG-PET scans may be performed to document PD per RECIST 1.1 (Appendix 
14.1). 
All Phase I retrospective and Phase II prospective study imaging (including any off-schedule 
imaging studies) performed to evaluate progression or response should be submitted to the 
designated imaging CRO for quality control and review by the BIRC, promptly after acquisition 
(as applicable). 
7.2.1.3 
Transmission of efficacy data to BIRC 
All radiological assessments will be read locally and by BIRC. The imaging assessments should 
be submitted promptly after acquisition to the imaging vendor designated by Novartis. Rapid 
image transmission to the central imaging vendor will be accomplished by transferring the 
images acquired by the investigator electronically in a secured website (e.g., via the internet) or 
by a courier. In all instances, the process at the imaging vendor will ensure that the central 
reviewers remain blinded to the results of the local assessment and the expedited nature of the 
review. 


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7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessment as well as collection of the adverse events at every visit. 
For details on AE collection and reporting, refer to Section 8. 
7.2.2.1 
Physical examination 
A complete physical examination must be performed as indicated in Table 7-1 and Table 7-2 
and will include the examination of general appearance, skin, neck (including thyroid), eyes, 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological assessments. 
Physical examination will be performed on the scheduled day, even if study treatment is being 
withheld. More frequent examinations may be performed at the discretion of the Investigator 
and if medically indicated. 
A targeted (short) physical examination will be performed according to the standards at each 
institution. 
Information about the physical examination must be present in source documentation at the 
study site. Significant findings that are present prior to signing of informed consent form for 
the study must be included in the Medical History page on the patient’s eCRF. Significant new 
findings that begin or worsen after informed consent for the study must be recorded on the 
Adverse Events eCRF. 
7.2.2.2 
Vital signs 
Vital signs (body temperature, pulse rate, blood pressure) must be performed as per institutional 
standards before dosing and as indicated in Table 7-1 and Table 7-2. 
Vital signs should be assessed on the scheduled day, even if study treatment is being withheld. 
More frequent examinations may be performed at the discretion of the Investigator and if 
medically indicated. 
7.2.2.3 
Height and weight 
Height (screening only) and body weight (in indoor clothing, but without shoes) will be 
measured at screening and at subsequent time points as specified in Table 7-1 and Table 7-2. 
7.2.2.4 
Performance status 
ECOG performance status will be assessed according to Table 7-1 and Table 7-2. 
Table 7-5 
ECOG performance status 
Grade 
ECOG Status 
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 


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7.2.2.5 
Laboratory evaluations 
For the phase I and phase II, all laboratory parameters assessed for safety purposes will be 
evaluated locally, at the site. Refer to Table 7-6 for a summary of the parameters to be evaluated 
and the frequency of the assessments according to Table 7-1 and Table 7-2 respectively. 
Local laboratory assessments may also be performed when an immediate clinical decision needs 
to be made. In those cases locally unscheduled testing may be performed.  
Each time local laboratory results (including unscheduled laboratory assessments) are reported 
on the eCRF page, the study monitor will collect and submit promptly the local laboratory 
normal ranges and local laboratory certification.Details on the collection, shipment of samples 
and reporting of results by the central laboratory are provided to investigators in a separate 
[Laboratory Manual]. 
Table 7-6 
Local clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, RBC Morphology 
with, Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, 
other) 
Chemistry 
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Gamma-glutamyl 
transpeptidase (GGT) Calcium, Chloride, Magnesium, Phosphorus (screening in Phase II 
part only), Potassium, Creatinine, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Total 
Protein, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (fasting at 
baseline),  
Urinalysis 
Dipstick measurements for specific gravity, pH, protein, glucose, bilirubin, ketones, 
leukocytes, and blood will be performed. Any clinically significant findings on dipstick will be 
followed up with a microscopic evaluation. (Red Blood Cells, White Blood Cells, Casts, 
Crystals, Bacteria, Epithelial cells)  
Coagulation 
Prothrombin time (PT) or International normalized ratio (INR),  
HBV and HCV  
HBsAg, HBsAb, HBcAb, HBV-DNA, HCV-Ab, HCV-RNA 
7.2.2.5.1 Hematology 
Hematology panel outlined in Table 7-6 will be performed as per the assessment schedule in 
Table 7-1 and Table 7-2. 
7.2.2.5.2 Clinical chemistry 
Clinical chemistry panel outlined in Table 7-6 will be performed as per the assessment schedule 
in Table 7-1 and Table 7-2. 
7.2.2.5.3 Coagulation 
Coagulation panel outlined in Table 7-6 will be performed as per the assessment schedule in 
Table 7-1 and Table 7-2. 
7.2.2.5.4 Urinalysis 
Urinalysis panel outlined in Table 7-6 will be performed as per the assessment schedule in Table 
7-1 and Table 7-2. 


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7.2.2.5.5 HBV and HCV testing 
HBV tests outlined in Table 7-6 will be performed as per the assessment schedule in Table 7-1 
and Table 7-2. 
HCV tests outlined in Table 7-6 will be performed as per the assessment schedule in Table 7-1 
and Table 7-2. 
7.2.2.5.6 Pregnancy and assessments of fertility 
For both Phase I and Phase II parts, a serum pregnancy test is required for women of 
childbearing potential at screening (within 72 hours) and/or at Cycle 1 Day 1 (prior to dosing) 
and at the end of the study treatment. During subsequent cycles, for women of childbearing 
potential urine pregnancy tests will be performed at day 1 of each cycle in the Phase I part, and 
as clinically indicated in the Phase II part. 
7.2.2.6 
Cardiac assessments 
7.2.2.6.1  Electrocardiogram (ECG) 
Standard 12 lead ECGs will be performed as per the assessment schedule in Table 7-7 for Phase 
I patients and Table 7-8 for Phase II patients. 
For all patients in Phase I, 3 sequential 12-lead ECGs must be performed during screening, at 
pre-dose and at 2 hr post dose (estimated Tmax) on Cycle 1 Day 1 and Cycle 2 Day 1, at pre-
dose on Cycle 3 Day 1 and at EOT. Triplicate ECGs will be performed at all time-points during 
the trial. 
Table 7-7 
Central ECG collection plan for all patients (for Phase I) 
Cycle 
Day 
Time 
 
Screening 
-28 to -1 
Anytime 
Triplicate 12 Lead 
1 
1 
Pre-dose 
Triplicate 12 Lead 
1 
1 
2 hr post dose  
Triplicate 12 Lead 
2 
1 
Pre-dose 
Triplicate12 Lead 
2 
1 
2 hr post dose  
Triplicate 12 Lead 
3  
1 
Pre-dose 
Triplicate 12 Lead 
EOT 
 
  
Triplicate 12 Lead 
Unscheduled  
Anytime 
Triplicate 12 Lead 
All patients from the Phase II part will have an extensive ECG collection as shown in Table 7-
8. 
Table 7-8 
Extensive ECG collection plan (for Phase II) 
Cycle 
Day 
Time 
 
Screening 
-28 to -1 
Anytime 
Triplicate 12 Lead 
1 
1 
Pre-dose 
Triplicate 12 Lead 
1 
1 
0.5, 2, 4, 8 and 24 hr  
Triplicate 12 Lead 
1 
15 
Pre-dose 
Triplicate 12 Lead 
1 
15 
2 hr post-dose 
Triplicate 12 Lead 


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Cycle 
Day 
Time 
 
2 
1 
Pre-dose 
Triplicate 12 Lead 
2 
1 
0.5, 2, 4, 8 and 24 hr 
Triplicate 12 Lead 
3-4 
1 
Pre-dose 
Triplicate 12 Lead 
EOT 
 
 
Triplicate12 Lead 
Unscheduled  
 
Anytime 
Triplicate12 Lead 
Interpretation of the tracing will be made by a central ECG lab. Each ECG tracing should be 
labeled with the study number, patient initials (where regulations permit), patient number, date, 
and kept in the source documents at the study site. New or worsened clinically significant 
abnormalities occurring after informed consent will be recorded in the AE eCRF page. 
Clinically significant abnormalities present when the patient signed informed consent at 
screening should be recorded on the Medical history eCRF page and discussed with Novartis 
prior to enrolling the patient in the study. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local ECG assessment may also be performed at any 
time during the study at the discretion of the investigator by a qualified physician and 
documented on the ECG CRF page.  
All ECGs, including unscheduled triplicate safety ECGs with clinically relevant findings, 
collected during the study should be transmitted to the central core ECG laboratory for review.  
7.2.3 
Pharmacokinetics 
Serial blood samples will be collected from all patients for the analysis of EGF816 and LMI258 
plasma PK. The PK analysis will be performed according to Section 10.5.3. 
 
 
 
7.2.3.1 
Pharmacokinetic blood sample collection and handling 
PK blood samples will be collected in both Phase I and Phase II parts. 
For patients treated in the Phase I part, three PK profiles will be collected on Day 1, Day 15 of 
Cycle 1, and Day 1 of Cycle 2. In addition, trough samples will be taken on Day 8 of Cycle 1, 
and Day 1 of Cycle 3 and Cycle 4 (Table 7-9). 
For patients treated in the Phase II part, two PK profiles will be collected on Cycle 1 Day 1 and 
Cycle 2 Day 1 in addition to several trough samples as shown in Table 7-10. 
Table 7-9 
Phase I part: schedule of blood sample collections for 
pharmacokinetics 
Dose 
reference ID 
following PK 
sampling 
Dose 
reference ID 
prior to PK 
sampling 
Sample 
number 
Cycle 
Day 
Scheduled time (hours) 
1 
 
1 
1 
1 
Pre-dose/0 hra 
1 
 
2 
1 
1 
0.5 hr (±10 minutes) 


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Dose 
reference ID 
following PK 
sampling 
Dose 
reference ID 
prior to PK 
sampling 
Sample 
number 
Cycle 
Day 
Scheduled time (hours) 
1 
 
3 
1 
1 
1 hr (±10 minutes) 
1 
 
4 
1 
1 
2 hr (±10 minutes) 
1 
 
5 
1 
1 
3 hr (±15 minutes) 
1 
 
6 
1 
1 
4 hr (±15 minutes) 
1 
 
7 
1 
1 
6 hr (±30 minutes) 
1 
 
8 
1 
1 
8 hr (±1 hr) 
1 
 
9 
1 
1 
12 hr (± 1 hr) b 
2 
1 
10 
1 
2 
24 hr/pre-C1D2 dose a 
3 
102 
11 
1 
8 
Pre-C1D8 dose 
4 
103 
12 
1 
15 
Pre- C1D15 dose/0 hr a 
4 
 
13 
1 
15 
0.5 hr (±10 minutes) 
4 
 
14 
1 
15 
1 hr (±10 minutes) 
4 
 
15 
1 
15 
2 hr (±10 minutes) 
4 
 
16 
1 
15 
3 hr (±15 minutes) 
4 
 
17 
1 
15 
4 hr (±15 minutes) 
4 
 
18 
1 
15 
6 hr (±30 minutes) 
4 
 
19 
1 
15 
8 hr (±1 hr) 
4 
 
20 
1 
15 
12 hr (± 1 hr) b 
5 
4 
21 
1 
16 
24 hr/pre-C1D16 dose a 
6 
105 
22 
2 
1 
Pre-C2D1 dose/0 hr a 
6 
 
23 
2 
1 
0.5 hr (±10 minutes) 
6 
 
24 
2 
1 
1 hr (±10 minutes) 
6 
 
25 
2 
1 
2 hr (±10 minutes) 
6 
 
26 
2 
1 
3 hr (±15 minutes) 
6 
 
27 
2 
1 
4 hr (±15 minutes) 
6 
 
28 
2 
1 
6 hr (±30 minutes) 
6 
 
29 
2 
1 
8 hr (±1 hr) 
6 
 
30 
2 
1 
12 hr (± 1 hr) b 
7 
6 
31 
2 
2 
24 hr/pre-C2D2 dose a 
8 
107 
32 
3 
1 
pre-C3D1 dose a 
9 
108 
33 
4 
1 
pre-C4D1 dose a 
 
 
1001+ 
 
 
At the time of newly obtained biopsy on 
C4D1 (±3 days) and time of progression d 
-- 
 
2001+c 
NA 
NA 
Unscheduled 
a Take samples immediately prior to the administration of EGF816 
b Optional 
c Unscheduled blood samples will be uniquely, sequentially numbered 2001, 2002, 
d Time of the dose taken prior to biopsy 
If biopsy is collected on Cycle 4 Day 1, no unscheduled blood PK sample needs to be collected 


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Table 7-10 
Phase II part: schedule of blood sample collections for 
pharmacokinetics  
Dose 
reference ID 
following PK 
sampling 
Dose 
reference ID 
prior to PK 
sampling 
Sample 
number 
Cycle 
Day 
Scheduled time (hours) 
11 
 
101 
1 
1 
Pre-dose/0 hr a 
11 
 
102 
1 
1 
0.5 hr (±10 minutes) 
11 
 
103 
1 
1 
1 hr (±10 minutes) 
11 
 
104 
1 
1 
2 hr (±10 minutes) 
11 
 
105 
1 
1 
3 hr (±15 minutes) 
11 
 
106 
1 
1 
4 hr (±15 minutes) 
11 
 
107 
1 
1 
6 hr (±30 minutes) 
11 
 
108 
1 
1 
8 hr (±1 hr) 
12 
11 
109 
1 
2 
24 hr/pre-C1D2 dose a 
13 
120 
110 
1 
8 
Pre-C1D8 dose 
14 
130 
111 
1 
15 
Pre-C1D15 dose a 
15 
140 
112 
2 
1 
Pre-C2D1 dose/0 hr a 
15 
 
113 
2 
1 
0.5 hr (±10 minutes) 
15 
 
114 
2 
1 
1 hr (±10 minutes) 
15 
 
115 
2 
1 
2 hr (±10 minutes) 
15 
 
116 
2 
1 
3 hr (±15 minutes) 
15 
 
117 
2 
1 
4 hr (±15 minutes) 
15 
 
118 
2 
1 
6 hr (±30 minutes) 
15 
 
119 
2 
1 
8 hr (±1 hr) 
16 
15 
120 
2 
2 
24 hr/pre-C2D2 dose a 
17 
160 
121 
3 
1 
pre-C3D1 dose a 
18 
170 
122 
4 
1 
pre-C4D1 dose a 
-- 
 
3001+b 
NA 
NA 
Unscheduled 
a Take samples immediately prior to the administration of EGF816 
b Unscheduled blood samples will be uniquely, sequentially numbered 3001, 3002, … 
The exact date and clock times of drug administration and PK blood draw will be recorded on 
the appropriate eCRF. The timing of meals, before and after the dose on days when PK samples 
are drawn, should be recorded in the source documents. If vomiting occurs within 4 hours 
following EGF816 administration on the day of PK blood sampling, the clock time of vomiting 
should be recorded on the transmittal form, which accompanies the sample. 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. At specified time points, 2 mL blood will be collected into tubes containing K2 
EDTA. Refer to the [EGF816X2101 Laboratory Manual] for detailed instructions for the 
collection, handling, and shipment of PK samples. 
7.2.3.2 
Analytical method 
EGF816 and LMI258 concentrations in human plasma will be determined with a validated 
liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Any results below the 
lower limit of quantification (LLOQ) of 1.0 ng/mL and any missing samples will be labeled 
accordingly. 


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7.2.4 
Biomarkers 
In this study biomarker analyses will be used to investigate the effect of the EGF816 at the 
molecular and cellular level 
 
 The sample collection information as required should be 
recorded on the eCRF page(s) and central laboratory requisition form(s). Detailed instructions 
for the collection, handling, and shipping of biomarker samples are outlined in the 
[EGF816X2101 Laboratory Manual]. 
7.2.4.1 
Biomarker assessments for Phase I part 
7.2.4.1.1 Pharmacodynamic assessments in newly obtained tumor specimens (For 
patients enrolled before protocol amendment 5 only (For Phase I part only) 
Collection of paired tumor specimens is critical to assess the pharmacodynamic effect of 
EGF816 on the EGFR pathway. Tumor specimens will be used to assess the phosphorylation 
state of pathway molecules (e.g. EGFR, AKT, ERK) by immunohistochemistry and genetic 
abnormalities in the EGFR signaling pathway, other pathways that may interact with the EGFR 
pathway, or are thought to be important in cancer. Additional markers or methods maybe 
utilized if indicated by new findings from the literature as well as from Novartis internal data. 
7.2.4.1.2 Assessment of tumor immune infiltrates in newly obtained tumor specimens 
(For Phase I part only) 
To assess whether treatment with EGF816 results in a change in tumor immune infiltrates, 
immunohistochemical analyses of immune cell markers will be performed on newly obtained 
tumor samples collected at screening/baseline, C4D1, C6D1 (optional) ,C8D1(optional) and 
EOT (optional). Additional markers or methods maybe utilized if indicated by new findings 
from the literature as well as from Novartis internal data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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Table 7-11 
Biomarker sample collection plan – Phase I part 
Sample type 
Analysis 
Collection visit schedule 
Newly obtained tumor 
samples  
Immune infiltrate 
assessment 
Screening/baseline, Cycle 4 Day 1, Cycle 6 Day 1 
(optional), Cycle 8 Day 1 (optional) and at EOT 
(optional)(+/- 28 days for each time point or 
otherwise as agreed between investigators and 
Novartis) 
7.2.4.2 
Biomarker Assessments for Phase II part 
7.2.4.2.1  Biomarker Assessments in Tumor 
Archival or newly acquired biopsy are required when a patient enters the screening phase; 
archival tumor material is requested to assess markers associated with EGFR signaling, EGF816 
and cancer with methods including but not limited to Next Generation Sequencing (NGS), 
immunohistochemistry and fluorescence in-situ hybridization. 
 
