Clinical trial NCT01543698
Conditions: Solid Tumors Harboring a BRAF V600 Mutation
Keywords: Advanced solid tumor, BRAF V600 mutation
Sponsor: Pfizer
Start date: 2012-05-28; Completion date: 2023-03-09
Enrollment: 189 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a multi-center, open-label, dose finding, Phase Ib dose escalation study to estimate the MTD(s) and/or RP2D(s) for the dual combination of LGX818 and MEK162 and the triple combination of LGX818 and MEK162 and LEE011, followed each independently by a Phase II part to assess the clinical efficacy and to further assess the safety of the combinations in selected patient populations. Oral LGX818 and MEK162 will be administered on a continuous schedule. Oral LEE011 will be administered once daily on a three weeks on, one week off schedule. Patients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. A cycle is defined as 28 days. The dose escalation parts of the trial will be conducted in adult patients with BRAF V600-dependent advanced solid tumors and is expected to enroll at least 18 patients for the dual combination and at least 12 patients for the triple combination. The dose escalation will be guided by a Bayesian logistic regression model (BLRM). Following MTD/RP2D declaration, patients will be enrolled in three Phase II arms for the dual combination and one Phase II arm for the triple combination. All patients will be followed for 30 days for safety assessments after study drugs discontinuation. All patients enrolled in the Phase II part of the study will be followed for survival.

Detailed description:

Arms: arm 1: LGX818 QD and MEK162 BID arm 2: LGX818 QD and MEK162 BID and LEE011 QD 3 weeks on, 1 week off.
Interventions: intervention 1: LGX818 intervention 2: MEK162 intervention 3: LEE011
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Development & Medical Affairs 
 
 
LGX818/MEK162 
 
Protocol CMEK162X2110 / C4221005 
 
 
A Phase Ib/II, multicenter, open-label, dose escalation 
study of LGX818 in combination with MEK162 in adult 
patients with BRAF V600 - dependent advanced solid 
tumors 
 
 
 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2011-005875-17 
Version number 
10 
Development phase Ib/II 
Document status 
Final 
Release date 
15-March-2021 
 
 
 
 
Property of Array BioPharma 
(a wholly owned subsidiary of Pfizer Inc.) 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Array BioPharma 


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Table of Contents 
Table of Contents ................................................................................................................. 2 
List of Tables ....................................................................................................................... 8 
List of Figures ...................................................................................................................... 9 
List of abbreviations ........................................................................................................... 10 
Glossary of terms ............................................................................................................... 14 
Amendment 10 ................................................................................................................... 15 
Amendment 9 ..................................................................................................................... 19 
Amendment 8 ..................................................................................................................... 25 
Amendment 7 ..................................................................................................................... 27 
Amendment 6 ..................................................................................................................... 28 
Amendment 5 ..................................................................................................................... 31 
Amendment 4 ..................................................................................................................... 33 
Amendment 3 ..................................................................................................................... 36 
Amendment 2 ..................................................................................................................... 38 
Amendment 1 ..................................................................................................................... 42 
Protocol Summary ............................................................................................................. 44 
1 
Background ........................................................................................................................ 47 
1.1 
Overview of disease pathogenesis, epidemiology and current treatments ............. 47 
1.1.1 
The RAF/MEK/ERK pathway, BRAF-mutations and cyclin- 
dependent kinases 4 and 6 in solid tumors ............................................ 47 
1.1.2 
Malignant Melanoma............................................................................. 48 
1.1.3 
Metastatic Colorectal Cancer (mCRC) .................................................. 50 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 50 
1.2.1 
Overview of LGX818 ............................................................................ 50 
1.2.2 
Overview of MEK162 ........................................................................... 54 
1.2.3 
Overview of LEE011 ............................................................................. 59 
1.2.4 
Overview of combination treatment ...................................................... 62 
1.3 
Anticipated risks and safety considerations of the study drug combinations ......... 64 
1.3.1 
Dual combination LGX818 and MEK162 ............................................. 64 
1.3.2 
Triple combination LGX818 and MEK162 and LEE011 ..................... 65 
2 
Rationale ............................................................................................................................ 66 
2.1 
Study rationale and purpose ................................................................................... 67 
2.2 
Rationale for the study design ................................................................................ 68 
2.3 
Rationale for dose and regimen selection .............................................................. 69 
2.4 
Rationale for choice of combination drugs ............................................................ 69 
3 
Objectives and endpoints ................................................................................................... 69 