 
  
 
 
  


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Table 7-12 
Biomarker sample collection plan -Phase II part 
Sample Type 
Volume 
Visit 
Time point 
Tumor samples 
Mandatory 
Newly obtained formalin-fixed biopsy or archival 
tumor block or slides from a formalin-fixed paraffin 
embedded (FFPE).  
Block or  
minimum of 11 
slides (5 microns) 
Screening 
 Screening 
Mandatory (if available) 
Either the remaining archival tumor block or 
additional 5 slides from same archival biopsy that 
was provided at molecular screening or the same 
block used to determine EGFR status locally 
 
 
Additional slides not required if a suitable block 
(newly acquired or archival) was submitted for 
molecular screening 
Block or  
additional 5 
slides  
 Cycle 1 Day 1  1Upon 
enrollment  


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Sample Type 
Volume 
Visit 
Time point 
Optional 
Newly obtained tumor biopsy or archival material if 
fresh not available at C1D1 
 
 
 
 
 
 
Requires separate consent within the main ICF. 
Newly acquired 
biopsy or archival 
material, block or 
3-10 slides  
Cycle 1 Day 1 
Pre-dose 
If a newly 
obtained tumor 
biopsy was 
submitted for 
screening, this 
biopsy is not 
required 
Newly acquired 
biopsy 
EOT 
Anytime 
Newly acquired 
biopsy 
On treatment  
Any time  
Sample Type 
Volume 
Visit 
Time point 
Blood samples 


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7.2.5 
[For Japan only] Radiological examinations 
7.2.5.1 
Chest X-ray 
A 2-view chest X-ray will be performed at screening, Day 15 of Cycle1, and on Day1 of Cycle 
2 and thereafter. If a chest CT scan is performed, a chest X-ray can be skipped except for at 
screening.  
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
For patients whose EGFR mutation status is unknown and who sign the molecular pre-screening 
ICF, AEs which occur after signature of this consent will only be captured if they meet the 
definition of serious as outlined in Section 8.2 and are reported to be causally related with study 
procedures (e.g. an invasive procedure such as biopsy). Once the main study ICF is signed, all 
AEs per the descriptions below will be captured in the Adverse Event eCRF. 
Patients whose EGFR mutation status is known will sign the main study ICF. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event. 
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding respectively to Grades 1 - 4, will be used. CTCAE Grade 5 
(death) will not be used in this study; rather information about any deaths (related to an Adverse 
Event or not) will also be collected through a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 


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(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine: 
1. The severity grade (CTCAE Grades 1-4) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
or 
Its relationship to the study treatment (Reasonable possibility that AE is related: No, 
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) Delete for NOVDD Trials as outcome 
is not collected 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For Grade 3 and 4 adverse events only, if improvement to 
a lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 


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followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator’s Brochure. 
The adverse events of special interest to be monitored for EGF816 are diarrhea and 
gastrointestinal toxicities; pneumonitis/ interstitial lung disease; hepatitis B reactivation;  skin 
adverse events including  rash and mucocutaneous dryness; and dry eye disorders. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 


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• Serious adverse events considered by the investigator to be possibly related to a biopsy 
procedure will be indicated as such in the AE eCRF. 
8.2.2 
Reporting 
For patients with unknown EGFR mutation status and who sign the molecular pre-screening 
ICF, SAE collection will start upon signing the molecular pre-screening ICF. SAEs will only 
be reported if the event is suspected to be causally related to a study procedure as assessed by 
the investigator (e.g., an invasive procedure such as biopsy). SAEs will be followed until 
resolution or until clinically relevant improvement or stabilization. If the main ICF is not signed 
(molecular screen failure), SAE collection ends 30 days after the last study related procedure. 
For patients with known EGFR mutation status who sign the main study ICF, SAE collection 
starts at time of main study informed consent whether the patient is a screen failure or not. 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period (or 5 half-lives, whichever is longer) should 
only be reported to Novartis if the investigator suspects a causal relationship to the study 
treatment. Recurrent episodes, complications, or progression of the initial SAE must be reported 
as follow-up to the original episode within 24 hours of the investigator receiving the follow-up 
information. An SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the submission process and requirements for signatures are to be found 
in the investigator folder provided to each site. 
Follow-up information is submitted the same way as each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the [Investigator’s Brochure] or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Chief Medical Office and Patient Safety (CMO&PS) department associate may 
urgently require further information from the investigator for Health Authority reporting. 
Novartis may need to issue an Investigator Notification (IN), to inform all investigators 
involved in any study with the same drug that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC 
or as per national regulatory requirements in participating countries. 


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8.3 
Pregnancies  
Study treatment must be stopped if a patient becomes pregnant. 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
8.4 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
8.5 
Data Monitoring Committee 
Phase I part 
A data monitoring board will not be used for the Phase I part of this study. Novartis will have 
access to the Safety Data on a regular basis. Novartis will host investigator teleconferences on 
a regular basis during the study. Further, Novartis and the investigators will meet at the end of 
each treatment cohort to discuss and evaluate all of the gathered safety data. At the dose-
escalation teleconference the clinical course (safety information including both DLTs and all 
CTCAE Grade 2 or higher toxicity data during the first cycle of treatment, and PK data) for 
each patient in the current dose cohort will be described in detail. Updated safety data on other 
ongoing patients, including data in later cycles, will be discussed as well. 
Dose-escalation decisions will be based on a clinical synthesis of all relevant available data and 
not solely on DLT information. Selection of the actual dose for the next cohort of patients will 
be guided by the Bayesian logistic regression model’s (with EWOC) recommendation, and a 
medical review of relevant clinical, PK and laboratory data. Novartis and the investigator parties 
must reach a consensus on whether to declare MTD, escalate the dose any further, or whether 
to de-escalate and/or recruit an additional cohort of patients at the current dose level (see Section 
10.4.2). 


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Phase II part 
This is a single arm trial (i.e. no comparator arm) and there is no apriori information as per the 
FDA Guidance of “situations in which safety concerns may be unusually high” or the patient 
population being studied are “potentially fragile population such as children, pregnant women 
or the very elderly, or other vulnerable populations, such as those who are terminally ill or of 
diminished mental capacity.” Thus, an independent data monitoring committee will not be 
constituted for the Phase II part of this study.  
The Novartis clinical team will review the safety data on a regular basis. A review of the safety 
data and assessment of futility based on the calculated Bayesian probability of success (POS) 
will be performed at the interim analysis by the Novartis clinical trial team and shared with the 
investigators in a data review meeting. 
At the time of the interim analysis, the best overall response for each patient will be derived 
from the overall lesion response assessments performed by the BIRC . These will be used to 
calculate the overall response rate for the respective group and a Bayesian analysis will be 
performed to estimate the POS of the trial given the current data (see Section 10.7 for details). 
It is envisioned that the team may make three types of recommendations at the respective 
interim analysis, namely: 
• No safety or efficacy issues, ethical to continue the study group as planned 
• POS is too small and the study group is terminated due to lack of significant activity 
• Serious safety concerns precluding further treatment in study group, regardless of efficacy. 
8.6 
Steering Committee 
Not applicable. 
8.7 
Blinded Independent Review Committee (BIRC) 
A Blinded Independent Review Committee (BIRC) will review the Phase I and Phase II part 
radiographic and photographic data to determine tumor response and progression. The 
designated imaging CRO will be responsible for assembling and managing the BIRC. This and 
all other imaging procedures will be documented in an independent review charter agreed upon 
between Novartis and the imaging vendor before initiation of any BIRC reviews. 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff. 


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The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
Blood and tumor samples for PK and biomarkers will be collected by sites and sent to a Central 
laboratory for processing. The Laboratory results will be sent electronically to Novartis 
database as third party data. Radiological and photography data will be acquired by the sites 
and interpreted locally. Additionally, radiological and photography data will be transmitted by 
the sites to the respective vendor designated to undergo quality checks and central review. 
Details regarding all vendor procedures including collection and shipment of data will be 
described in the manual provided by the respective vendor.  
PK and Biomarker (blood and tissue) samples drawn during the course of the study will be 
collected from the Investigator sites and analyzed by a Novartis assigned laboratory or 
contracted central laboratories. The site staff designated by the Investigator will enter the 
information required by the protocol onto the PK and Biomarker Sample Collection eCRFs, 
respectively, as well as the designated laboratory’s requisition forms that will be printed on 2- 
part paper. One copy of the requisition form will be forwarded to the central laboratory along 
with the corresponding samples with required information (including study number, subject ID, 
etc.) and the other copy will be retained by the site. The field monitor will review the relevant 
eCRFs for accuracy and completeness and will work with the site staff to adjust any 
discrepancies as required. The field monitor will also review the requisition forms for 
completeness. 
Biomarker, ECG and central laboratory data obtained by designated central laboratories will be 
transferred to Novartis database as third party data. 
In addition, data entered into the IRT for drug assignment and patient identifiers (i.e. date of 
birth, gender and Patient ID) will be transferred electronically to Novartis as described in the 
Data Transfer Specifications for the designated IRT vendor. 
If a patient enrolls on a companion sample collection study to evaluate the mechanisms of 
resistance, data required for the companion sample collection study are collected in the clinical 
trial database for the treatment protocol.  A description of the data to be collected for the study 
of resistance is provided in the companion sample collection protocol. 
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel will review the data entered by investigational 
staff for completeness and accuracy. Electronic data queries stating the nature of the problem 
and requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigational site staff is required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
PK, biomarker samples, ECG, imaging and IRT data will be processed centrally and the results 
will be sent electronically to Novartis. 


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For Phase II patients, data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The system 
will be supplied by a vendor(s), who will also manage the database. The data will be sent 
electronically to Novartis personnel. 
The occurrence of any protocol violations will be determined. 
After these actions have been completed and the data have been verified to be complete and 
accurate, the database will be declared locked and made available for data analysis. 
Authorization is required prior to making any database changes to the locked data by joint 
written agreement between the Global Head of Biostatistics and Data Management and the 
Global Head of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM of the patient 
data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. 
Study data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, and all 
relevant PK and PD measurements. 
Categorical data will be presented as contingency tables (frequencies and percentages). For 
continuous data summary statistics of mean, standard deviation, median, minimum, and 
maximum will be presented. 
The following rules will be followed for reporting results unless stated otherwise: 
• Phase I part: Patients treated during the Phase I part (dose escalation) with the same dose 
level, formulation (capsule vs. tablet) and schedule of EGF816 will be pooled into a single 
treatment group. All summaries, listings, figures and analyses will be performed by 
treatment group (unless otherwise specified). Subgroup analyses by mutation type and prior 
lines of systemic antineoplastic therapy(s) may be performed as appropriate. 
• Phase II part: The primary analysis will be performed when patients enrolled have 
completed at least 6 cycles of treatment or discontinued treatment prior to that time. Any 
additional data for patients continuing to receive study treatment past the data cut-off date 
for the primary analysis will be reported in the final CSR at the end of the study.  
10.1 
Analysis sets 
10.1.1 
Phase I part 
10.1.1.1 Full analysis set 
The full analysis set (FAS) includes all patients who received at least one dose of EGF816. 
Patients will be analyzed according to the planned treatment (regimen). The FAS will be used 
for all listings of raw data. Unless otherwise specified, the FAS will be the default analysis set 
used for all analyses. 


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10.1.1.2 Safety set 
The Safety Set includes all patients who received at least one dose of EGF816. Patients will be 
analyzed according to the study treatment (regimen) they actually received. 
A precise definition of “actually received” will be added in the Reporting and Analysis Plan 
(RAP). 
10.1.1.3 Dose-determining set 
The dose-determining set (DDS) consists of all patients from the safety set of phase I part who 
either meet the following minimum exposure criterion and have sufficient safety evaluations, 
during the first 28 days of dosing or discontinue earlier due to DLT. A patient is considered to 
have met the minimum exposure criterion if he received at least 75% of the planned doses of 
EGF816 in the first 28 days of dosing (e.g., 21 of the planned 28 doses on a q.d. schedule). 
Patients who do not experience DLT during the first cycle are considered to have sufficient 
safety evaluations if they have been observed for ≥ 28 days following the first dose, and are 
considered by both the Sponsor and Investigators to have enough safety data to conclude that a 
DLT did not occur. 
Patients who do not meet these minimum safety evaluation requirements will be regarded as 
ineligible for the DDS and an additional patient may be recruited (see Section 7.1.4). 
10.1.1.4 Pharmacokinetic analysis set 
The pharmacokinetic analysis set (PAS) consists of all patients who received at least one dose 
of EGF816 and have at least one evaluable EGF816 PK sample. Details of PAS definition can 
be found in the statistical analysis plan. 
10.1.2 
Phase II part 
10.1.2.1 Full analysis set 
The full analysis set (FAS) includes all patients who received at least one dose of EGF816. The 
FAS will be used for all listings of raw data. Unless otherwise specified, the FAS will be the 
default analysis set used for all analyses. 
10.1.2.2 Per protocol set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with the requirements of the clinical study protocol. The protocol deviations or conditions 
leading to exclusion from the PPS will be detailed in the statistical analysis plan. 
10.1.2.3 Safety set 
The Safety Set includes all patients who received at least one dose of EGF816. 
10.1.2.4 Pharmacokinetic analysis set 
The pharmacokinetic analysis set (PAS) consists of all patients who received at least one dose 
of EGF816 and have at least one evaluable EGF816 PK sample. Details of PAS definition can 
be found in the statistical analysis plan. 


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10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data will be summarized descriptively by treatment group for 
the FAS. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
10.3.1 
Study treatment 
The actual dose and duration in days of EGF816 treatment as well as the dose intensity (dose 
received/duration) and relative dose intensity (the ratio of dose intensity to planned 
dose/planned duration) will be listed and summarized by means of descriptive statistics by 
treatment group for the Safety set. 
10.3.2 
Concomitant therapies 
Use of concomitant medications and significant non-drug therapies prior to and after the start 
of the study treatment will be listed by patient and summarized by ATC term by means of 
contingency tables by treatment group for the Safety set. 
10.3.3 
Compliance 
Compliance to the protocol will be assessed by the number and proportion of patients with 
protocol deviations. These will be identified prior to database lock and will be listed and 
summarized by treatment group for the Safety set. 
10.4 
Primary objective 
Phase I part: The primary objective is to determine the MTD and or RP2D of single agent 
EGF816 when administered orally to adult patients with NSCLC harboring EGFR T790M 
mutations. 
The corresponding primary analysis method is an adaptive Bayesian logistic regression model 
(BLRM) guided by the escalation with overdose control (EWOC) principle (Neuenschwander 
et al 2008). 
Phase II part: The primary objective of the Phase II part is to estimate antitumor activity of 
EGF816 as measured by overall response rate (ORR) determined by Blinded Independent 
Review Committee (BIRC) assessment in accordance to RECIST 1.1: 
• At least 40 treatment-naïve patients who have advanced NSCLC with EGFR activating 
mutation (e.g., L858R and/or ex19del) 
10.4.1 
Variable 
10.4.1.1 Phase I part 
The primary endpoint is the incidence of dose-limiting toxicities (DLTs) in Cycle 1. Estimation 
of the MTD of the treatment will be based upon the estimation of the probability of DLT in 


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Cycle 1 for patients in the DDS. This probability is estimated by the model described in Section 
10.4.2. 
10.4.1.2 Phase II part 
The primary endpoint is the overall response rate, determined as the proportion of patients in 
FAS experiencing a best overall response of CR or PR per RECIST 1.1 at any time on study by 
BIRC assessment. 
Overall response rate and best overall response are based on confirmed responses only. 
10.4.2 
Statistical hypothesis, model and method of analysis 
10.4.2.1 Phase I part 
An adaptive, 2 parameter Bayesian logistic regression model (BLRM) guided by the escalation 
with overdose control principle will be used to make dose recommendations and estimate the 
MTD/ RP2D during the dose-escalation part of the study. 
The dose-toxicity (DLT) relationship in each dose escalation will be described by the following 
logistic regression model: 
logit(π(d)) = log(α) + β log(d/d*), 
α>0, β>0                               [1] 
where logit(π(d))= ln (π(d)/(1- π(d))), π(d) is the probability of a DLT at dose d, where d 
represents the total daily dose in capsule. Doses are rescaled as d/d* with reference dose d*= 
300 mg of EGF816 as total daily dose. As a consequence α is equal to the odds of toxicity at 
d*. Note that for a dose equal to zero, the probability of toxicity is zero. 
The Bayesian approach requires the specification of prior distributions for the model parameters. 
The prior distributions and the process for their derivation based on available pre-clinical data 
are provided in Section 14.2 Appendix 2, along with examples of hypothetical decisions that 
may be followed during the dose escalation. 
Change in drug formulation 
By amendment 07, the dose escalation decisions were already made and no additional patients 
were included for BLRM, hence the change in formulation doesn’t impact this part of the study.  
Change in dosing schedule 
In the event of a change in dosing schedule, then a new BLRM will be set up. This new BLRM 
will have the same functional form as equation [1] and will incorporate down-weighted existing 
dose-escalation data in the prior distribution. For comparability, doses for the new and old 
models will be normalized to dose in mg per day. The process by which the prior distributions 
are to be derived for this updated BLRM is described in Section 14.2 Appendix 2. 
Dose recommendation 
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels are obtained. The results of this analysis are summarized in terms of the 
estimated probabilities that the true rate of DLT at each dose-level will lie within each of the 
following intervals: 


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• [0, 0.16) under-dosing 
• [0.16, 0.33) targeted toxicity 
• [0.33, 1.00] excessive toxicity 
The overdose control criterion mandates that any dose of EGF816 for which the DLT rate has 
more than a 25% chance of being excessively toxic, i.e. P(DLT) is 0.33 or higher, will not be 
considered for the next dose cohort. The final estimate of the MTD/ RP2D will also satisfy this 
condition. 
Details of the criteria for dose escalation and the estimation of the MTD/ RP2D are provided in 
Section 6.2.3. 
Listing/ summary of DLTs 
DLTs will be listed and their incidence summarized by primary system organ class, preferred 
term type of adverse event, and by treatment group. The dose-determining set will be used for 
these summaries. 
10.4.2.2 Phase II part 
The primary analysis will be performed when patients enrolled have completed at least 6 cycles 
of treatment or discontinued treatment prior to that time. Any additional data for patients 
continuing to receive study treatment past the data cut-off date for the primary analysis will be 
reported in the final CSR at the end of the study.   There will be one interim analysis for futility 
when approximately 20 patients have completed at least 4 cycles of treatment or discontinued 
treatment prior to that time. 
The primary analysis will be performed using the FAS when all patients enrolled have 
completed at least 6 cycles of treatment or discontinued prior to that time for any reason.  
The preliminary anti-tumor activity of the study treatment will be assessed using dual criteria: 
• The posterior median ORR is equal to or greater than 55% 
• The posterior risk of being in the unacceptable anti-tumor activity is lower than 5%. 
An observed ORR ≥ 55% based on BIRC assessments will be considered clinically meaningful 
as this similar with the reported ORRs for 1st-generation EGFR TKI (gefitinib, erlotinib) and 
2nd-generation EGFR TKI (afatinib) in similar setting, (Refer to Table 1-1). 
The ORR < 40% will be considered as unacceptable anti-tumor activity. This is based on the 
ORR for carboplatin/paclitaxel-treated patients with metastatic adenocarcinoma histology 
NSCLC receiving first-line treatment. (AstraZeneca Pharmaceuticals LP (2015)). 
A Bayesian design will be used in order to estimate the ORR and to provide inferential 
summaries (e.g., mean, median, standard deviation, 90% credible intervals) based on the 
posterior distribution of ORR in the Phase II part. A minimally informative unimodal Beta 
distribution (Neuenschwander et al. 2008) will be used as a prior distribution. This prior 
distribution reflects the current uncertainty about the efficacy of EGF816. For the primary 
analysis, the posterior distributions of the ORR will be computed using the available data.  
Additionally, the ORR and 95% exact CI will be provided. 


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An interim analysis for futility will be performed when approximately 20 patients have 
completed at least 4 cycles of treatment or discontinued treatment prior to that time. More 
details on the interim analysis are presented in Section 10.7. 
The sample size calculation and rationale are provided in Section 10.8. 
10.4.3 
Handling of missing values/censoring/discontinuations 
For continuing events (e.g., AEs, concomitant medication, etc.), there will be an indication 
within listings that the event is continuing. 
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study drug treatment, duration of exposure to study drug treatment and date of 
discontinuation for each patient. 
Patients who have missing BOR will be considered as a treatment failure within the interim and 
final analyses of ORR. 
Patients who have disease progression and continue to receive study drug after progression will 
qualify for PD at the time of progression and will be counted as PD in the derivation of efficacy 
endpoints. 
Other missing data will simply be noted as missing on appropriate tables/listings. 
10.4.4 
Supportive analyses 
Additional supportive 
 analyses will be conducted to support the primary 
objective if appropriate and details of the analysis will be defined in the RAP. 
10.5 
Secondary objectives 
10.5.1 
Safety objectives 
10.5.1.1 Analysis set and grouping for the analyses 
Listings of all safety data will be provided; these will be based on the FAS. For all safety 
analyses, the safety set will be used. The overall observation period will be divided into three 
mutually exclusive periods: 
1. Pre-treatment period: From the day of informed consent until the day before first dose of 
study medication 
2. On-treatment period: From the day of first dose of study medication until 30 days after the 
last dose of study medication 
3. Post-treatment period: Starting 31 days after last dose of study medication 
All safety data will be listed. Where applicable, a flag indicating into which period observations 
fall will be provided. Safety summaries will contain only data collected in the On-treatment 
period, unless otherwise specified. For the phase I part subgroup analyses by mutation type and 
prior lines of systemic antineoplastic therapy(s) may be performed as appropriate. 
10.5.1.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 


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(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment by treatment group. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group 
Serious adverse events, non-serious adverse events and adverse events of special interest during 
the on-treatment period will be tabulated. 
10.5.1.3 Laboratory abnormalities 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, laboratory data will be graded accordingly. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all 
non-missing values not graded as 1 or higher. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests: 
• frequency table for newly occurring on-treatment grades 3 or 4 
• shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value. 
• listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges. 
 
 
 
10.5.1.4 Other safety data 
ECG 
The following analysis will be performed for ECG: 
• shift table baseline to worst on-treatment result for overall assessments 
• listing of ECG evaluations for all patients with at least one abnormality. 
Vital signs 
The following analysis will be performed for vital signs: 
• shift table baseline to worst on-treatment result 


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• table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
10.5.1.5 Tolerability 
Tolerability of study drug will be assessed by summarizing the number of dose interruptions 
and dose reductions. Reasons for dose interruption and dose reductions will be listed by patient 
and summarized. 
10.5.2 
Efficacy objectives 
CT/MRI assessments will be used for all efficacy assessments of antitumor activity on study. 
Best overall response (BOR), overall response rate (ORR), progression-free survival (PFS), 
disease control rate (DCR), duration of response (DOR) and time to response (TTR) will be 
defined as per RECIST v1.1 (see Section 14.1). Analyses will performed separately for data 
based on Investigator assessment for the Phase I part and both BIRC assessment and 
Investigator assessment for the Phase II part. 
The analyses will be based on the FAS. 
10.5.2.1 Analysis set and the grouping for analyses 
The analyses of all secondary efficacy objectives will be based on FAS. 
Phase I part: All secondary efficacy analyses will be summarized by treatment group. 
Subgroup analyses by mutation type and prior lines of systemic antineoplastic therapy(s) may 
be performed as appropriate. 
Phase II part: All secondary efficacy analyses will be summarized for all patients. 
10.5.2.2 Secondary efficacy endpoints 
The secondary efficacy endpoints including:  
Phase I part: Overall response rate (ORR), duration of response (DOR), disease control rate 
(DCR), time to response (TTR), and progression-free survival (PFS) by Investigator 
assessments in accordance to RECIST 1.1 
Phase II part: ORR by investigator assessment, DOR, DCR, TTR, PFS by both BIRC and 
Investigator assessment in accordance to RECIST 1.1 and overall survival (OS). 
Phase I/II secondary efficacy endpoints  
Best overall response 
BOR is the best response recorded from the start of the treatment until documented radiological 
disease progression/recurrence. However, any assessments taken more than 28 days after the 
last dose of study treatment will not be included in the best overall response derivation.  
The study requires that for a partial response (PR) or complete response (CR) changes in tumor 
measurements must be confirmed by repeat assessments performed not less than 4 weeks after 
the criteria for the response are first met. 
BOR will be summarized by phase and group. 


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Overall response rate (ORR) 
ORR is defined as the proportion of patients in FAS with a best overall response of complete 
response (CR) or partial response (PR) per RECIST 1.1. 
ORR will be estimated together with 95% confidence intervals (CIs) based on the exact 
binomial distribution will be presented. 
Duration of response (DOR) 
Among patients with a confirmed PR or CR per RECIST 1.1, DOR is defined as the time from 
first documented response (PR or CR) to the date of first documented disease progression or 
death due to any cause. A patient who has not progressed or died at the date of the analysis or 
when he/she receives any further anticancer therapy in the absence of disease progression will 
be censored at the time of the last adequate tumor evaluation before the earlier of the cut-off 
date or the anticancer therapy date. 
DOR will be described using Kaplan-Meier methods and including estimated median (in 
months) with 95% CI, 25th and 75th percentiles. Summary statistics of DOR for patients whose 
best response is CR or PR will be provided for groups with ≤ 5 responders. 
Disease control rate (DCR) 
DCR is defined as the proportion of patients in FAS with a best overall complete response (CR) 
or partial response (PR) or stable disease (SD) per RECIST 1.1. 
DCR will be estimated together with 95% confidence intervals (CIs) based on the exact 
binomial distribution will be presented. 
Time to response (TTR) 
TTR is defined as the time between date of start of treatment until first documented response 
(CR or PR). For patients who did not achieve a confirmed PR or CR, their TTR will be censored. 
TRR will be described using Kaplan-Meier methods and including estimated median (in months) 
with 95% CI, 25th and 75th percentiles. A summary statistics of TTR for patients whose best 
response is CR or PR will also be provided. 
Progression-free survival (PFS) 
PFS is defined as the time from the date of first dose of study treatment to the date of first 
documented disease progression per RECIST 1.1 or death due to any cause. A patient who has 
not progressed or died at the date of the analysis will be censored at the time of the last adequate 
tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. By default, 
if disease progression or death is documented after one single missing tumor evaluation, the 
actual event date of disease progression/death will be used for the PFS event date. If disease 
progression or death is documented after two or more missing tumor evaluations, the PFS time 
of these patients will be censored at the date of the last adequate tumor evaluation without PD. 
PFS will be described using Kaplan-Meier methods and including estimated median (in months) 
with 95% CI, 25th and 75th percentiles. 
Phase II only efficacy endpoints 
Overall survival (OS) 


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OS is defined as the time from the date of first dose of study drug to the date of death due to 
any cause. OS time for patients who are alive at the analysis cut-off date or are lost to follow-
up will be censored at the date of last contact. OS analysis will only be performed for phase II 
part of patients. 
OS will be described using Kaplan-Meier methods and including estimated median (in months) 
with 95% CI, 25th and 75th percentiles. 
10.5.3 
Pharmacokinetics 
The plasma samples from all patients will be assayed for EGF816 and LMI258 concentrations 
by Novartis or a Novartis-designated facility. 
Pharmacokinetic parameters will be determined by non-compartmental method(s) using the 
pharmacokinetic profile of EGF816 and LMI258. PK parameters such as listed in Table 10-1 
will be derived and reported, as appropriate. PK data generated from this study may be used in 
conjunction with PK data from other clinical studies for population PK  analysis.. 
 
 
 
 
Table 10-1 
Noncompartmental pharmacokinetic parameters 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x 
volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) (amount x time x volume-1) 
Cmax 
Maximum (peak) observed plasma drug concentration (mass x volume-1) 
Tmax 
Time to reach maximum (peak) plasma drug concentration (time) 
CL/F 
Apparent total body clearance of drug from plasma after oral administration (volume x time-1) 
Vz/F 
Apparent volume of distribution during terminal phase after oral administration (volume) 
T1/2, eff 
Effective half-life calculated from Racc (time) 
T1/2 
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives 
Racc 
Accumulation ratio calculated using AUCtau at steady state divided by AUCtau  on C1D1 
10.5.3.1 Data handling principles 
All concentrations of EGF816 and LMI258 below their respective LLOQs (lower limits of 
quantification) or missing data will be labeled as such in the concentration data listings. 
Concentrations below the LLOQ will be treated as zero in summary statistics and for the 
calculation of pharmacokinetic parameters. Any missing PK parameters will not be imputed. 
10.5.3.2 Data analysis principles 
10.5.3.2.1 
Analysis sets 
Only PK plasma concentrations with non-missing sampling date and time, and for which the 
last dose date and time prior to the PK sample draw are non -missing will be included in the PK 
analysis. Unscheduled samples are not included in any analysis, but these samples will be listed 
using FAS and flagged in the corresponding concentration listing. 


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10.5.3.2.2 
Tables, figures and listings 
Descriptive statistics (n, mean, standard deviation, median, geometric mean, coefficient of 
variation CV (%), geometric CV (%), minimum, and maximum) will be presented for EGF816 
and LMI258 plasma concentrations by treatment group. Corresponding graphical presentation 
of the plasma concentration profiles will also be provided using the arithmetic mean (+/- SD) 
and geometric mean values at each scheduled time point for full PK collections. The trough 
concentration-time profile will also be plotted. PK parameters will be summarized as well using 
descriptive statistics for EGF816 and LMI258. For Tmax, median values and ranges will be 
given.  
10.5.3.2.3 
Dose proportionality and inter- and intra-individual variability 
An initial assessment of dose-proportionality and steady-state attainment will be conducted 
Inter- and intra-individual variability in systemic exposures will be assessed. 
 
 
 
 
 
 


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10.7 
Interim analysis 
Phase I part 
No formal interim analyses are planned. However, the dose-escalation design foresees that 
decisions based on the current data are taken before the end of the study. More precisely, after 
each cohort in the dose-escalation part, the next dose will be chosen depending on the observed 
data. Details of this procedure and the process for communication with investigators are 
provided in Section 6.2.3. 
Phase II part 
A futility interim analysis (IA) will be performed when approximately 20 patients have 
completed at least 4 cycles or discontinued treatment prior to that time.  
The decision to stop enrollment will be based on the predictive probability of success (PPS), 
which is the predictive probability that the observed ORR at the end of the study will reach the 
target 55% (i.e., the probability of a positive conclusion of the study, should the trial be 
conducted to the maximum planned sample size). Given the interim observed data: x responders 
among n patients,  
PPS = Prob [Final Observed ORRAll patients ≥ 55%| x, n] 
The enrollment and/or treatment will be stopped at the interim analysis if PPS < 0.10 (i.e., if 
less than 9 out of the first 20 patients have the best overall response of CR or PR). The criterion 
(number of responders) will be based on the actual number of patients in the FAS at the time of 
the interim analysis. 
For the purpose of PPS computation, vague prior beliefs about the ORR distribution reflecting 
the current uncertainty about the efficacy of EGF816 in the study populationwill be summarized 
in prior distribution. A minimally informative Beta distribution prior (Neuenschwander et al. 
2008) with prior mean equal to a clinical threshold for futility on this population (55%) will be 
used (beta distribution with parameters a = 1 and b = (1 – 0.55)/0.55 = 0.818). At the time of 
interim analysis, the posterior parameters of the beta distribution of ORR will be computed 
using the available data. The number of responses in the potential future patients follows a beta-
binomial distribution with the same parameters. From this, the probability that the final 
observed ORRs exceeds a given threshold can be computed. 
Table 10-2 
Probability of success at the primary analysis based on various numbers 
of responders observed at the IA 
Responders at IA out of 20 evaluable patients at IA 
Probability of Success 
8/20 
0.04 
9/20 
0.14 
10/20 
0.33 
11/20 
0.57 
12/20 
0.79 


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10.8 
Sample size calculation 
10.8.1 
Phase I part 
Each cohort will consist of 1 to 6 evaluable patients in the Phase I dose-escalation part. At least 
six patients at the MTD/ RP2D level will be enrolled, as described in Section 6.2.3. Multiple 
cohorts may be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients 
may be enrolled at any dose level below the estimated MTD/RP2D for further elaboration of 
safety and pharmacokinetic parameters as required. At least 21 patients are expected to be 
treated in the dose-escalation part, for the model to have reasonable operating characteristics 
relating to its MTD recommendation. 
10.8.2 
Phase II part 
The operating characteristics of the statistical design are presented below with the probabilities 
to stop for futility at the interim analysis and to declare preliminary anti-tumor activity of the 
study treatment at the primary analysis (observing at least 22 responses in 40 patients) under 
different true ORR values (see also Table 10-3). The actual total sample size may be greater 
than 40. The cut-off for the number of responders needed will be determined at the time of the 
interim analysis based on the actual number of patients who completed up to 4 cycles of study 
treatment. 
Table 10-3 displays the probabilities to stop for futility at the interim analysis and to declare 
preliminary anti-tumor activity of the study treatment at the primary analysis (observing at least 
22 responses in 40 patients) under different true ORR values  
Table 10-3 
Operating characteristics given sample size of 40 patients and interim 
analysis at 20 patients 
True ORR 
Probability to stop for futility at IA 
Success probability at primary analysis 
0.40 
0.596 
0.038 
0.45 
0.414 
0.129 
0.50 
0.252 
0.309 
0.55 
0.131 
0.553 
0.60 
0.057 
0.780 
0.65 
0.020 
0.923 
0.70 
0.005 
0.982 
0.75 
0.001 
0.998 
0.80 
0.000 
1.000 
With a sample size of 40 patients, the operating characteristics show reasonable characteristics 
of stopping for futility when the true ORR is below the expected rate of 55% and low 
probabilities of stopping for cases with ORR in the range of 55% or above. The probability of 
a positive conclusion at the primary analysis with 40 patients is greater than 0.55 if the true 
ORR is greater or equal to 55%. 
10.9 
Power for analysis of key secondary variables 
Not applicable. 