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4 
Study design ....................................................................................................................... 71 
4.1 
Description of study design .................................................................................... 72 
4.2 
Timing of interim analyses and design adaptations ................................................ 74 
4.3 
Definition of end of the study ................................................................................ 75 
4.4 
Early study termination .......................................................................................... 75 
5 
Population .......................................................................................................................... 75 
5.1 
Patient population .................................................................................................. 75 
5.2 
Inclusion criteria ..................................................................................................... 76 
5.3 
Exclusion criteria ................................................................................................... 76 
6 
Treatment ........................................................................................................................... 79 
6.1 
Investigational treatment, other study treatment, supportive treatment ................. 79 
6.1.1 
Dosing regimen ..................................................................................... 79 
6.1.2 
Supportive treatment/precautions .......................................................... 81 
6.1.3 
Ancillary treatments .............................................................................. 82 
6.1.4 
Guidelines for continuation of treatment ............................................... 82 
6.1.5 
Treatment duration ................................................................................ 82 
6.2 
Dose escalation guidelines ..................................................................................... 82 
6.2.1 
Definition of treatment cycle ................................................................. 82 
6.2.2 
Starting dose rationale ........................................................................... 83 
6.2.3 
Provisional dose levels .......................................................................... 84 
6.2.4 
Criteria for dose escalation and determination of MTD ........................ 86 
6.2.5 
Definitions of dose limiting toxicities (DLTs) ...................................... 88 
6.2.6 
Follow-up for toxicities ......................................................................... 90 
6.3 
Dose modifications ................................................................................................. 91 
6.3.1 
Dose modification and dose delay ......................................................... 91 
6.3.2 
Treatment interruption and treatment discontinuation ........................... 91 
6.3.3 
Additional follow-up for hepatic toxicities in patients receiving 
LEE011 ................................................................................................ 108 
6.4 
Concomitant medications ..................................................................................... 108 
6.4.1 
Permitted concomitant therapy ............................................................ 108 
6.4.2 
Permitted concomitant therapy requiring caution and/or action for 
LGX818 and MEK162 ........................................................................ 109 
6.4.3 
Prohibited concomitant therapy dual and triple combination .............. 111 
6.5 
Patient numbering, treatment assignment and randomization ............................. 111 
6.5.1 
Patient numbering ................................................................................ 111 
6.5.2 
Treatment assignment and randomization ........................................... 112 
6.6 
Study drug supply ................................................................................................ 112 


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6.6.1 
Study drug preparation and dispensation ............................................. 112 
6.6.2 
Study drug packaging and labeling ..................................................... 112 
6.6.3 
Drug supply and storage ...................................................................... 112 
6.6.4 
Study drug compliance and accountability .......................................... 113 
6.6.5 
Disposal and destruction ...................................................................... 113 
7 
Visit schedule and assessments ........................................................................................ 113 
7.1 
Study flow and visit schedule .............................................................................. 113 
7.1.1 
Molecular Pre-screening assessments .................................................. 123 
7.1.2 
Screening ............................................................................................. 123 
7.1.3 
Treatment period ................................................................................. 124 
7.1.4 
End of treatment visit, including premature withdrawal and study 
completion visit ................................................................................... 124 
7.1.5 
Follow-up period ................................................................................. 126 
7.2 
Assessment types ................................................................................................. 126 
7.2.1 
Efficacy assessments ........................................................................... 126 
7.2.2 
Safety and tolerability assessments ..................................................... 128 
7.2.3 
Pharmacokinetics ................................................................................. 135 
7.2.4 
Biomarkers .......................................................................................... 139 
7.2.5 
Other assessments ................................................................................ 144 
8 
Safety monitoring and reporting ...................................................................................... 144 
8.1 
Adverse events and Serious Adverse Events ....................................................... 144 
8.1.1 
Time Period and Frequency for Collecting AE and SAE 
Information .......................................................................................... 144 
8.1.2 
Methods of Detecting AEs and SAEs .................................................. 146 
8.1.3 
Follow-up of AEs and SAEs ............................................................... 146 
8.1.4 
Regulatory Reporting Requirements for SAEs .................................... 147 
8.1.5 
Exposure During Pregnancy or Breastfeeding and Occupational 
Exposure .............................................................................................. 147 
8.1.6 
Cardiovascular and Death Events ........................................................ 149 
8.1.7 
Disease-Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs ................................................................. 149 
8.1.8 
Adverse Events of Special Interest ...................................................... 149 
8.1.9 
Medical Device Deficiencies ............................................................... 150 
8.1.10 
Medication Errors ................................................................................ 150 
8.2 
Treatment Overdose ............................................................................................. 150 
8.3 
Warnings and precautions .................................................................................... 151 
8.4 
Data Monitoring Committee ................................................................................ 151 