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11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent if applicable:, or, if 
incapable of doing so, after such consent has been provided by a legally acceptable 
representative of the patient. In cases where the patient’s representative gives consent, the 
patient should be informed about the study to the extent possible given his/her understanding. 
If the patient is capable of doing so, he/she should indicate assent by personally signing and 
dating the written informed consent document or a separate assent form. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of childbearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
Additional consent form 
Companion study will have a separate consent form covering this study. This form will be 
adapted for each Study based on a standard template used globally for all Studies. These 


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informed consent forms will be submitted for ethical approval together with the Study Protocol 
and the main informed consent form of the Study. If a subject opts not to participate in the 
optional assessments, this in no way affects the subject’s ability to participate in the main 
research study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in  
Section 4.4. 
11.5 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted in a publicly accessible database e.g. such as ...clinicaltrials.gov, before study 
start. In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of upon study completion (i.e., LPLV), and finalization of the study report the results of 
this study will be either submitted for publication and/or posted in those for interventional 
clinical trials involving pediatric patients within 6 months of study completion. 
Novartis follows the ICMJE authorship guidelines (...icmje.org) and other specific guidelines 
of the journal or congress to which the publication will be submitted  
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.  
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.  
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to ...novartis.com. 


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11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 


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11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days. 


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13 
References (available upon request) 
AstraZeneca Pharmaceuticals LP (2015). IRESSA (gefitinib) [package insert]. Wilmington, 
DE: AstraZeneca Pharmaceuticals LP. 
Babb J, Rogatko A and Zacks S. (1998) Cancer Phase I clinical trials; efficient dose escalation 
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Bean J, Brennan C, Shih JY, et al. (2007) MET amplification occurs with or without T790M 
mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc 
Natl Acad Sci U S A. 104(52):20932–7.  
Brawley OW (2011) Avoidable cancer deaths globally. CA Cancer J Clin.  61(2):67-8.  
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01961.jsp&mid=WC0b01ac058001d124 
Engelman JA, Zejnullahu K, Mitsudomi T, et al. (2007) MET amplification leads to gefitinib 
resistance in lung cancer by activating ERBB3 signaling. Science. 316(5827):1039–43. 
fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472565.htm 
Fowell DJ, Shinkai K, Liao XC,et al. (1999) Impaired NFATc translocation and failure of Th2 
development in Itk-deficient CD4+ T cells. Immunity. 11(4):399-409. 
Han J Y, Park K, Kim SW, et al (2012). First-SIGNAL: first-line single-agent iressa versus 
gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin 
Oncol. 30(10):1122-28. 
Hirsch FR, Varella-Garcia M, Bunn Jr PA, et al. (2003) Epidermal growth factor receptor in 
non-small-cell lung carcinomas: correlation between gene copy number and protein 
expression and impact on prognosis. J Clin Oncol. 21(20):3798–807. 
Inoue A, Kobayashi K, Usui K, et al. (2009) First-line gefitinib for patients with advanced 
non-small-cell lung cancer harboring epidermal growth factor receptor mutations without 
indication for chemotherapy. J Clin Oncol. 27(9):1394–400. 
Jänne PA, Yang JC, Kim DW, et al (2015). AZD9291 in EGFR inhibitor-resistant non-small 
cell lung cancer. N Engl J Med; 372(18): 1689-99. 
Kobayashi S, Boggon TJ, Dayaram T, et al. (2005) EGFR mutation and resistance of non-
small-cell lung cancer to gefitinib. N Engl J Med. 352(8):786–92. 
Lynch TJ, Bell DW, Sordella R, et al. (2004) Activating mutations in the epidermal growth 
factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J 
Med. 350(21):2129–39. 
 
Mendelsohn J, Baselga J. (2000) The EGF receptor family as targets for cancer therapy. 
Oncogene. 19(56):6550–65. 
Mitsudomi T, Morita S, Yatabe Y, et al. (2010) Gefitinib versus cisplatin plus docetaxel in 
patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor 
receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 11(2):121–8. 


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Mok TS, Wu YL, Thongprasert S, et al. (2009) Gefitinib or carboplatin-paclitaxel in 
pulmonary adenocarcinoma. N Engl J Med. 361(10):947–57. 
Neuenschwander B, Branson M, Gsponer T. (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Statist. Med. 27:2420-2439. 
Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter DJ. (2010) Summarizing 
historical information on controls in clinical trials. Clinical Trials. 7, 5-18. 
Paez JG, Janne PA, Lee JC, et al. (2004) EGFR mutations in lung cancer: correlation with 
clinical response to gefitinib therapy. Science. 304(5676):1497–500. 
Pao W, Miller V, Zakowski M, et al. (2004) EGF receptor gene mutations are common in 
lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib 
and erlotinib. Proc Natl Acad Sci U S A. 101(36):13306–11. 
Rosell R, Carcereny E, Gervais R, et al. (2012) Erlotinib versus standard chemotherapy as 
first-line treatment for European patients with advanced EGFR mutation positive non-small-
cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet 
Oncol. 13(3):239–46. 
Rosell R, Molina MA, Costa C, et al. (2011) Pretreatment EGFR T790M mutation and 
BRCA1 mRNA expression in erlotinib-treated advanced nonsmall-cell lung cancer patients 
with EGFR mutations. Clin Cancer Res. 17(5):1160–8. 
Sagiv-Barfi I1, Kohrt HE1, Czerwinski DK1, et al. (2015). Therapeutic antitumor immunity 
by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl 
Acad Sci U S A. 112(9):E966-72. doi: 10.1073/pnas.1500712112. Epub 2015 Feb 17. 
Sangodkar J, Katz S, Melville H, et al. (2010) Lung adenocarcinoma: lessons in ranslation 
from bench to bedside. Mt Sinai J Med. 77(6):597-605.  
Sequist LV, Yang JC, Yamamoto N, et al. (2013) Phase III study of afatinib or cisplatin plus 
pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin 
Oncol. 31(27):3327-34.  
Sequist LV, Waltman BA, Dias-Santagata D, et al. (2011) Genotypic and histological 
evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 
3(75):75ra26.  
Soria J, Sequist LV, Goldman JW, et al. (2-14) EORTC-NCI-AACR LATE BREAKING 
ABSTRACT Interim phase 2 results of study CO-1686-008: A phase 1/2 study of the 
irreversible, mutant selective, EGFR inhibitor rociletinib. Presented at EORTC-NCI-AACR 
Annual Meeting. 
Su KY, Chen HY, Li KC, et al. (2012) Pretreatment epidermal growth factor receptor (EGFR) 
T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients 
with non-small-cell lung cancer. J Clin Oncol. 30(4):433–40. 
Takezawa K, Pirazzoli V, Arcila ME, et al. (2012)  HER2 amplification: a potential 
mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack 
the second-site EGFR T790M mutation. Cancer Discov. 2(10):922–33.  


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Tan S-W D, Yang C-H J,(2016) Updated results of a phase 1 study of EGF816, a third-
generation, mutant-selective EGFR tyrosine kinase inhibitor, in advanced non-small cell lung 
cancer harboring T790M, J Clin Oncol 34, (suppl; abstr 9044) 
Terrault NA, Lok ASF, McMahon BJ, et al (2018) Update on Prevention, Diagnosis, and 
Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance. Hepatology. 
67(4): 1560-1599 
Wu YL, Zhou C, Hu CP, et al. (2014) Afatinib versus cisplatin plus gemcitabine for first-line 
treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR 
mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. S1470-
2045(13)70604-1. 
Yang, J,et al. (2014) Updated safety andefficacy from a Phase 1 study of AZD9291 in patients (pts) 
withEGFR-TKI-resistant non-small cell lung cancer (NSCLC). Presented at European Society for 
Medical Oncology (ESMO) Annual Meeting,   
 Yu H, Arcila ME, Rekhtman N, et al. (2013) Analysis of Mechanisms of Acquired 
Resistance to EGFR TKI therapy in 155 patients with EGFR-mutant Lung Cancers. Clin 
Cancer Res. 19(8): 2240–2247. 
Yu HA, Pao W. (2013) Afatinib-new therapy option for EGFR-mutant lung cancer. Nat Rev 
Clin Oncol. 10(10):551-2.  
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12:735–42. 


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14 
Appendices 
14.1 
Appendix 1 – Guidelines for response, duration of overall 
response, TTF, TTP, progression-free survival and overall 
survival (based on RECIST 1.1) 
 
Document type: 
TA Specific Guideline 
Document status: 
Version 3.2: --> February 11, 2016 
Version 3.1: 
29-Nov-2011 
Version 3:0: 
19-Oct-2009 
Version 2:0: 
18-Jan-2007 
Version 1:0: 
13-Dec-2002 
Release date: 
11-Feb-2016 
Authors (Version 3.2): 
 
 
Authors (Version 3.1): 
 
 
Authors (Version 3): 
 
 
Authors (Version 2): 
 
 
Authors (Version 1): 
 


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Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
GBM 
Glioblastoma multiforme 
MRI 
Magnetic resonance imaging 
LPLV 
Last patient last visit 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
UNK 
Unknown 


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14.1.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.18 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.29 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming. 
14.1.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247. 
14.1.3 
Definitions 
14.1.4 
Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
• Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. If 
the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For patients without measurable disease see Section 14.1.27. 
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft tissue 
component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease. 
• Cystic lesions: 


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• Lesions that meet the criteria for radiographically defined simple cysts (i.e. spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no septations, 
and low CT density [water-like] content) 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. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with  10 
to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques.  
14.1.5 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in Section 
14.1.27. 
14.1.6 
Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-up. 
Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed using 
a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan slice 
thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. If, at 
baseline, a patient is known to have a medical contraindication to CT contrast or develops 
a contraindication during the trial, the following change in imaging modality will be 
accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 
• A change in methodology can be defined as either a change in contrast use (e.g. keeping the 
same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 


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conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response assessment can 
be justified, based on the available information. 
• FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline with a positive FDG-PET at follow-up: 
• If new disease is indicated by a positive PET scan but is not confirmed by CT (or some other 
conventional technique such as MRI) at the same assessment, then follow-up assessments 
by CT will be needed to determine if there is truly progression occurring at that site. In all 
cases PD will be the date of confirmation of new disease by CT (or some other conventional 
technique such as MRI) rather than the date of the positive PET scan. If there is a positive 
PET scan without any confirmed progression at that site by CT, then a PD cannot be 
assigned.  
• 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. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Physical exams: Evaluation of lesions by physical examination is accepted when lesions 
are superficial, with at least 10mm size, and can be assessed using calipers.  
• Ultrasound: When the primary endpoint of the study is overall response rate, ultrasound 
(US) should not be used to measure tumor lesions, unless pre-specified by the protocol. It 
is, however, a possible alternative to clinical measurements of superficial palpable lymph 
nodes, subcutaneous lesions and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained. 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, some 
disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, PSA 
for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be integrated 
as non-target disease. If markers are initially above the upper normal limit they must 
normalize for a patient to be considered in complete clinical response when all lesions have 
disappeared. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e. after treatment to differentiate between residual benign lesions and 


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residual malignant lesions in tumor types such as germ cell tumors). Cytologic confirmation 
of neoplastic nature of any effusion that appears or worsens during treatment is required 
when the measurable tumor has met the criteria for response or stable disease. Under such 
circumstances, the cytologic examination of the fluid collected will permit differentiation 
between response and stable disease (an effusion may be a side effect of the treatment) or 
progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e. skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
14.1.7 
Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF (even 
if it resides in the same organ). 
Minimum target lesion size at baseline 
• Non-nodal target: Non-nodal target lesions identified by methods for which slice thickness 
is not applicable (e.g. clinical examination, photography) should be at least 10 mm in longest 
diameter. See Section 14.1.4. 
• Nodal target: See Section 14.1.4. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of non-
target lesions should be assessed throughout the study; measurements of these lesions are 
not required. Multiple non-target lesions involved in the same organ can be assessed as a 
group and recorded as a single item (i.e. multiple liver metastases). Each non-target lesion 
identified at baseline must be followed at each subsequent evaluation and documented on 
eCRF. 
14.1.8 
Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. These 


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evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-3) as well as the presence or absence of new lesions. 
14.1.9 
Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number. 
14.1.10 Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e. size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
14.1.11 Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 


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14.1.12 Determination of target lesion response 
Table 14-1 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes 
assigned as target lesions must have a reduction in short axis to < 10 mm 1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, taking as reference 
the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameter of all measured target lesions, taking as 
reference the smallest sum of diameter of all target lesions recorded at or after baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm2. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which 
would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions have not been 
assessed or have been assessed using a different method than baseline.3 
1.SOD for CR may not be zero when nodal lesions are part of target lesions 
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all  
nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
3. In exceptional circumstances an UNK response due to change in method could be over-ruled by the  
investigator or central reviewer using expert judgment based on the available information (see Notes on  
target lesion response and methodology change See Section 14.1.6. 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e. 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered as 
progressive disease 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-1 above (i.e. a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who have 
not achieved target response of CR. For patients who have achieved CR, please refer to last 
bullet in this section. 
• For those patients who have only one target lesion at baseline, the reappearance of the target 
lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 100 
mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit is 140 


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mm (with data for 2 other lesions missing) then a PD should be assigned. However, in other 
cases where a PD cannot definitely be attributed, the target lesion response would be UNK. 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal in 
order not to overstate progression should it be based on increase in the size of nodes. 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at baseline 
and appears to be one mass can split to become two or more smaller sub-lesions. When this 
occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of the two split 
lesions should be added together and the sum recorded in the diameter field on the case report 
form under the original lesion number. This value will be included in the sum of diameters 
when deriving target lesion response. The individual split lesions will not be considered as 
new lesions, and will not automatically trigger a PD designation. 
• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they are 
no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - nodal 
lesions) of the “merged lesion” should be used when calculating the sum of diameters for 
target lesions. On the case report form, the diameter of the “merged lesion” should be 
recorded for the size of one of the original lesions while a size of “0”mm should be entered 
for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response should 
be assigned when all nodal target lesions shrink to less than 10 mm and all non-nodal target 
lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters. 
• A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression in 
which case the investigator might assign an SD target lesion response; however, this should 
be done with caution and conservatively as the response categories have well defined 
criteria.  


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14.1.13 Determination of non-target lesion response 
Table 14-2 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-
target lesions must be non-pathological in size (< 10 mm short axis) 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.1 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target lesions have not 
been assessed or have been assessed using a different method than baseline2. 
1 The assignment of PD solely based on change in non-target lesions in light of target lesion response of CR,  
PR or SD should be exceptional. In such circumstances, the opinion of  Investigator or central review does  
prevail and the progression status should be confirmed later on by the review panel (or study chair). 
2 It is recommended that the investigator and/or central reviewer should use expert judgment to assign  
a Non-UNK response wherever possible (see notes section for more details)  
Notes on non-target lesion response 
• The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned  
• The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions returned 
to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or there are 
any abnormal nodal lesions (i.e.  10 mm) the response can only be ‘Non-CR/Non-PD’ 
there is unequivocal progression of the non-target lesions (in which case response is PD) or 
it is not possible to determine whether there is unequivocal progression (in which case 
response is UNK). 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable disease 
at baseline. If there is unequivocal progression of non-target lesion(s), then at least one of 
the non-target lesions must be assigned a status of “Worsened”. Where possible, similar 
rules to those described in Section 14.1.12 for assigning PD following a CR for the non-
target lesion response in the presence of non-target lesions nodal lesions should be applied. 


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14.1.14 New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page. 
• 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 
first observation of the lesion. 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.15). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to  10 mm for the first time in the study plus 5 
mm absolute increase. FDG-PET: can complement CT scans in assessing progression 
(particularly possible for ‘new’ disease). See Section 14.1.6. 
14.1.15 Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 14-3. 
Table 14-3 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall 
lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.2. Once 
confirmed PR was achieved, all these assessments are considered PR. 
3. As defined in Section 14.1.8. 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 


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14.1.16 Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.27 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 
14.1.17 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• -For non-randomized trials where response is the primary endpoint, confirmation is needed. 
• -For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR prior 
to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment 
(and not qualifying for CR or PR). 
• PD = progression  12 weeks after randomization/ start of treatment (and not qualifying for 
CR, PR or SD). 


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• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks) 
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6 
week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment.  
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD. 
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 


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The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses. 
Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.  
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach). 
14.1.18 Time to event variables 
The protocol should state which of the following variables is used in that study. 
14.1.19 Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment. 


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PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint. 
14.1.20 Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive. 
14.1.21 Time to progression 
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment. 
14.1.22 PFS2  
A recent EMA guidance (EMA, 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”.  
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol. 
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments.  
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen. 
14.1.23 Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 


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reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease. 
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment. 
14.1.24 Duration of response 
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by Morgan 
(1988). 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression. 
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen. 
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression. 
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression. 


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14.1.25 Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 14.1.24. It is recommended that an 
analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the worst 
possible outcome as it means the patient cannot subsequently respond. Since the statistical 
analysis usually makes use of the ranking of times to response it is sufficient to assign the 
worst possible censoring time which could be observed in the study which is equal to the 
maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
14.1.26 Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number. 
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations. 
Start dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion response 
of CR (for duration of overall complete response) or CR / PR (for duration of overall 
response) respectively, when this status is later confirmed. 


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End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the date 
of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus the 
protocol specified time interval for assessments. This date may be used if back-dating is 
considered when the event occurred beyond the acceptable time window for the next tumor 
assessment as per protocol (see Section 14.1.26). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is used. 
If no survival follow-up is available, the date of discontinuation is used as last contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
14.1.27 Handling of patients with non-measurable disease only at baseline 
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations. 
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with non-
measurable disease is derived slightly differently according to Table 14-4. 
Table 14-4 
Overall lesion response at each assessment: patients with non-target 
disease only 
Non-target lesions 
New Lesions 
Overall lesion response 


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CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 14.1.8. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease. 
14.1.28 Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and SAP specify the primary 
analysis in detail with respect to the definition of event and censoring dates and also include a 
description of one or more sensitivity analyses to be performed. 
Based on definitions outlined in Section 14.1.26, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) 
as a reference, the following analyses can be considered: 
Table 14-5 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified differently in 
the protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of treatment3 
Censored 
B 
Progression at or before next scheduled 
assessment 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 
Progression or death after exactly one 
missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 


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Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified differently in 
the protocol or RAP 
Outcome 
C2 
Progression or death after two or more 
missing assessments 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate assessment 
Censored 
E 
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim 
(1) Ignore clinical progression and follow 
situations above 
(2) Date of discontinuation (visit date at which 
clinical progression was determined) 
As per above 
situations  
Progressed 
F 
New anticancer therapy given 
(1) Ignore the new anticancer therapy and 
follow situations above (ITT approach)  
(2) Date of last adequate assessment prior to 
new anticancer therapy  
(2) Date of secondary anti-cancer therapy 
(3) Date of secondary anti-cancer therapy 
As per above 
situations  
Censored 
Censored 
Event 
G 
Deaths due to reason other than 
deterioration of ‘Study indication’ 
(1) Date of last adequate assessment 
Censored 
(only TTP and 
duration of 
response) 
1.=Definitions can be found in Section 14.1.26 
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.1.26. 
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death. 
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e. 
• (C1) taking the actual progression or death date, in the case of only one missing 
assessment. 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments. 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 


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would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy. 
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan.  
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.  
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly followed 
from baseline, immediately before or on the date of the last adequate tumor assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or SAP documentation. 
14.1.29 Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 
14.1.30 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
SAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the SAP documentation. 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the SAP 
documentation before database lock). 


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14.1.31 End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
Death is a reason which “must” lead to discontinuation of patient from trial 
14.1.32 End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 


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14.1.33 Medical validation of programmed overall lesion response 
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD), This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses  
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled. 
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
SAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
14.1.34 Programming rules 
The following should be used for programming of efficacy results: 
14.1.35 Calculation of ‘time to event’ variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
14.1.36 Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.1.26). If all measurement dates have no 
day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 


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previous and following assessment is not available, this assessment will not be used for any 
calculation. 
14.1.37 Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
14.1.38 Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
14.1.39 Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
14.1.40 Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see Table 14-5) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy 
*Adequate assessment is defined in Section 14.1.26. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted: 
• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 


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• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment. 
• This reason will also be used to censor in case of no baseline assessment. 


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14.1.41 References (available upon request) 
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791 
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47 
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465 
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man 
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18 
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16 


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14.2 
Appendix 2 – Operating characteristics of the Bayesian logistic 
regression mode and hypothetical dose-escalation scenarios 
14.2.1 
Introduction 
An adaptive Bayesian logistic regression model (with 2 parameters) guided by the escalation 
with overdose control principle will be used to make dose recommendations and estimate the 
MTD/ RP2D during the escalation part of the study. The use of Bayesian response adaptive 
models for Phase I studies has been advocated by the EMEA guideline on small populations 
(2006) and by Rogatko (2007) and is one of the key elements of the FDA’s Critical Path 
Initiative. 
14.2.2 
Model specifications 
14.2.2.1 Statistical model for capsule formulation in qd schedule 
The dose-toxicity (DLT) relationship in the escalation part of the study will be described by the 
following logistic regression model: 
logit(π(d)) = log(α) + β log(d/d*),  
α>0, β>0 
where logit(π(d))= ln ((d)/(1-(d))), and π(d) is the probability of a DLT at dose d in capsule. 
Doses are rescaled as d/d* with reference dose d*=300 mg of EGF816. As a consequence α is 
equal to the odds of toxicity at d*. Note that for a dose equal to zero, the probability of toxicity 
is zero. 
This study uses a weakly informative bivariate normal prior for the model parameters 
(log(),log()) based on prior guesses (medians) from preclinical data and wide confidence 
intervals for the probabilities of DLT at each dose, and can be obtained as follows: 
• For the purposes of tuning the prior for the model, the median DLT rate at 75 mg qd is 
assumed to be at 0.1%, and the median DLT rate at 750 mg qd is assumed to be at 25%. For 
the remaining doses, median DLT rates a priori are assumed linear in the logit-scale as a 
function of log-dose. 
• Based on the above specified medians for the DLT rate at certain dose and wide prior 
confidence intervals, the optimal parameters of the bivariate normal distribution can be 
obtained following the procedure described by (Neuenschwander et al 2008). 
All the information to derive the prior distributions for the model parameters is provided in 
Table 14-6. Table 14-7 summarizes the associated prior distribution of the DLT rates. The doses 
not meeting the overdose criteria are bold in the table, i.e. doses not eligible at the start of the 
study (under the prior). 


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Table 14-6 
Prior distribution of model parameters 
Parameter 
Means 
Standard deviations 
Correlation 
log(α), log(β) 
-3.068,0.564 
2.706,0.728 
-0.817 
Table 14-7 
Summary of prior distribution of DLT rates 
EGF816 dose (mg 
qd) 
Prior probabilities that Pr(DLT) is 
in interval: 
Mean 
SD 
Quantiles 
[0, 0.16) 
[0.16, 0.33) 
[0.33, 1] 
2.50% 
50.00% 
97.50% 
50 
0.871 
0.047 
0.082 
0.075 
0.186 
0.000 
0.002 
0.772 
75 (starting dose) 
0.849 
0.055 
0.096 
0.088 
0.199 
0.000 
0.004 
0.808 
150 
0.794 
0.076 
0.130 
0.119 
0.223 
0.000 
0.013 
0.860 
300 
0.700 
0.110 
0.190 
0.170 
0.251 
0.000 
0.044 
0.903 
450 
0.603 
0.147 
0.251 
0.220 
0.267 
0.002 
0.095 
0.923 
600 
0.485 
0.185 
0.330 
0.280 
0.277 
0.006 
0.170 
0.938 
800 
0.338 
0.207 
0.455 
0.364 
0.290 
0.014 
0.286 
0.958 
1000 
0.237 
0.197 
0.566 
0.439 
0.297 
0.024 
0.398 
0.975 
Note: bold values indicate doses not meeting the overdose criterion (more than 25% chance of excessive toxicity) 
with the prior information only. 
To check the performance of the model, some hypothetical dose-escalation scenarios were 
investigated and are summarized in Section 14.2.3.1 below. Details regarding dose 
recommendation are described in Section 10.4.2 of the protocol. 
14.2.2.2 Statistical model for tablet formulation in qd schedule 
A new BLRM will be set up for tablet formulation. This new BLRM will have the same 
functional form as above: 
logit(πT(d)) = log(αT) + βT log(d/d*),  αT>0, βT>0 
where logit(πT(d))= ln (T(d)/(1-T(d))), and πT(d) is the probability of a DLT at dose d in tablet. 
Doses are rescaled as d/d* with reference dose d*=300 mg of EGF816. As a consequence αT is 
equal to the odds of toxicity at d*. Note that for a dose equal to zero, the probability of toxicity 
is zero. 
The prior distributions for the model parameters (log(T), log(T)) are the same as those for 
(log(), log()) in Table 14-6.  
Prior to each dose-escalation meeting the available capsule dose-DLT data will be included in 
the likelihood with a discounted weight w: 
𝑤=
1
1 + 2𝑛𝜏2/𝜎2 
In this formula n is the total number of evaluable patients in the DDS of capsule formulation, σ 
is the “outcome standard deviation” for one observation and set to 2, and τ is the between-
formulation standard deviation and set to 0.25 for moderate heterogeneity between capsule and 


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tablet (Neuenschwander et al. 2010). This choice of τ is based on the similar dissolution profiles 
of capsule and of tablet as described in Section 6.2.1. 
14.2.3 
Hypothetical dose-escalation scenarios 
In order to show how the Bayesian model reacts, different hypothetical dose-escalation 
scenarios were investigated. The design should make reasonable dose-recommendations during 
the clinical trial based on the observed DLTs. During the study, the decision to dose escalate 
after completion of a given cohort and the actual dose chosen for the subsequent cohort will 
depend on the recommendation of the BLRM per EWOC principle and medical review of 
available clinical and laboratory data. 
14.2.3.1 Scenarios for capsule formulation in qd schedule  
Some scenarios to illustrate the dose escalation up to the fifth dose cohort are listed in Table 
14-8. The maximum dose increment allowed in the scenarios did not exceed 100% as per 
escalation rules defined in Section 6.2.3. The recommended next dose level satisfied the EWOC 
principle. 
Table 14-8 
Hypothetical scenarios for capsule on-study decisions (cohort size: 1-
6) 
Scenario 
Current capsule status 
For next capsule cohort 
EGF816 
dose 
(mg qd) 
Npat 
Ntox 
EGF816 
dose 
(mg qd) 
P(Target) 
P(Over) 
Median 
DLT rate 
1 
75 
1 
0 
 
150 
 
0.074 
 
0.070 
 
0.009 
2 
75 
2 
0 
 
150 
 
0.069 
 
0.042 
 
0.008 
3 
75 
3 
1 
 
50 
 
0.255 
 
0.208 
 
0.143 
4 
75 
6 
1 
 
150 
 
0.328 
 
0.228 
 
0.183 
5 
75 
150 
1 
2 
0 
0 
 
 
300 
 
 
0.102 
 
 
0.057 
 
 
0.024 
6 
75 
150 
1 
3 
0 
1 
 
 
150 
 
 
0.296 
 
 
0.225 
 
 
0.169 
7 
75 
150 
300 
1 
2 
4 
0 
0 
0 
 
 
 
600 
 
 
 
0.186 
 
 
 
0.098 
 
 
 
0.078 
8 
75 
150 
300 
1 
2 
4 
0 
0 
1 
 
 
 
300 
 
 
 
0.294 
 
 
 
0.110 
 
 
 
0.127 
9 
75 
150 
300 
1 
2 
4 
0 
0 
2 
 
 
 
150 
 
 
 
0.314 
 
 
 
0.126 
 
 
 
0.140 


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Scenario 
Current capsule status 
For next capsule cohort 
EGF816 
dose 
(mg qd) 
Npat 
Ntox 
EGF816 
dose 
(mg qd) 
P(Target) 
P(Over) 
Median 
DLT rate 
10 
75 
150 
300 
1 
2 
6 
0 
0 
1 
 
 
 
450 
 
 
 
0.353 
 
 
 
0.171 
 
 
 
0.169 
11 
75 
150 
300 
600 
 
1 
2 
4 
5 
 
0 
0 
0 
0 
 
 
 
 
 
1000 
 
 
 
 
0.264 
 
 
 
 
0.216 
 
 
 
 
0.152 
12 
75 
150 
300 
600 
1 
2 
4 
5 
0 
0 
0 
1 
 
 
 
 
600 
 
 
 
 
0.315 
 
 
 
 
0.082 
 
 
 
 
0.130 
13 
75 
150 
300 
600 
1 
2 
4 
5 
0 
0 
0 
2 
 
 
 
 
450 
 
 
 
 
0.314 
 
 
 
 
0.081 
 
 
 
 
0.129 
14 
75 
150 
300 
600 
800 
1 
2 
4 
5 
4 
0 
0 
0 
0 
0 
 
 
 
 
 
1000 
 
 
 
 
 
0.234 
 
 
 
 
 
0.082 
 
 
 
 
 
0.101 
15 
75 
150 
300 
600 
800 
1 
2 
4 
5 
4 
0 
0 
0 
0 
1 
 
 
 
 
 
800 
 
 
 
 
 
0.345 
 
 
 
 
 
0.098 
 
 
 
 
 
0.144 
16 
75 
150 
300 
600 
800 
1 
2 
4 
5 
4 
0 
0 
0 
0 
2 
 
 
 
 
 
600 
 
 
 
 
 
0.289 
 
 
 
 
 
0.037 
 
 
 
 
 
0.117 
17 
75 
150 
300 
600 
800 
1 
2 
4 
5 
4 
0 
0 
0 
0 
3 
 
 
 
 
 
600 
 
 
 
 
 
0.421 
 
 
 
 
 
0.101 
 
 
 
 
 
0.165 
Within Table 14-8, P(Target) represents the probability that the true DLT rate for the dose lies 
in the target interval (16%, 33%) while P(Over) represents the probability that the true DLT 
rate for the dose exceeds 33%. Note, the actual number of evaluable patients per cohort is 
variable (see Section 6.2.3) and the recommendations during the study will depend on the 
number of evaluable patients at each dose level and the observed number of DLT. 


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For this FIH trial, in early cohort scenarios, the model is showing appropriate behaviors which 
are conservative but sensitive to data. Overall, the model is showing appropriate behaviors, in 
agreement with clinical sense and decision making process. The dose levels investigated 
correspond to the provisional dose levels specified in Section 6.2.2. 
Similarly, Table 14-9 shows some scenarios with exactly 3 evaluable patients in each cohort. 
Table 14-9 
Hypothetical scenarios for capsule on-study decisions (cohort size: 3) 
Scenario 
Current capsule status 
For next  capsule cohort 
EGF816 
dose 
(mg qd) 
Npat 
Ntox 
EGF816 
dose 
(mg qd) 
P(Target) 
P(Over) 
Median 
DLT rate 
1 
75 
3 
0 
 
150 
 
0.059 
 
0.032 
 
0.006 
2 
75 
3 
1 
 
50 
 
0.255 
 
0.208 
 
0.143 
3 
75 
3 
2 
 
STOP 
 
 
 
 
4 
75 
150 
3 
3 
0 
0 
 
 
300 
 
 
0.085 
 
 
0.030 
 
 
0.050 
5 
75 
150 
3 
3 
0 
1 
 
 
150 
 
 
0.280 
 
 
0.130 
 
 
0.128 
6 
75 
150 
3 
3 
0 
2 
 
 
75 
 
 
0.358 
 
 
0.206 
 
 
0.184 
7 
75 
150 
300 
3 
3 
3 
0 
0 
0 
 
 
 
600 
 
 
 
0.193 
 
 
 
0.103 
 
 
 
0.080 
8 
75 
150 
300 
3 
3 
3 
0 
0 
1 
 
 
 
300 
 
 
 
0.287 
 
 
 
0.103 
 
 
 
0.124 
9 
75 
150 
300 
3 
3 
3 
0 
0 
2 
 
 
 
150 
 
 
 
0.308 
 
 
 
0.085 
 
 
 
0.127 
10 
75 
150 
150 
3 
3 
3 
0 
1 
0 
 
 
 
300 
 
 
 
0.352 
 
 
 
0.200 
 
 
 
0.182 
11 
75 
150 
150 
3 
3 
3 
0 
1 
1 
 
 
 
150 
 
 
 
0.427 
 
 
 
0.199 
 
 
 
0.201 
12 
75 
150 
150 
3 
3 
3 
0 
1 
2 
 
 
 
75 
 
 
 
0.424 
 
 
 
0.174 
 
 
 
0.191 


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Scenario 
Current capsule status 
For next  capsule cohort 
EGF816 
dose 
(mg qd) 
Npat 
Ntox 
EGF816 
dose 
(mg qd) 
P(Target) 
P(Over) 
Median 
DLT rate 
13 
75 
150 
75 
3 
3 
3 
0 
2 
0 
 
 
 
75 
 
 
 
0.304 
 
 
 
0.071 
 
 
 
0.123 
14 
75 
150 
75 
3 
3 
3 
0 
2 
1 
 
 
 
50 
 
 
 
0.400 
 
 
 
0.144 
 
 
 
0.173 
15 
75 
150 
75 
3 
3 
3 
0 
2 
2 
 
 
 
STOP 
 
 
 
 
16 
75 
50 
3 
3 
1 
0 
 
 
 
75 
 
 
0.265 
 
 
0.101 
 
 
0.111 
17 
75 
50 
3 
3 
1 
1 
 
 
 
STOP 
 
 
 
18 
75 
50 
75 
3 
3 
3 
1 
0 
0 
 
 
 
150 
 
 
 
0.327 
 
 
 
0.134 
 
 
 
0.147 
19 
75 
50 
75 
3 
3 
3 
1 
0 
1 
 
 
 
75 
 
 
 
0.420 
 
 
 
0.166 
 
 
 
0.186 
20 
75 
50 
75 
3 
3 
3 
1 
0 
2 
 
 
 
STOP 
 
 
 
 
 
 
 
 
 
 
 
 
21 
75 
50 
75 
150 
3 
3 
3 
3 
1 
0 
0 
0 
 
 
 
 
 
300 
 
 
 
 
0.376 
 
 
 
 
0.223 
 
 
 
 
0.196 
22 
75 
50 
75 
150 
3 
3 
3 
3 
1 
0 
0 
1 
 
 
 
 
 
150 
 
 
 
 
0.458 
 
 
 
 
0.188 
 
 
 
 
0.204 
23 
75 
50 
75 
150 
3 
3 
3 
3 
1 
0 
0 
2 
 
 
 
 
 
75 
 
 
 
 
0.456 
 
 
 
 
0.125 
 
 
 
 
0.182 
14.2.3.2 Scenarios for tablet formulation in qd schedule 
The dose-escalation scenarios for tablet formulation will depend on the available capsule dose-
DLT data. Three hypothetical capsule datasets are considered (Table 14-10). 