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9 
Data collection and management ..................................................................................... 151 
9.1 
Data confidentiality .............................................................................................. 151 
9.2 
Site monitoring ..................................................................................................... 152 
9.3 
Data collection ..................................................................................................... 152 
9.4 
Database management and quality control .......................................................... 153 
10 Statistical methods and data analysis ............................................................................... 153 
10.1 
Analysis sets ......................................................................................................... 154 
10.1.1 
Full Analysis Set .................................................................................. 154 
10.1.2 
Safety Set ............................................................................................. 154 
10.1.3 
Dose-Determining Set ......................................................................... 154 
10.2 
Patient demographics/other baseline characteristics ............................................ 155 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ...................... 155 
10.3.1 
Study treatment .................................................................................... 155 
10.3.2 
Concomitant therapies ......................................................................... 155 
10.3.3 
Compliance .......................................................................................... 155 
10.4 
Primary objective ................................................................................................. 155 
10.4.1 
Variable ............................................................................................... 156 
10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 157 
10.4.3 
Handling of missing values/censoring/discontinuations ...................... 162 
10.4.4 
Supportive analyses ............................................................................. 162 
10.5 
Secondary objectives ............................................................................................ 163 
10.5.1 
Efficacy ............................................................................................... 163 
10.5.2 
Safety ................................................................................................... 164 
10.5.3 
Pharmacokinetics ................................................................................. 165 
10.5.4 
Biomarkers .......................................................................................... 167 
10.5.5 
Resource utilization ............................................................................. 168 
10.5.6 
Patient-reported outcomes ................................................................... 168 
10.6 
Exploratory objectives ......................................................................................... 168 
10.7 
Interim analysis .................................................................................................... 168 
10.8 
Sample size calculation ........................................................................................ 168 
11 Ethical considerations and administrative procedures ..................................................... 170 
11.1 
Regulatory and ethical compliance ...................................................................... 170 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ........................................ 170 
11.3 
Informed consent procedures ............................................................................... 170 
11.4 
Discontinuation of the study ................................................................................ 171 
11.5 
Publication of study protocol and results ............................................................. 171 


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11.6 
Data Sharing ......................................................................................................... 171 
11.7 
Study documentation, record keeping and retention of documents ..................... 171 
11.8 
Confidentiality of study documents and patient records ...................................... 172 
11.9 
Audits and inspections ......................................................................................... 172 
11.10 Financial disclosures ............................................................................................ 172 
12 Protocol adherence ........................................................................................................... 172 
12.1 
Amendments to the protocol ................................................................................ 173 
13 References (available upon request) ................................................................................ 174 
14 Appendices ....................................................................................................................... 178 
14.1 
Appendix 1 - Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
Harmonization of Efficacy Analysis of Solid Tumor Studies ............................. 178 
14.1.1 
Introduction ......................................................................................... 178 
14.1.2 
Efficacy assessments ........................................................................... 179 
14.1.3 
Definitions ........................................................................................... 179 
14.1.4 
Disease measurability .......................................................................... 179 
14.1.5 
Eligibility based on measurable disease .............................................. 180 
14.1.6 
Methods of tumor measurement - general guidelines .......................... 180 
14.1.7 
Baseline documentation of target and non-target lesions .................... 182 
14.1.8 
Follow-up evaluation of target and non-target lesions ........................ 183 
14.1.9 
Follow-up & recording of lesions ........................................................ 183 
14.1.10 
Non-nodal lesions ................................................................................ 183 
14.1.11 
Nodal lesions ....................................................................................... 183 
14.1.12 
Determination of target lesion response .............................................. 184 
14.1.13 
Determination of non-target lesion response ....................................... 186 
14.1.14 
New lesions ......................................................................................... 187 
14.1.15 
Evaluation of overall lesion response .................................................. 187 
14.1.16 
Efficacy definitions .............................................................................. 188 
14.1.17 
Best overall response ........................................................................... 188 
14.1.18 
Time to event variables ........................................................................ 191 
14.1.19 
Progression-free survival ..................................................................... 191 
14.1.20 
Overall survival ................................................................................... 191 
14.1.21 
Time to progression ............................................................................. 191 
14.1.22 
Time to treatment failure ..................................................................... 191 
14.1.23 
Duration of response ............................................................................ 192 
14.1.24 
Time to response .................................................................................. 192 
14.1.25 
Definition of start and end dates for time to event variables ............... 193 
14.1.26 
Handling of patients with non-measurable disease only at baseline...195 