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Table 14-10 
Hypothetical capsule dose-DLT datasets prior to the first tablet dose-
escalation meeting 
Capsule 
dataset 
75mg 
150mg 
300mg 
Dose 
for 
next 
capsule cohort 
Tablet 
starting dose 
Npat 
Ntox 
Npat 
Ntox 
Npat 
Ntox 
1 
3 
0 
3 
0 
3 
0 
600mg 
300mg 
2 
3 
0 
3 
0 
3 
1 
300mg 
300mg 
3 
3 
0 
3 
0 
3 
2 
150mg 
150mg 
Assuming no further capsule data are available, some scenarios to illustrate the tablet dose 
escalation up to two cohorts based on specific hypothetical capsule datasets are listed in Table 
14-11 through Table 14-13. The dose levels investigated correspond to the provisional dose 
levels specified in Section 6.2.2. The maximum dose increments allowed in the scenarios do 
not exceed 100% as per escalation rules defined in Section 6.2.3. The recommended next dose 
levels satisfy the EWOC principle and other rules specified in Section 6.2.3.2. 
Table 14-11 
Hypothetical scenarios for tablet on-study decisions (cohort size: 3) 
using hypothetical capsule dataset 1 
Scenario 
Current tablet status 
For next tablet cohort 
EGF816 dose 
(mg qd) 
Npat 
Ntox 
EGF816 dose 
(mg qd) 
P(Target) 
P(Over) 
Median 
DLT rate 
1 
300 
3 
0 
600 
0.181 
0.080 
0.075 
2 
300 
3 
1 
450 
0.354 
0.185 
0.173 
3 
300 
3 
2 
150 
0.232 
0.040 
0.096 
4 
300 
600 
3 
3 
0 
0 
800 
0.232 
0.121 
0.105 
5 
300 
600 
3 
3 
0 
1 
600 
0.341 
0.145 
0.156 
6 
300 
600 
3 
3 
0 
2 
450 
0.350 
0.120 
0.151 
7 
300 
450 
3 
3 
1 
0 
600 
0.381 
0.184 
0.182 
8 
300 
450 
3 
3 
1 
1 
450 
0.460 
0.232 
0.224 
9 
300 
450 
3 
3 
1 
2 
300 
0.479 
0.170 
0.202 
10 
300 
150 
3 
3 
2 
0 
300 
0.428 
0.142 
0.181 
11 
300 
150 
3 
3 
2 
1 
150 
0.382 
0.072 
0.148 
12 
300 
150 
3 
3 
2 
2 
75 
0.320 
0.054 
0.128 


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Table 14-12 
Hypothetical scenarios for tablet on-study decisions (cohort size: 3) 
using hypothetical capsule dataset 2 
Scenario 
Current tablet status 
For next tablet cohort 
EGF816 dose 
(mg qd) 
Npat 
Ntox 
EGF816 dose 
(mg qd) 
P(Target) 
P(Over) 
Median 
DLT rate 
1 
300 
3 
0 
450 
0.316 
0.126 
0.140 
2 
300 
3 
1 
300 
0.412 
0.176 
0.187 
3 
300 
3 
2 
150 
0.363 
0.112 
0.152 
4 
300 
450 
3 
3 
0 
0 
600 
0.335 
0.141 
0.152 
5 
300 
450 
3 
3 
0 
1 
450 
0.438 
0.184 
0.197 
6 
300 
450 
3 
3 
0 
2 
300 
0.446 
0.137 
0.184 
7 
300 
300 
3 
3 
1 
0 
450 
0.454 
0.249 
0.229 
8 
300 
300 
3 
3 
1 
1 
300 
0.497 
0.224 
0.225 
9 
300 
300 
3 
3 
1 
2 
150 
0.409 
0.092 
0.160 
10 
300 
150 
3 
3 
2 
0 
150 
0.289 
0.038 
0.116 
11 
300 
150 
3 
3 
2 
1 
150 
0.492 
0.151 
0.198 
12 
300 
150 
3 
3 
2 
2 
75 
0.414 
0.105 
0.165 


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Table 14-13 
Hypothetical scenarios for tablet on-study decisions (cohort size: 3) 
using hypothetical capsule dataset 3 
Scenario 
Current tablet status 
For next tablet cohort 
EGF816 dose 
(mg qd) 
Npat 
Ntox 
EGF816 dose 
(mg qd) 
P(Target) 
P(Over) 
Median 
DLT rate 
1 
150 
3 
0 
300 
0.398 
0.199 
0.193 
2 
150 
3 
1 
150 
0.424 
0.158 
0.183 
3 
150 
3 
2 
75 
0.393 
0.135 
0.168 
4 
150 
300 
3 
3 
0 
0 
300 
0.337 
0.081 
0.137 
5 
150 
300 
3 
3 
0 
1 
150 
0.251 
0.029 
0.103 
6 
150 
300 
3 
3 
0 
2 
150 
0.419 
0.095 
0.164 
7 
150 
150 
3 
3 
1 
0 
150 
0.356 
0.060 
0.139 
8 
150 
150 
3 
3 
1 
1 
150 
0.520 
0.194 
0.220 
9 
150 
150 
3 
3 
1 
2 
75 
0.445 
0.119 
0.177 
10 
150 
75 
3 
3 
2 
0 
150 
0.513 
0.248 
0.240 
11 
150 
75 
3 
3 
2 
1 
75 
0.496 
0.177 
0.209 
12 
150 
75 
3 
3 
2 
2 
50 
0.492 
0.236 
0.230 
Using hypothetical capsule dataset 1 the model results in Table 14-11 are in agreement with 
clinical sense and decision making process, i.e. allow dose escalation, stay at the same dose, 
and dose de-escalation when no, 1 and 2 DLTs are observed, respectively.  
Using hypothetical capsule dataset 2 the model results in Table 14-12 have the same behaviors, 
except for Scenario 10, where the model does not allow dose escalation after observing no DLTs 
in the second cohort at 150mg. This is due to already 2 DLTs in the first cohort at 300mg. 
Using hypothetical capsule dataset 3 the model results in Table 14-13 are more conservative 
and generally do not allow dose escalation even without observing DLTs, except for Scenario 
1. This is due to 2 DLTs at 300mg in the hypothetical capsule dataset.  
Overall, the model is showing appropriate behaviors, in agreement with clinical sense and 
decision making process. The dose levels investigated correspond to the provisional dose levels 
specified in Section 6.2.2. 
14.2.4 
References 
EMEA (2006) Guideline on small populations (Internet) Available from: emea.europa.eu/ 
docs/en_GB/document_library/Scientific_guidiline/2009/09/WC500003615.pdf. 
Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter DJ. (2010) Summarizing 
historical information on controls in clinical trials. Clinical Trials; 7 (1):5-18. 


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Rogatko A, Schoeneck D, Jonas W, et al (2007) Translation of innovative designs into phase I 
trials. J Clin Oncol; 25(31): 4982-6. 


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14.3 
Appendix 3- Permitted Concomitant Medications requiring 
caution 
Table 14-14 
Permitted concomitant medications requiring caution 
Mechanism of interaction 
Drug name 
Moderate CYP3A4 inhibitor 
aprepitant, amprenavir, atazanavir, cimetidine, ciprofloxacin, crizotinib, 
cyclosporine, darunavir, diltiazem, dronedarone, erythromycin, faldaprevir, 
fluconazole, imatinib, isavuconazole, netupitant, nilotinib, tofisopam, Schisandra 
sphenanthera (nan wu wei zi), asafoetida resin (Ferula asafoetida), verapamil 
Moderate CYP3A4 inducer 
bosentan, dabrafenib, efavirenz, etravirine, genistein, lopinavir, modafinil, 
nafcillin, telotristat, thioridazine 
BCRP substrate 
atorvastatin daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, imatinib, 
methotrexate, mitoxantrone, paritaprevir, pitavastatin, rosuvastatin, irinotecan, 
ethinyl estradiol, simvastatin, sulfasalazine, sofosbuvir, topotecan, tenofovir, 
topotecan, venetoclax 
MATE substrate 
acyclovir, cephalexin, cimetidine, ganciclovir, fexofenadine, glycopyrronium, 
metformin, pindolol, pilsicainide, procainamide, ranitidine, topotecan, 
varenicline, ,  
Potent P-gp inhibitor 
alogliptin, amiodarone, azithromycin, canaglifozin, captopril, carvedilol, 
clopidrogel, cremophor EL and RH40, curcumin, daclatasvir, diltiazem, 
dronedarone, eliglustat, erythromycin, felodipine, fluvoxamine, fostamatinib, 
ginkgo (Ginkgo biloba), green tea, isavuconazole, ivacaftor, lapatinib, lopinavir, 
milk thistle (silymarin, silibinin), mirabegron, nifedipine, nitrendipine, paroxetine, 
propafenone, quercetin, quinidine, quinine, ranolazine, rolapitant, saquinavir, 
Schisandra chinensis extract (wuweizi), simeprevir, survorexant, talinolol, 
telmisartan, ticagrelor, tipranavir, tolvaptan, valspodar, vandetanib, velpatasvir, 
verapamil, voclosporin, vorapaxar 
Source: Adapted Drug-Drug Interactions (DDI) and Co-medication Considerations for Novartis Clinical Trials 
PK Sciences Internal Memorandum (release date: Jan 2018) which was compiled from the Indiana University 
School of Medicine’s “Clinically Relevant” Table and supplemented with the FDA Draft Guidance for Industry, 
Drug Interaction Studies – Study Design, Data Analysis, and Implications for Dosing and Labeling (February 
2012), and the University of Washington’s Drug Interaction Database. Please note that this list may not be 
exhaustive. For the latest information, please refer to the above mentioned database. 
 


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14.4 
Appendix 4 - Prohibited Concomitant Medications 
Table 14-15 
Prohibited concomitant medications 
Mechanism of interaction 
Drug name 
Strong CYP3A4 inhibitor 
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak), indinavir/ritonavir, 
tipranavir/ritonavir, ritonavir, cobicistat, indinavir, ketoconazole, troleandomycin, 
telaprevir, danoprevir/ritonavir, elvitegravir/ritonavir, saquinavir/ritonavir, 
lopinavir/ritonavir, itraconazole, voriconazole, mibefradil, clarithromycin, 
posaconazole, telithromycin, grapefruit juice, conivaptan, nefazodone, nelfinavir, 
idelalisib, boceprevir, atazanavir/ritonavir, darunavir/ritonavir 
Strong CYP3A4 inducer 
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, rifabutin, 
rifampicin, mitotane, St. John’s wort (Hypericum perforatum) 
Live vaccines 
e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow 
fever, varicella, and TY21a typhoid vaccines 
NTI: narrow therapeutic index 
Source: Adapted from Drug-Drug Interactions (DDI) and Co-medication Considerations for Novartis Clinical Trials 
PK Sciences Internal Memorandum (release date: Jan 2018) which was compiled from the Indiana University 
School of Medicine’s “Clinically Relevant” Table and supplemented with the FDA Draft Guidance for Industry, 
Drug Interaction Studies – Study Design, Data Analysis, and Implications for Dosing and Labeling (February 
2012), and the University of Washington’s Drug Interaction Database. Please note that this list may not be 
exhaustive. For the latest information, please refer to the above mentioned database. 
 

SAP_003.pdf: 
Clinical Development 
EGF816 (Nazartinib) 
CEGF816X2101 / NCT02108964  
A Phase I/II, multicenter, open-label study of EGFRmut–TKI EGF816 
administered orally in adult patients with EGFRmut solid malignancies 
Statistical Analysis Plan (SAP)  for close-out CSR 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
16-May-2023
Number of pages: 
15 
Property of Novartis 
 Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 4.0, Effective from 23-Apr-2021 


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SAP 
 
Study No. CEGF816X2101 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
16-May-
2023 
Prior to 
DBL 
Creation of final 
version 
N/A - First version 
NA 
 


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SAP 
 
Study No. CEGF816X2101 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 3 
1 
Introduction ......................................................................................................................... 3 
2 
Planned tables, figures, and listings .................................................................................... 3 
 
1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the close-out clinical 
study report (CSR) of study CEGF816X2101, a phase I/II, multicenter, open-label study of 
EGFRmut-TKI EGF816 administered orally in adult patients with EGFRmut solid 
malignancies.  
The close-out CSR will present the results of cumulative study data which are collected up to 
the LPLV date. The outputs planned for the close-out CSR will be a subset of the primary 
analysis outputs that need to be updated after the data cut-off date for the primary analysis. The 
list of outputs are specified in Section 2.  
The statistical methods for the analyses in the final CSR, including data analysis general 
information, analysis of baseline characteristics, treatments and analysis supporting primary, 
secondary and exploratory objectives, will remain unchanged from that documented in the SAP 
for the primary analysis. 
At the time of the finalization of the SAP, the following versions of study documents referred 
to are in place: 
• [CEGF816X2101_SAP_CSR_1_amendment3 ](dated 14-Jun-2018) 
• [CEGF816X2101_TFL_CSR_addendum_1_0] (date 18-Oct-2018) 
2 
Planned tables, figures, and listings 
The table below provides the list of outputs that need to be generated, with additional guidelines 
added under ‘Programming notes’. 
Output number 
in close-out CSR 
Output title in 
close-out CSR 
Output number 
in primary 
analysis CSR 
Output title in 
primary analysis CSR 
Programming 
Notes 
Table 2-1 
Overview of 
adverse events  - 
Phase I (Safety set) 
Table 12-4a 
Overview of adverse 
events  - Phase I 
(Safety set) 
 
Table 2-2 
Overview of 
adverse events  - 
Phase II (Safety 
set) 
Table 12-4b 
Overview of adverse 
events  - Phase II 
(Safety set) 
 
Table 2-3 
Adverse events by 
preferred term  - 
Phase I (Safety set) 
Table 12-5a 
Adverse events by 
preferred term  - 
Phase I (Safety set) 
 


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SAP 
 
Study No. CEGF816X2101 
 
 
 
Table 2-4 
Adverse events by 
preferred term  - 
Phase II (Safety 
set) 
Table 12-5b 
Adverse events by 
preferred term  - 
Phase II (Safety set) 
 
Table 2-5 
Overall survival  - 
Phase I (Full 
analysis set) 
Table 14.2-2.12a 
Overall survival  - 
Phase I (Full analysis 
set) 
Prepared as cell-
based table to be 
used as in-text. 
Table 2-6 
Overall survival  - 
Phase II (Full 
analysis set) 
Table 14.2-2.12b 
Overall survival  - 
Phase II (Full 
analysis set) 
Prepared as cell-
based table to be 
used as in-text. 
Table 14.1-1.1a 
Subject disposition  
- Phase I (Full 
analysis set) 
Table 14.1-1.1a 
Subject disposition  - 
Phase I (Full analysis 
set) 
 
Table 14.1-1.1b 
Subject disposition  
- Phase II (Full 
analysis set) 
Table 14.1-1.1b 
Subject disposition  - 
Phase II (Full 
analysis set) 
 
Table 14.1-1.3a 
Protocol deviations  
- Phase I (Full 
analysis set) 
Table 14.1-1.3a 
Protocol deviations  - 
Phase I (Full analysis 
set) 
 
Table 14.1-1.3b 
Protocol deviations  
- Phase II (Full 
analysis set) 
Table 14.1-1.3b 
Protocol deviations  - 
Phase II (Full 
analysis set) 
 
Table 14.1-3.1a 
Demographics and 
baseline 
characteristics  - 
Phase I (Full 
analysis set) 
Table 14.1-3.1a 
Demographics and 
baseline 
characteristics  - 
Phase I (Full analysis 
set) 
 
Table 14.1-3.1b 
Demographics and 
baseline 
characteristics  - 
Phase II (Full 
analysis set) 
Table 14.1-3.1b 
Demographics and 
baseline 
characteristics  - 
Phase II (Full 
analysis set) 
 
Table 14.1-3.9a 
Antineoplastic 
therapy since 
discontinuation of 
study drug by ATC 
class and preferred 
term - Medication  
- Phase I (Full 
analysis set) 
Table 14.1-3.9a 
Antineoplastic 
therapy since 
discontinuation of 
study drug by ATC 
class and preferred 
term - Medication  - 
Phase I (Full analysis 
set) 
 
Table 14.1-3.9b 
Antineoplastic 
therapy since 
discontinuation of 
study drug by ATC 
class and preferred 
term - Medication  
- Phase II (Full 
analysis set) 
Table 14.1-3.9b 
Antineoplastic 
therapy since 
discontinuation of 
study drug by ATC 
class and preferred 
term - Medication  - 
Phase II (Full 
analysis set) 
 
Table 14.2-1.4b 
Progression-free 
survival per BIRC  
- Phase II (Full 
analysis set) 
Table 14.2-1.4b 
Progression-free 
survival per BIRC  - 
Phase II (Full 
analysis set) 
 


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Confidential 
Page 5 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
Table 14.2-1.5b 
Time to response 
(CR+PR) as per 
BIRC  - Phase II 
(Full analysis set) 
Table 14.2-1.5b 
Time to response 
(CR+PR) as per 
BIRC  - Phase II 
(Full analysis set) 
 
Table 14.2-1.6b 
Duration of 
response (CR+PR) 
as per BIRC  - 
Phase II (Full 
analysis set) 
Table 14.2-1.6b 
Duration of response 
(CR+PR) as per 
BIRC  - Phase II 
(Full analysis set) 
 
Table 14.2-2.4a 
Progression-free 
survival per 
investigator 
assessment  - Phase 
I (Full analysis set) 
Table 14.2-2.4a 
Progression-free 
survival per 
investigator 
assessment  - Phase I 
(Full analysis set) 
 
Table 14.2-2.4b 
Progression-free 
survival per 
investigator 
assessment  - Phase 
II (Full analysis 
set) 
Table 14.2-2.4b 
Progression-free 
survival per 
investigator 
assessment  - Phase II 
(Full analysis set) 
 
Table 14.2-2.5a 
Time to response 
(CR+PR) as per 
investigator  - 
Phase I (Full 
analysis set) 
Table 14.2-2.5a 
Time to response 
(CR+PR) as per 
investigator  - Phase I 
(Full analysis set) 
 
Table 14.2-2.5b 
Time to response 
(CR+PR) as per 
investigator  - 
Phase II (Full 
analysis set) 
Table 14.2-2.5b 
Time to response 
(CR+PR) as per 
investigator  - Phase 
II (Full analysis set) 
 
Table 14.2-2.6a 
Duration of 
response (CR+PR) 
as per investigator  
- Phase I (Full 
analysis set) 
Table 14.2-2.6a 
Duration of response 
(CR+PR) as per 
investigator  - Phase I 
(Full analysis set) 
 
Table 14.2-2.6b 
Duration of 
response (CR+PR) 
as per investigator  
- Phase II (Full 
analysis set) 
Table 14.2-2.6b 
Duration of response 
(CR+PR) as per 
investigator  - Phase 
II (Full analysis set) 
 
Table 14.2-2.12a 
Overall survival  - 
Phase I (Full 
analysis set) 
Table 14.2-2.12a 
Overall survival  - 
Phase I (Full analysis 
set) 
 
Table 14.2-2.12b 
Overall survival  - 
Phase II (Full 
analysis set) 
Table 14.2-2.12b 
Overall survival  - 
Phase II (Full 
analysis set) 
 
Table 14.3-1.1a 
Duration of 
exposure to 
EGF816  - Phase I 
(Safety set) 
Table 14.3-1.1a 
Duration of exposure 
to EGF816  - Phase I 
(Safety set) 
 
Table 14.3-1.1b 
Duration of 
exposure to 
Table 14.3-1.1b 
Duration of exposure 
to EGF816  - Phase II 
(Safety set) 
 


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Confidential 
Page 6 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
EGF816  - Phase II 
(Safety set) 
Table 14.3-1.2a 
Dose of EGF816 
received  - Phase I 
(Safety set) 
Table 14.3-1.2a 
Dose of EGF816 
received  - Phase I 
(Safety set) 
 
Table 14.3-1.2b 
Dose of EGF816 
received  - Phase II 
(Safety set) 
Table 14.3-1.2b 
Dose of EGF816 
received  - Phase II 
(Safety set) 
 
Table 14.3-1.3a 
Dose adjustments 
and discontinuation 
of EGF816  - Phase 
I (Safety set) 
Table 14.3-1.3a 
Dose adjustments and 
discontinuation of 
EGF816  - Phase I 
(Safety set) 
 
Table 14.3-1.3b 
Dose adjustments 
and discontinuation 
of EGF816  - Phase 
II (Safety set) 
Table 14.3-1.3b 
Dose adjustments and 
discontinuation of 
EGF816  - Phase II 
(Safety set) 
 
Table 14.3-3.1a 
Hematology shift 
table based on CTC 
grades  - Phase I 
(Safety set) 
Table 14.3-3.1a 
Hematology shift 
table based on CTC 
grades  - Phase I 
(Safety set) 
 
Table 14.3-3.1b 
Hematology shift 
table based on CTC 
grades  - Phase II 
(Safety set) 
Table 14.3-3.1b 
Hematology shift 
table based on CTC 
grades  - Phase II 
(Safety set) 
 
Table 14.3-3.2a 
Hematology shift 
table based on 
normal ranges - 
Phase I (Safety set) 
Table 14.3-3.2a 
Hematology shift 
table based on normal 
ranges - Phase I 
(Safety set) 
 
Table 14.3-3.2b 
Hematology shift 
table based on 
normal ranges - 
Phase II (Safety 
set) 
Table 14.3-3.2b 
Hematology shift 
table based on normal 
ranges - Phase II 
(Safety set) 
 
Table 14.3-3.3a 
Biochemistry shift 
table based on CTC 
grades  - Phase I 
(Safety set) 
Table 14.3-3.3a 
Biochemistry shift 
table based on CTC 
grades  - Phase I 
(Safety set) 
 
Table 14.3-3.3b 
Biochemistry shift 
table based on CTC 
grades  - Phase II 
(Safety set) 
Table 14.3-3.3b 
Biochemistry shift 
table based on CTC 
grades  - Phase II 
(Safety set) 
 
Table 14.3-3.4a 
Biochemistry shift 
table based on 
normal ranges - 
Phase I (Safety set) 
Table 14.3-3.4a 
Biochemistry shift 
table based on normal 
ranges - Phase I 
(Safety set) 
 
Table 14.3-3.4b 
Biochemistry shift 
table based on 
normal ranges - 
Phase II (Safety 
set) 
Table 14.3-3.4b 
Biochemistry shift 
table based on normal 
ranges - Phase II 
(Safety set) 
 
Table 14.3-3.5a 
Categorical 
analysis of hepatic 
Table 14.3-3.5a 
Categorical analysis 
of hepatic laboratory 
 


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Page 7 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
laboratory values  - 
Phase I (Safety set) 
values  - Phase I 
(Safety set) 
Table 14.3-3.5b 
Categorical 
analysis of hepatic 
laboratory values  - 
Phase II (Safety 
set) 
Table 14.3-3.5b 
Categorical analysis 
of hepatic laboratory 
values  - Phase II 
(Safety set) 
 
Table 14.3-4.1a 
Vital signs shift 
table based on 
normal ranges  - 
Phase I (Safety set) 
Table 14.3-4.1a 
Vital signs shift table 
based on normal 
ranges  - Phase I 
(Safety set) 
 
Table 14.3-4.1b 
Vital signs shift 
table based on 
normal ranges  - 
Phase II (Safety 
set) 
Table 14.3-4.1b 
Vital signs shift table 
based on normal 
ranges  - Phase II 
(Safety set) 
 
Table 14.3-4.2a 
Notable vital sign 
values  - Phase I 
(Safety set) 
Table 14.3-4.2a 
Notable vital sign 
values  - Phase I 
(Safety set) 
 
Table 14.3-4.2b 
Notable vital sign 
values  - Phase II 
(Safety set) 
Table 14.3-4.2b 
Notable vital sign 
values  - Phase II 
(Safety set) 
 
Table 14.3-5.1a 
Change from 
baseline ECG 
parameters by 
timepoint  - Phase I 
(Safety set) 
Table 14.3-5.1a 
Change from baseline 
ECG parameters by 
timepoint  - Phase I 
(Safety set) 
 
Table 14.3-5.1b 
Change from 
baseline ECG 
parameters by 
timepoint  - Phase 
II (Safety set) 
Table 14.3-5.1b 
Change from baseline 
ECG parameters by 
timepoint  - Phase II 
(Safety set) 
 
Table 14.3-5.2a 
Notable ECG 
values  - Phase I 
(Safety set*) 
Table 14.3-5.2a 
Notable ECG values  
- Phase I (Safety 
set*) 
 
Table 14.3-5.2b 
Notable ECG 
values  - Phase II 
(Safety set*) 
Table 14.3-5.2b 
Notable ECG values  
- Phase II (Safety 
set*) 
 
Figure 14.3-1.1a 
eDISH plot: Total 
bilirubin vs 
ALT/AST  - Phase 
I (Safety set) 
Figure 14.3-1.1a 
eDISH plot: Total 
bilirubin vs 
ALT/AST  - Phase I 
(Safety set) 
 
Figure 14.3-1.1b 
eDISH plot: Total 
bilirubin vs 
ALT/AST  - Phase 
II (Safety set) 
Figure 14.3-1.1b 
eDISH plot: Total 
bilirubin vs 
ALT/AST  - Phase II 
(Safety set) 
 
Figure 14.3-1.2a 
Individual subject 
plot of ULN-
normalized LFT 
values for subjects 
with ALT>3xULN 
or AST>3xULN or 
Total Bilirubin>2x 
Figure 14.3-1.2a 
Individual subject 
plot of ULN-
normalized LFT 
values for subjects 
with ALT>3xULN or 
AST>3xULN or 
Total Bilirubin>2x 
 


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Confidential 
Page 8 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
ULN post-baseline  
- Phase I (Safety 
set) 
ULN post-baseline  - 
Phase I (Safety set) 
Figure 14.3-1.2b 
Individual subject 
plot of ULN-
normalized LFT 
values for subjects 
with ALT>3xULN 
or AST>3xULN or 
Total Bilirubin>2x 
ULN post-baseline  
- Phase II (Safety 
set) 
Figure 14.3-1.2b 
Individual subject 
plot of ULN-
normalized LFT 
values for subjects 
with ALT>3xULN or 
AST>3xULN or 
Total Bilirubin>2x 
ULN post-baseline  - 
Phase II (Safety set) 
 
Table 14.3.1-
1.2a 
Adverse events by 
system organ class, 
preferred term and 
maximum grade  - 
Phase I (Safety set) 
Table 14.3.1-
1.2a 
Adverse events by 
system organ class, 
preferred term and 
maximum grade  - 
Phase I (Safety set) 
 
Table 14.3.1-
1.2b 
Adverse events by 
system organ class, 
preferred term and 
maximum grade  - 
Phase II (Safety 
set) 
Table 14.3.1-
1.2b 
Adverse events by 
system organ class, 
preferred term and 
maximum grade  - 
Phase II (Safety set) 
 
Table 14.3.1-
1.3a 
Treatment-related 
adverse events by 
system organ class, 
preferred term and 
maximum grade  - 
Phase I (Safety set) 
Table 14.3.1-
1.3a 
Treatment-related 
adverse events by 
system organ class, 
preferred term and 
maximum grade  - 
Phase I (Safety set) 
 
Table 14.3.1-
1.3b 
Treatment-related 
adverse events by 
system organ class, 
preferred term and 
maximum grade  - 
Phase II (Safety 
set) 
Table 14.3.1-
1.3b 
Treatment-related 
adverse events by 
system organ class, 
preferred term and 
maximum grade  - 
Phase II (Safety set) 
 
Table 14.3.1-
1.4a 
Serious adverse 
events by system 
organ class, 
preferred term and 
maximum grade  - 
Phase I (Safety set) 
Table 14.3.1-
1.4a 
Serious adverse 
events by system 
organ class, preferred 
term and maximum 
grade  - Phase I 
(Safety set) 
 
Table 14.3.1-
1.4b 
Serious adverse 
events by system 
organ class, 
preferred term and 
maximum grade  - 
Phase II (Safety 
set) 
Table 14.3.1-
1.4b 
Serious adverse 
events by system 
organ class, preferred 
term and maximum 
grade  - Phase II 
(Safety set) 
 
Table 14.3.1-
1.6a 
Adverse events 
leading to 
treatment 
Table 14.3.1-
1.6a 
Adverse events 
leading to treatment 
discontinuation, by 
 


Novartis 
Confidential 
Page 9 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
discontinuation, by 
system organ class, 
preferred term and 
maximum grade  - 
Phase I (Safety set) 
system organ class, 
preferred term and 
maximum grade  - 
Phase I (Safety set) 
Table 14.3.1-
1.6b 
Adverse events 
leading to 
treatment 
discontinuation, by 
system organ class, 
preferred term and 
maximum grade  - 
Phase II (Safety 
set) 
Table 14.3.1-
1.6b 
Adverse events 
leading to treatment 
discontinuation, by 
system organ class, 
preferred term and 
maximum grade  - 
Phase II (Safety set) 
 
Table 14.3.1-
1.10a 
Overview of 
adverse events of 
special interest  - 
Phase I (Safety set) 
Table 14.3.1-
1.10a 
Overview of adverse 
events of special 
interest  - Phase I 
(Safety set) 
 
Table 14.3.1-
1.10b 
Overview of 
adverse events of 
special interest  - 
Phase II (Safety 
set) 
Table 14.3.1-
1.10b 
Overview of adverse 
events of special 
interest  - Phase II 
(Safety set) 
 
Table 14.3.1-
1.17a 
All deaths, by 
system organ class 
and preferred term  
- Phase I (Safety 
set) 
Table 14.3.1-
1.17a 
All deaths, by system 
organ class and 
preferred term  - 
Phase I (Safety set) 
 
Table 14.3.1-
1.17b 
All deaths, by 
system organ class 
and preferred term  
- Phase II (Safety 
set) 
Table 14.3.1-
1.17b 
All deaths, by system 
organ class and 
preferred term  - 
Phase II (Safety set) 
 
Table 14.3.1-
1.19 
Non-serious 
adverse events 
(threshold = 5%) 
by system organ 
class and preferred 
term for all 
subjects (Safety 
set) 
Table 14.3.1-
1.19 
Non-serious adverse 
events (threshold = 
5%) by system organ 
class and preferred 
term for all subjects 
(Safety set) 
 
Table 14.3.1-
1.21a 
On-treatment 
deaths and serious 
adverse events with 
fatal outcome  - 
Phase I (Safety set) 
Table 14.3.1-
1.21a 
On-treatment deaths 
and serious adverse 
events with fatal 
outcome  - Phase I 
(Safety set) 
 
Table 14.3.1-
1.21b 
On-treatment 
deaths and serious 
adverse events with 
fatal outcome  - 
Phase II (Safety 
set) 
Table 14.3.1-
1.21b 
On-treatment deaths 
and serious adverse 
events with fatal 
outcome  - Phase II 
(Safety set) 
 


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Confidential 
Page 10 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
Listing 14.2-1.1b 
Tumor assessments 
and responses per 
BIRC – Phase II 
Full analysis set 
Listing 14.2-1.1b 
Tumor assessments 
and responses per 
BIRC – Phase II Full 
analysis set 
 
Listing 14.2-1.2b 
Progression-free 
survival per BIRC 
– Phase II Full 
analysis set 
Listing 14.2-1.2b 
Progression-free 
survival per BIRC – 
Phase II Full analysis 
set 
 
Listing 14.2-1.3b 
Time to response 
and duration of 
response per BIRC 
– Phase II Full 
analysis set 
Listing 14.2-1.3b 
Time to response and 
duration of response 
per BIRC – Phase II 
Full analysis set 
 
Listing 14.2-2.1a 
Tumor assessments 
and response per 
investigator 
assessment – Phase 
I Full analysis set 
Listing 14.2-2.1a 
Tumor assessments 
and response per 
investigator 
assessment – Phase I 
Full analysis set 
 
Listing 14.2-2.1b 
Tumor assessments 
and response per 
investigator 
assessment – Phase 
II Full analysis set 
Listing 14.2-2.1b 
Tumor assessments 
and response per 
investigator 
assessment – Phase II 
Full analysis set 
 