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14.1.27 
Sensitivity analyses ............................................................................. 196 
14.1.28 
Data handling and programming rules ................................................ 198 
14.1.29 
Study/project specific decisions .......................................................... 198 
14.1.30 
Treatment and study completion CRFs ............................................... 198 
14.1.31 
Study evaluation completion ............................................................... 199 
14.1.32 
Medical validation of programmed overall lesion response................ 200 
14.1.33 
Programming rules .............................................................................. 200 
14.1.34 
Calculation of ‘time to event’ variables .............................................. 200 
14.1.35 
Incomplete assessment dates ............................................................... 200 
14.1.36 
Incomplete dates for last contact or death ........................................... 201 
14.1.37 
Non target lesion response ................................................................... 201 
14.1.38 
Study/project specific programming .................................................... 201 
14.1.39 
Censoring reason ................................................................................. 201 
14.1.40 
References (available upon request) .................................................... 202 
14.2 
Appendix 2 - The 2009 American Joint Committee on Cancer (AJCC) 
staging system ...................................................................................................... 203 
14.3 
Appendix 3 - Guidelines for the treatment of study drug combination induced 
skin toxicity .......................................................................................................... 204 
14.3.1 
Rash ..................................................................................................... 204 
14.3.2 
Hand Foot Skin Reaction ..................................................................... 205 
14.3.3 
References (available upon request) .................................................... 206 
14.4 
Appendix 4 - List of concomitant medications prohibited or to be used with 
caution for dual and triple combination ............................................................... 207 
14.5 
Appendix 5 – Statistical methodology LGX818 and MEK162 dual 
combination .......................................................................................................... 212 
14.5.1 
Prior Distributions of 5 parameter dual combo 
(LGX818+MEK162) model ................................................................ 212 
14.5.2 
Data from the ongoing study LGX818X2101 ..................................... 215 
14.5.3 
LGX818 change in regimen ................................................................ 215 
14.5.4 
Operating characteristics of the Bayesian Logistic Regression 
Model and hypothetical dose escalation scenarios .............................. 216 
14.5.5 
Simulated operating characteristics ..................................................... 216 
14.5.6 
Hypothetical dose escalation scenarios ............................................... 221 
14.5.7 
Power for analysis of key secondary variables .................................... 223 
14.5.8 
References (available upon request) .................................................... 223 
14.6 
Appendix 6 - Operating characteristics of the combination Bayesian logistic 
regression model and hypothetical dose escalation scenarios LGX818 and 
MEK162 and LEE011 triple combination ........................................................... 224 


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14.6.1 
Statistical Model .................................................................................. 224 
14.6.2 
Prior Specification ............................................................................... 224 
14.6.3 
References (available upon request) .................................................... 227 
14.7 
Appendix 7: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ................................................................. 228 
14.7.1 
Definition of AE .................................................................................. 228 
14.7.2 
Definition of an SAE ........................................................................... 229 
14.7.3 
Recording/Reporting and Follow-up of AEs and/or SAEs ................. 231 
14.7.4 
Reporting of SAEs ............................................................................... 234 
14.8 
Appendix 8: Liver Safety: Suggested Actions and Follow-up Assessments ........ 234 
14.9 
Appendix 9: ECG Findings of Potential Clinical Concern ................................... 236 
14.10 Appendix 10: Alternative Measures During Public Emergencies ........................ 237 
14.10.5 
Adverse Events and Serious Adverse Events ...................................... 240 
 
List of Tables 
Table 1-1 
Incidence of BRAF- mutations in human cancers ................................. 48 
Table 3-1 
Objectives and related endpoints ........................................................... 69 
Table 6-1 
Provisional dose levels dual combination ............................................. 84 
Table 6-2 
Provisional dose levels triple combination ............................................ 84 
Table 6-3      Criteria for defining dose-limiting toxicities for dual and triple 
combination ............................................................................................................................... 89 
Table 6-4 
Criteria for interruption and re-initiation of LGX818/MEK162/LEE011 
triple-combination treatment ..................................................................................................... 93 
Table 7-1 
Visit evaluation schedule ..................................................................... 115 
Table 7-2 
Visit evaluation schedule for patients as of Amendment 10 ............... 121 
Table 7-3 
WHO performance status scale ........................................................... 130 
Table 7-4 
Schedule of blood sample collections for PK in dose escalation ........ 136 
Table 7-5 
Schedule of blood sample collections for PK in dual-combination Phase 
II arms 2 and 3, (and arm 1 if requireda) / triple-combination Phase II arm A ....................... 137 
Table 7-6 
Biomarker sample collection schedule ................................................ 140 
Table 7-7 
Processing requirements for fresh tumor biopsy samples ................... 142 
Table 10-1 
PK parameters ..................................................................................... 166 
Table 14-1 
Response criteria for target lesions ..................................................... 184 
Table 14-2 
Response criteria for non-target lesions ............................................... 186 
Table 14-3 
Overall lesion response at each assessment ......................................... 187 


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Table 14-4      Overall lesion response at each assessment: patients with non-target 
disease only ............................................................................................................................. 195 
Table 14-5 
Options for event dates used in PFS, TTP, duration of response ......... 196 
Table 14-6 
The 2009 American Joint Committee on Cancer (AJCC) staging system 
for malignant melanoma ......................................................................................................... 203 
Table 14-7 
Treatment of skin toxicity.................................................................... 205 
Table 14-8 
Supportive care for the prevention and management of HFSR ........... 206 
Table 14-9 
Narrow therapeutic index substrates of CYP3A4*, CYP2B6, CYP2C9 
prohibited or to be administered with caution ........................................................................ 207 
Table 14-10      List of CYP inhibitors and inducers prohibited or to be used with 
caution ..................................................................................................................................... 208 
Table 14-11     List of BCRP substrates, BSEP inhibitors, P-gp inhibitors/inducers, and 
MATE1/2, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1 and OATP1B3 substrates to be 
used with caution .................................................................................................................... 209 
Table 14-12 
List of QT prolonging drugs ................................................................ 211 
Table 14-13 
Data from ARRAY-162-111 ............................................................... 212 
Table 14-14 
Predictive distribution of model parameters ........................................ 213 
Table 14-15 
Summary of prior probabilities of DLT rates ...................................... 214 
Table 14-16 
Data from LGX818X2101- as of 23/Nov/2011 ................................... 215 
Table 14-17 
True underlying probabilities of DLT for Scenario 1 .......................... 218 
Table 14-18 
True underlying probabilities of DLT for Scenario 2 .......................... 218 
Table 14-19 
True underlying probabilities of DLT for Scenario 3 .......................... 218 
Table 14-20 
True underlying probabilities of DLT for Scenario 4 .......................... 219 
Table 14-21 
True underlying probabilities of DLT for Scenario 5 .......................... 219 
Table 14-22 
Preference matrix ................................................................................. 220 
Table 14-23 
Results ................................................................................................. 221 
Table 14-24 
Hypothetical dose escalation scenarios ............................................... 222 
Table 14-25 
Data from CLEE11X2101 ................................................................... 225 
Table 14-26 
Prior, posterior and predictive distribution of (log(alpha4),log(beta4))..... 
225 
Table 14-27 
Prior distribution of model parameters ................................................ 226 
Table 14-28 
Summary of prior distribution of DLT rates for triple combo 
(LGX818+MEK162+LEE011) including current DLT data (up to Apr 16, 2013) from dual 
combo (LGX818+MEK162) ................................................................................................... 226 
Table 14-29 
Dose decisions recommended by BLRM ............................................ 227 
List of Figures 
Figure 1-1 
Overview of Ras-Raf-ERK-MEK pathway (adopted from Cho 2009) ............. 47 
Figure 4-1 
Study Design ..................................................................................................... 72 


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List of abbreviations 
 
AE 
Adverse event 
AKT/PKB 
See PKB 
ALT/SGPT 
Alanine aminotransferase/glutamic pyruvic transaminase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST/SGOT 
Aspartate aminotransferase/glutamic oxaloacetic transaminase 
ATP 
Adenosine triphosphate 
AUC 
Area under the curve 
AV 
Atrioventricular 
BCRP 
Breast cancer resistance protein 
BID 
Bis in diem/twice daily 
BLRM 
Bayesian logistic regression model 
BOR 
Best overall response 
BRAF 
V-raf murine sarcoma viral oncogene homolog B1 
BRAFi 
BRAF inhibitor 
BUN 
Blood urea nitrogen 
CHF 
Congestive heart failure 
CK/CPK 
Creatine kinase / Creatine phosphokinase 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
COVID-19 
Coronavirus disease 2019 
CR 
Complete response 
CRC / mCRC 
Colorectal cancer / metastatic CRC 
CrCl 
Creatinine clearance 
CRF 
Case report form 
CRO 
Contract research organization 
CSF 
Clinical service form 
CSR 
Central serous retinopathy / Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DDS 
Dose determining set 
DILI 
Drug-induced liver injury 
DLT 
Dose limiting toxicity 
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DS&E 
Drug safety and epidemiology 
DTIC 
Dacarbazine 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern cooperative oncology group 


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eCRF 
Electronic case report/record form 
EDC 
Electronic data capture 
EDP 
Exposure during pregnancy 
EGF 
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor 
EMEA 
European Medicines Evaluation Agency 
EOT 
End of treatment 
ErbB 
Erythroblastic leukemia viral oncogene 
ERG 
Electroretinogram 
ERK 
Extracellular signal regulated kinase 
EUA 
Emergency use authorization 
EWOC 
Escalation with overdose control 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
FFPE 
Formalin-fixed paraffin embedded 
FMI 
Final market image 
FU 
Follow-up 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
GTPase 
Guanosine-5'-triphosphatase 
hCG 
Human chorionic gonadotropin 
HDL 
High-density lipoprotein 
HDPE 
High-density polyethylene 
hERG 
Human ether-à-go-go related gene 
HFSR 
Hand foot skin reaction 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr(s) 
Hour(s) 
i.v. 
Intravenous 
IB 
Investigator brochure 
IC50 
Inhibition concentration 50% 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Institutional ethics committee 
IHC 
Immunohistochemistry 
ILD 
Interstitial lung disease 
IN 
Investigator notification 
INR 
International normalized ratio 
IOP 
Intra ocular pressure 
IRB 
Institutional review board 
IUD 
Intra-uterine device 
IUS 
Intra-uterine system 
KA 
Keratoacanthomas 