Listing 14.2-2.2a 
Progression-free 
survival per 
investigator 
assessment – Phase 
I Full analysis set 
Listing 14.2-2.2a 
Progression-free 
survival per 
investigator 
assessment – Phase I 
Full analysis set 
 
Listing 14.2-2.2b 
Progression-free 
survival per 
investigator 
assessment – Phase 
II Full analysis set 
Listing 14.2-2.2b 
Progression-free 
survival per 
investigator 
assessment – Phase II 
Full analysis set 
 
Listing 14.2-2.3a 
Time to response 
and duration of 
response per 
investigator 
assessment – Phase 
I Full analysis set 
Listing 14.2-2.3a 
Time to response and 
duration of response 
per investigator 
assessment – Phase I 
Full analysis set 
 
Listing 14.2-2.3b 
Time to response 
and duration of 
response per 
investigator 
assessment – Phase 
II Full analysis set 
Listing 14.2-2.3b 
Time to response and 
duration of response 
per investigator 
assessment – Phase II 
Full analysis set 
 
Listing 14.2-2.6a 
Overall survival – 
Phase I Safety set 
Listing 14.2-2.6a 
Overall survival – 
Phase I Safety set 
 
Listing 14.2-2.6b 
Overall survival – 
Phase II Safety set 
Listing 14.2-2.6b 
Overall survival – 
Phase II Safety set 
 
Listing 14.3.2-
1.1a 
Deaths  - Phase I 
(Safety set) 
Listing 14.3.2-
1.1a 
Deaths  - Phase I 
(Safety set) 
 
Listing 14.3.2-
1.1b 
Deaths  - Phase II 
(Safety set) 
Listing 14.3.2-
1.1b 
Deaths  - Phase II 
(Safety set) 
 


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Confidential 
Page 11 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
Listing 14.3.2-
2.1a 
Serious adverse 
events  - Phase I 
(Safety set) 
Listing 14.3.2-
2.1a 
Serious adverse 
events  - Phase I 
(Safety set) 
 
Listing 14.3.2-
2.1b 
Serious adverse 
events  - Phase II 
(Safety set) 
Listing 14.3.2-
2.1b 
Serious adverse 
events  - Phase II 
(Safety set) 
 
Listing 14.3.2-
2.2a 
Serious adverse 
events with fatal 
outcome  - Phase I 
(Safety set) 
Listing 14.3.2-
2.2a 
Serious adverse 
events with fatal 
outcome  - Phase I 
(Safety set) 
 
Listing 14.3.2-
2.2b 
Serious adverse 
events with fatal 
outcome  - Phase II 
(Safety set) 
Listing 14.3.2-
2.2b 
Serious adverse 
events with fatal 
outcome  - Phase II 
(Safety set) 
 
Listing 14.3.2-
3.1a 
Adverse events 
leading to 
discontinuation  - 
Phase I (Safety set) 
Listing 14.3.2-
3.1a 
Adverse events 
leading to 
discontinuation  - 
Phase I (Safety set) 
 
Listing 14.3.2-
3.1b 
Adverse events 
leading to 
discontinuation  - 
Phase II (Safety 
set) 
Listing 14.3.2-
3.1b 
Adverse events 
leading to 
discontinuation  - 
Phase II (Safety set) 
 
Listing 14.3.2-
4.1a 
Adverse events 
leading to dose 
adjustment and/or 
interruption  - 
Phase I (Safety set) 
Listing 14.3.2-
4.1a 
Adverse events 
leading to dose 
adjustment and/or 
interruption  - Phase I 
(Safety set) 
 
Listing 14.3.2-
4.1b 
Adverse events 
leading to dose 
adjustment and/or 
interruption  - 
Phase II (Safety 
set) 
Listing 14.3.2-
4.1b 
Adverse events 
leading to dose 
adjustment and/or 
interruption  - Phase 
II (Safety set) 
 
Listing 14.3.2-
5.1a 
Adverse events of 
special interest  - 
Phase I (Safety set) 
Listing 14.3.2-
5.1a 
Adverse events of 
special interest  - 
Phase I (Safety set) 
 
Listing 14.3.2-
5.1b 
Adverse events of 
special interest  - 
Phase II (Safety 
set) 
Listing 14.3.2-
5.1b 
Adverse events of 
special interest  - 
Phase II (Safety set) 
 
Listing 16.2.1-
1.1a 
Subject disposition  
- Phase I (Full 
analysis set) 
Listing 16.2.1-
1.1a 
Subject disposition  - 
Phase I (Full analysis 
set) 
 
Listing 16.2.1-
1.1b 
Subject disposition  
- Phase II (Full 
analysis set) 
Listing 16.2.1-
1.1b 
Subject disposition  - 
Phase II (Full 
analysis set) 
 
Listing 16.2.1-
1.3 
Informed consent 
(All screened 
subjects) 
Listing 16.2.1-
1.3 
Informed consent 
(All screened 
subjects) 
 
Listing 16.2.2-
1.1a 
Protocol deviations  
- Phase I (Full 
analysis set) 
Listing 16.2.2-
1.1a 
Protocol deviations  - 
Phase I (Full analysis 
set) 
 


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Confidential 
Page 12 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
Listing 16.2.2-
1.1b 
Protocol deviations  
- Phase II (Full 
analysis set) 
Listing 16.2.2-
1.1b 
Protocol deviations  - 
Phase II (Full 
analysis set) 
 
Listing 16.2.4-
1.3a 
Relevant medical 
history and current 
medical conditions  
- Phase I (Full 
analysis set) 
Listing 16.2.4-
1.3a 
Relevant medical 
history and current 
medical conditions  - 
Phase I (Full analysis 
set) 
 
Listing 16.2.4-
1.3b 
Relevant medical 
history and current 
medical conditions  
- Phase II (Full 
analysis set) 
Listing 16.2.4-
1.3b 
Relevant medical 
history and current 
medical conditions  - 
Phase II (Full 
analysis set) 
 
Listing 16.2.4-
1.7a 
Antineoplastic 
therapies since 
discontinuation of 
study drug - 
Surgery  - Phase I 
(Full analysis set) 
Listing 16.2.4-
1.7a 
Antineoplastic 
therapies since 
discontinuation of 
study drug - Surgery  
- Phase I (Full 
analysis set) 
 
Listing 16.2.4-
1.7b 
Antineoplastic 
therapies since 
discontinuation of 
study drug - 
Surgery  - Phase II 
(Full analysis set) 
Listing 16.2.4-
1.7b 
Antineoplastic 
therapies since 
discontinuation of 
study drug - Surgery  
- Phase II (Full 
analysis set) 
 
Listing 16.2.4-
1.8a 
Antineoplastic 
therapies since 
discontinuation of 
study drug - 
Radiotherapy  - 
Phase I (Full 
analysis set) 
Listing 16.2.4-
1.8a 
Antineoplastic 
therapies since 
discontinuation of 
study drug - 
Radiotherapy  - Phase 
I (Full analysis set) 
 
Listing 16.2.4-
1.8b 
Antineoplastic 
therapies since 
discontinuation of 
study drug - 
Radiotherapy  - 
Phase II (Full 
analysis set) 
Listing 16.2.4-
1.8b 
Antineoplastic 
therapies since 
discontinuation of 
study drug - 
Radiotherapy  - Phase 
II (Full analysis set) 
 
Listing 16.2.4-
1.9a 
Antineoplastic 
therapies since 
discontinuation of 
study drug - 
Medications  - 
Phase I (Full 
analysis set) 
Listing 16.2.4-
1.9a 
Antineoplastic 
therapies since 
discontinuation of 
study drug - 
Medications  - Phase 
I (Full analysis set) 
 
Listing 16.2.4-
1.9b 
Antineoplastic 
therapies since 
discontinuation of 
study drug - 
Medications  - 
Phase II (Full 
analysis set) 
Listing 16.2.4-
1.9b 
Antineoplastic 
therapies since 
discontinuation of 
study drug - 
Medications  - Phase 
II (Full analysis set) 
 


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Confidential 
Page 13 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
Listing 16.2.5-
1.1a 
Dose 
administration 
record  - Phase I 
(Safety set) 
Listing 16.2.5-
1.1a 
Dose administration 
record  - Phase I 
(Safety set) 
 
Listing 16.2.5-
1.1b 
Dose 
administration 
record  - Phase II 
(Safety set) 
Listing 16.2.5-
1.1b 
Dose administration 
record  - Phase II 
(Safety set) 
 
Listing 16.2.7-
1.1a 
Adverse events  - 
Phase I (Safety set) 
Listing 16.2.7-
1.1a 
Adverse events  - 
Phase I (Safety set) 
 
Listing 16.2.7-
1.1b 
Adverse events  - 
Phase II (Safety 
set) 
Listing 16.2.7-
1.1b 
Adverse events  - 
Phase II (Safety set) 
 
Listing 16.2.8-
1.1a 
CTC grade 3 or 4 
laboratory values  - 
Phase I (Safety set) 
Listing 16.2.8-
1.1a 
CTC grade 3 or 4 
laboratory values  - 
Phase I (Safety set) 
 
Listing 16.2.8-
1.1b 
CTC grade 3 or 4 
laboratory values  - 
Phase II (Safety 
set) 
Listing 16.2.8-
1.1b 
CTC grade 3 or 4 
laboratory values  - 
Phase II (Safety set) 
 
Listing 16.2.8-
1.2a 
Hematology - 
primary 
hematology 
variables  - Phase I 
(Safety set) 
Listing 16.2.8-
1.2a 
Hematology - 
primary hematology 
variables  - Phase I 
(Safety set) 
 
Listing 16.2.8-
1.2b 
Hematology - 
primary 
hematology 
variables  - Phase 
II (Safety set) 
Listing 16.2.8-
1.2b 
Hematology - 
primary hematology 
variables  - Phase II 
(Safety set) 
 
Listing 16.2.8-
1.3a 
Hematology - 
WBC and 
differentials  - 
Phase I (Safety set) 
Listing 16.2.8-
1.3a 
Hematology - WBC 
and differentials  - 
Phase I (Safety set) 
 
Listing 16.2.8-
1.3b 
Hematology - 
WBC and 
differentials  - 
Phase II (Safety 
set) 
Listing 16.2.8-
1.3b 
Hematology - WBC 
and differentials  - 
Phase II (Safety set) 
 
Listing 16.2.8-
1.4a 
Hematology - 
coagulation  - 
Phase I (Safety set) 
Listing 16.2.8-
1.4a 
Hematology - 
coagulation  - Phase I 
(Safety set) 
 
Listing 16.2.8-
1.4b 
Hematology - 
coagulation  - 
Phase II (Safety 
set) 
Listing 16.2.8-
1.4b 
Hematology - 
coagulation  - Phase 
II (Safety set) 
 
Listing 16.2.8-
1.5a 
Biochemistry - 
liver  - Phase I 
(Safety set) 
Listing 16.2.8-
1.5a 
Biochemistry - liver  
- Phase I (Safety set) 
 
Listing 16.2.8-
1.5b 
Biochemistry - 
liver  - Phase II 
(Safety set) 
Listing 16.2.8-
1.5b 
Biochemistry - liver  
- Phase II (Safety set) 
 


Novartis 
Confidential 
Page 14 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
Listing 16.2.8-
1.6a 
Biochemistry - 
renal - Phase I 
(Safety set) 
Listing 16.2.8-
1.6a 
Biochemistry - renal - 
Phase I (Safety set) 
 
Listing 16.2.8-
1.6b 
Biochemistry - 
renal - Phase II 
(Safety set) 
Listing 16.2.8-
1.6b 
Biochemistry - renal - 
Phase II (Safety set) 
 
Listing 16.2.8-
1.7a 
Biochemistry - 
other - Phase I 
(Safety set) 
Listing 16.2.8-
1.7a 
Biochemistry - other 
- Phase I (Safety set) 
 
Listing 16.2.8-
1.7b 
Biochemistry - 
other - Phase II 
(Safety set) 
Listing 16.2.8-
1.7b 
Biochemistry - other 
- Phase II (Safety set) 
 
Listing 16.2.8-
1.8a 
Urinary 
parameters: 
urinalysis (dipstick 
analysis)  - Phase I 
(Safety set) 
Listing 16.2.8-
1.8a 
Urinary parameters: 
urinalysis (dipstick 
analysis)  - Phase I 
(Safety set) 
 
Listing 16.2.8-
1.8b 
Urinary 
parameters: 
urinalysis (dipstick 
analysis)  - Phase II 
(Safety set) 
Listing 16.2.8-
1.8b 
Urinary parameters: 
urinalysis (dipstick 
analysis)  - Phase II 
(Safety set) 
 
Listing 16.2.8-
1.9a 
Urinary 
parameters: 
urinalysis 
(microscopic 
analysis)  - Phase I 
(Safety set) 
Listing 16.2.8-
1.9a 
Urinary parameters: 
urinalysis 
(microscopic 
analysis)  - Phase I 
(Safety set) 
 
Listing 16.2.8-
1.9b 
Urinary 
parameters: 
urinalysis 
(microscopic 
analysis)  - Phase II 
(Safety set) 
Listing 16.2.8-
1.9b 
Urinary parameters: 
urinalysis 
(microscopic 
analysis)  - Phase II 
(Safety set) 
 
Listing 16.2.8-
1.10a 
Subjects with worst 
post-baseline Total 
bilirubin > 2xULN 
and AT > 3xULN 
values  - Phase I 
(Safety set) 
Listing 16.2.8-
1.10a 
Subjects with worst 
post-baseline Total 
bilirubin > 2xULN 
and AT > 3xULN 
values  - Phase I 
(Safety set) 
 
Listing 16.2.8-
1.10b 
Subjects with worst 
post-baseline Total 
bilirubin > 2xULN 
and AT > 3xULN 
values  - Phase II 
(Safety set) 
Listing 16.2.8-
1.10b 
Subjects with worst 
post-baseline Total 
bilirubin > 2xULN 
and AT > 3xULN 
values  - Phase II 
(Safety set) 
 
Listing 16.2.8-
1.11a 
Subject laboratory 
profile of hepatic 
laboratory values  - 
Phase I (Safety set) 
Listing 16.2.8-
1.11a 
Subject laboratory 
profile of hepatic 
laboratory values  - 
Phase I (Safety set) 
 
Listing 16.2.8-
1.11b 
Subject laboratory 
profile of hepatic 
laboratory values  - 
Listing 16.2.8-
1.11b 
Subject laboratory 
profile of hepatic 
 


Novartis 
Confidential 
Page 15 of 15 
SAP 
 
Study No. CEGF816X2101 
 
 
 
Phase II (Safety 
set) 
laboratory values  - 
Phase II (Safety set) 
Listing 16.2.9-
1.1a 
Notable vital sign 
values  - Phase I 
Safety set 
Listing 16.2.9-
1.1a 
Notable vital sign 
values  - Phase I 
Safety set 
 
Listing 16.2.9-
1.1b 
Notable vital sign 
values  - Phase II 
Safety set 
Listing 16.2.9-
1.1b 
Notable vital sign 
values  - Phase II 
Safety set 
 
Listing 16.2.9-
1.2a 
Vital signs  - Phase 
I Safety set 
Listing 16.2.9-
1.2a 
Vital signs  - Phase I 
Safety set 
 
Listing 16.2.9-
1.2b 
Vital signs  - Phase 
II Safety set 
Listing 16.2.9-
1.2b 
Vital signs  - Phase II 
Safety set 
 
Listing 16.2.9-
2.1a 
Notable ECG 
values  - Phase I 
Safety set 
Listing 16.2.9-
2.1a 
Notable ECG values  
- Phase I Safety set 
 
Listing 16.2.9-
2.1b 
Notable ECG 
values  - Phase II 
Safety set 
Listing 16.2.9-
2.1b 
Notable ECG values  
- Phase II Safety set 
 
Listing 16.2.9-
2.2a 
ECG values  - 
Phase I Safety set 
Listing 16.2.9-
2.2a 
ECG values  - Phase I 
Safety set 
 
Listing 16.2.9-
2.2b 
ECG values  - 
Phase II Safety set 
Listing 16.2.9-
2.2b 
ECG values  - Phase 
II Safety set 
 
Listing 16.2.9-
3.1a 
Pregnancy test 
results  - Phase I 
Safety set 
Listing 16.2.9-
3.1a 
Pregnancy test results  
- Phase I Safety set 
 
Listing 16.2.9-
3.1b 
Pregnancy test 
results  - Phase II 
Safety set 
Listing 16.2.9-
3.1b 
Pregnancy test results  
- Phase II Safety set 
 
Listing 16.2.9-
5.1a 
Hepatitis screen 
and monitoring  - 
Phase I Safety set 
Listing 16.2.9-
5.1a 
Hepatitis screen and 
monitoring  - Phase I 
Safety set 
Please change 
column title 
“Hepatitis screen” 
to “Hepatitis 
assessment” 
Listing 16.2.9-
5.1b 
Hepatitis screen 
and monitoring  - 
Phase II Safety set 
Listing 16.2.9-
5.1b 
Hepatitis screen and 
monitoring  - Phase II 
Safety set