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KRAS 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LC/MS/MS 
Liquid chromatography tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LFT 
Liver function test 
LIMS 
Laboratory information management system 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantitation 
LPLT 
Last patient last treatment 
LPLV 
Last patient last visit 
LVEF 
Left ventricular ejection fraction 
MAPK 
Mitogen-activated protein kinase 
MedDRA 
Medical dictionary for regulatory activities 
MEK 
Mitogen-activated protein kinase kinase 
MIA 
Melanoma inhibitory activity 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multi-gated acquisition scan 
NaF PET 
Sodium fluoride positron emission tomography 
NCI 
National Cancer Institute 
NRAS 
Neuroblastoma RAS viral oncogene homolog 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
OAT 
Organic anion transporter 
OCT 
Optical coherence tomography / organic cation transporter 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Pharmacodynamic / Progression of disease 
PFS 
Progression free survival 
P-gp 
Permeability glycoprotein 
PHI 
Protected health information 
Pi 
Inorganic phosphorus/phosphate 
PI3K 
Phosphatidylinositol 3' kinase 
PIK3CA 
Phosphatidylinositol 3' kinase catalytic alphapolypeptide 
PK 
Pharmacokinetic 
PKB 
Protein kinase B (also known as AKT) 
PLT 
Platelets 
po 
Per os/by mouth/orally 
PPS 
Per protocol set 
PR 
Partial response 
PS 
Performance status 
PT 
Prothrombin time 
PTEN 
Phosphatase and tensin homolog 
PVC 
Premature ventricular contraction 
QD 
Quaque die/once daily 
QOD 
Every other day 
QTcB 
QT interval adjusted according to Bazett 


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QTcF 
QT interval adjusted according to Fredericia 
RAF 
V-raf murine sarcoma viral oncogene 
RAP 
Report and Analysis Plan (RAP) (i.e. regulatory document which provides evidence of 
preplanned analyses) 
RAS 
Rat sarcoma viral oncogene homologue 
Rb 
Retinoblastoma protein 
RBC 
Red blood cells 
REB 
Research ethics board 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended Phase II dose 
RT-PCR 
Reverse-transcriptase polymerase chain reaction 
RVO 
Retinal vein occlusion 
SAE 
Serious adverse event 
SARS-CoV2 
Severe acute respiratory syndrome coronavirus 2 
SCC 
Squamous cell carcinoma 
SD 
Stable disease 
SEC 
Study evaluation completion 
SUSAR 
Suspected unexpected serious adverse reactions 
T/C 
Tumor volume over control volume 
T1/2 
Terminal elimination half-life 
TBili 
Total bilirubin 
tCa 
Total calcium 
TEN 
Toxic Epidermal Necrolysis 
TGI 
Tumor growth inhibition 
TKIs 
Tyrosine kinase inhibitors 
tmax 
Time to reach maximum plasma concentration 
TSH 
Thyroid-stimulating hormone 
TTP 
Time to progression 
ULN 
Upper limit of normal 
US 
United States 
Vss 
Volume of distribution at steady state 
WBC 
White blood cells 
WHO 
World Health Organization 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study. 
Baseline 
Baseline (i.e. Screening/baseline) assessments are the most recent 
assessments which are performed prior to the first administration of 
study treatment. 
Cycle 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (i.e. every 28 days) 
Dose cohort 
A group of newly enrolled patients treated at a specific dose and regimen 
at the same time. 
Dose level 
The dose of drugs given to the patient. 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent is obtained and patient meets all inclusion and none of the 
exclusion criteria. 
Patient number 
A unique identifier number (consisting of the center number and patient 
number) assigned to each patient who enrolls in the study. 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening/baseline, treatment, washout, etc. 
Phase II 
Selected group of patients enrolled during the Phase II part of the study. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size 
of the tumor, whether lymph nodes contain cancer, and whether the 
cancer has spread from the original site to other parts of the body 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, completion of treatment, etc. 
Study evaluation completion 
(SEC) 
Point/time which marks the end of study for an individual patient. Survival 
continues beyond SEC. 
Study treatment 
Drugs whose properties are being tested in combination in the study (i.e. 
study drugs or study drugs combination). 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason (i.e. end of treatment). 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 


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Amendment 10 
Amendment rationale 
In 2018, LGX818 (encorafenib) 450 mg orally QD, in combination with MEK162 (binimetinib) 
45 mg orally BID, received marketing approval in several jurisdictions, including the United 
States and the European Union, for the treatment of patients with unresectable or metastatic 
BRAF V600-mutant melanoma. This approval was based on the ongoing randomized Phase III 
COLUMBUS Study (CMEK162B2301). 
At this stage of the trial, the safety and efficacy of the dual combination of LGX818/MEK162 
and the triple combination of LGX818/MEK162/LEE011 have been thoroughly assessed. 
Therefore, Amendment 10 allows for patients still on treatment to be monitored in a manner 
that is consistent with local standard-of-care practice. In addition, post-treatment disease 
progression follow-up (if applicable) and/or survival follow-up (including documentation of 
subsequent antineoplastic therapies) will no longer be performed for patients in the Phase II 
part of the study. 
As of the date of this amendment, 10 patients are still on study treatment, with 5 patients 
receiving the dual combination (LGX818/MEK162) and 5 patients receiving the triple 
combination (LGX818/MEK162/LEE011). In addition, 20 patients enrolled in the Phase II part 
of the study who have discontinued study treatment are still in the disease progression/survival 
follow-up period, with 12 patients who had received the dual combination (LGX818/MEK162) 
and 8 patients who had received the triple combination (LGX818/MEK162/LEE011). 
The purpose of this amendment is to: 
1. To modify the frequency of assessments to allow for patients still on treatment to be 
monitored in a manner that is consistent with local standard-of-care practice. 
2. To discontinue post-treatment disease progression follow-up (if applicable) and/or 
survival follow-up (including documentation of subsequent antineoplastic therapies) for 
patients in the Phase II part of the study. 
3. To revise the Adverse Event and Serious Adverse Events sections to align with Pfizer 
standard operating procedures, with SAE reporting directly to Pfizer Safety; 
4. To reflect the dose modification and management related to MEK162- and LEE011- 
emerging ILD/pneumonitis and LEE011-emerging Toxic Epidermal Necrolysis (TEN); 
Changes to the Protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. 
Section 1.2 
• Section 1.2.1: addition of nomenclatures used for LGX818; 
• Section 1.2.2: addition of nomenclatures used for MEK162; 


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• 
Section 1.2.3: addition of nomenclatures used for LEE0l 1 and references to the cmTent 
LEE0l 1 Investigator's Brochure. 
Section 4 
• 
 Section 4.1 Description of study design: Section was updated to add text regarding study 
evaluation completion and discontinuation of post-treatment disease progression 
follow-up (if applicable) and/or smvival follow-up (including documentation of 
subsequent antineoplastic therapies). 
• 
Section 4.3 Definition of end of study: The definition for the end of study was updated. 
Section 6 
• 
 Section 6.3 Dose modifications: Table 6-4: Added dose modifications related to 
ILD/pneumonitis based upon MEK162 and LEE0ll prescribing info1mation and for 
TEN based upon LEE011 prescribing info1mation. In addition, clarifications were added 
to dose modifications related to ECG QTcF inte1val prolonged. 
• 
Section 6.4.1: Pennitted concomitant therapy: Clarification that COVID-19 vaccination 
may be administered. 
Section 7 
• 
 Section 7.1 Study flow and visit schedule: added new table outlining the visit 
evaluation schedule for patients (Table 7-2) along with references to Table 7-2 
(multiple locations). This section was updated to allow for patients to be monitored in 
a manner that is consistent with local standard-of-care practice for patients with 
advanced or metastatic melanoma or advanced CRC. 
• 
Section 7.1.3 Treatment period: This section was updated to indicate patients are to be 
monitored in a manner that is consistent with local standard-of-care practice. 
• 
 Section 7.1.4 End of treatment visit, including prematme withdrawal and study 
completion visit: This section was updated to define study completion for individual 
patients and to discontinue post-treatment disease progression follow-up (if 
applicable) and/or smvival follow-up (including documentation of subsequent 
antineoplastic therapies) for patients in the Phase II paiis of the study. 
• 
 Section 7.1.5.2 Disease progression follow-up period: This section was updated to 
discontinue post-treatment disease progression follow-up (if applicable) for patients in 
the Phase II paiis of the study. 
• 
 Section 7.1.5.3 Smvival follow-up period: This section was updated to discontinue 
smvival follow-up (including documentation of subsequent antineoplastic therapies) 
for patients in the Phase II paiis of the study. 
• 
Section 7.2.2 Safety and tolerability assessments and subsections: These sections were 
updated to indicate assessments will be perfonned as outlined in Table 7-2. 
• 


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Section 8 
The following sections were revised or added to align with Pfizer standard operating 
procedures: 
• Section 8.1 Adverse Events and Serious Adverse Events. 
• Section 8.1.1 Time Period and Frequency for Collecting AE and SAE Information: 
Previous Section Definitions and Reporting was deleted. Definitions of AE and SAEs 
can be found in Section 14.7 Appendix 7. 
• Section 8.1.1.1 Reporting SAEs to Pfizer Safety. 
• Section 8.1.1.2 Recording Nonserious AEs and SAEs on the CRF. 
• Section 8.1.2 Methods of Detecting AEs and SAEs. 
• Section 8.1.3 Follow-up of AEs and SAEs 
• Section 8.1.4 Regulatory Reporting Requirements for SAEs 
• Section 8.1.5 Exposure During Pregnancy or Breastfeeding and Occupational 
Exposure 
• Section 8.1.5.1 Exposure During Pregnancy 
• Section 8.1.5.2 Exposure During Breastfeeding 
• Section 8.1.5.3 Occupational Exposure 
• Section 8.1.6 Cardiovascular and Death Events 
• Section 8.1.7 Disease-Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs 
• Section 8.1.8 Adverse Events of Special Interest 
• Section 8.1.8.1 Lack of Efficacy 
• Section 8.1.9 Medical Device Deficiencies 
• Section 8.1.10 Medication Errors 
• Section 8.2 Treatment Overdose: Section added to align with Pfizer standard operating 
procedures. Previous Section 8.2 Serious Adverse Events was revised and moved to 
Section 8.1 Adverse Events and Serious Adverse Events. 
Section 11 
• Section 11.6 Data Sharing: Added section to align with Pfizer standard operating 
procedures. 


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Appendices 
The following Sections and Appendices were added to align with Pfizer standard operating 
procedures. 
• Section 14.7 Appendix 7: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting. 
• Section 14.8 Appendix 8: Liver Safety: Suggested Actions and Follow-up 
Assessments. 
• Section 14.9 Appendix 9 ECG Findings of Potential Clinical Concern. 
• Section 14.10 Appendix 10: Alternative Measures During Public Emergencies 


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Amendment 9 
Amendment rationale 
As of the release date of this amendment, 20 patients in the CMEK162X2110 study (11 in Phase 
Ib/II dual combination [LGX818 + MEK162] and 9 patients in the Phase Ib/II triple 
combination [LGX818/MEK162/LEE011]) were continuing to derive benefit from study 
treatment. In order to minimize the burden on the patients and to reduce their radiation exposure, 
this amendment allows the frequency of tumor assessments in all continuing patients to be 
reduced to every 8-12 weeks based on Investigator discretion. Patients (both dual- and 
triple-combination patients) may be transitioned to this less frequent imaging schedule once 
they have completed ≥ 24 months of study treatment (Cycle 25 Day 1 onward). In order to more 
fully assess the safety and efficacy in all patients following prolonged treatment, the definition 
of end of study has been revised to be when all patients in Phase II have died or when all patients 
have completed study evaluation completion (SEC), or have been lost to follow-up or withdrew 
consent, whichever occurs first. 
In addition, this protocol is also being amended to change the frequency and type of 
ophthalmologic 
examinations. 
In 
a 
separate 
Phase 
3 
study 
(CMEK162B2301; 
ClinicalTrials.gov identifier NCT01909453) in patients with BRAF V600-mutant melanoma 
treated with the combination of LGX818 (450 mg once daily [QD]) plus MEK162 (45 mg twice 
daily [BID]), the median time to onset of retinopathy (all grades) was 1.2 months, and there 
were no patients with a new onset event after 24 months. No patients treated with the 
combination LGX818 (450 mg once daily [QD]) plus MEK162 (45 mg BID) experienced a 
retinal vein occlusion (RVO) event. Based on these findings, and in order to minimize the 
burden on both dual- and triple-combination patients who continue to derive benefit from study 
treatment, this amendment allows patients who have been receiving study treatment 
≥ 24 months (Cycle 25 Day 1 onwards) who have not had a retinal adverse event (AE) to be 
evaluated for visual acuity at each scheduled patient visit and at the End of Treatment. Patients 
with changes in visual acuity or other ocular complaints at any time on study should be referred 
to an ophthalmologist for full ophthalmic examination. 
This protocol is also being amended to remove the collection of an unscheduled PK sample 
taken in the event of a QTcF change from baseline > 60 msec, or a new absolute QTcF interval 
≥ 501 msec. This is being done to reduce burden on the patients and the sites and would not 
significantly contribute to the PK data already accumulated on this study. Additionally, 
collection of the PK data upon a specified DLT or QT prolongation provides minimal actionable 
information to the investigator in the event these adverse events happen due to the processing 
time of PK samples. 
Additionally, the protocol is being amended to remove the fasting requirement for both the dual- 
and triple-combination treatments. Based on results of two dedicated clinical pharmacology 
studies, both binimetinib (CMEK162A2103) and encorafenib (ARRAY-818-102) exposures 
were unaffected by food, suggesting patients can take the dual-combination treatment with or 
without food. Since the package insert for LEE011 (ribociblib) indicates patients can also take 
LEE011 with or without food, the fasting restriction was removed for the triple combination. 


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Furthermore, the protocol is being amended to remove the restriction of agents that elevate 
gastric pH, including antacids, proton pump inhibitors and H2-antagonists. Based on the 
results of a dedicated clinical pharmacology study, both binimetinib and encorafenib 
(ARRAY-162-105) exposures were unaffected by rabeprazole, a proton pump inhibitor, 
suggesting patients can take the dual-combination treatment with agents that elevate gastric 
pH. 
Additional revisions have been made to sections of the protocol that are specific to the triple- 
combination arms with LEE011 in order to reflect recent clinical development changes 
pertaining to dose modification for LEE011. 
In Appendix 4 of the protocol, language was added to Table 14-9 through Table 14-11 stating 
that the substrates in the tables do not represent an exhaustive list of substrates, inducers or 
inhibitors. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. 
• 4.3 Definition of end of study, 7.1.5.2 Disease progression follow-up period, and 7.1.5.3 
Survival follow-up period. 
The above section was amended to clearly define the end of study. 
• 6.1.1.1 Dose Administration of dual combination (LGX818 and MEK162) and 6.1.1.2 Dose 
Administration of triple combination (LGX818 and MEK162 and LEE011) 
The above sections were modified to allow patients to take either the dual combination 
(LGX818 and MEK162) or the triple combination (LGX818 and MEK162 and LEE011) 
with or without food. 
• 6.2.5 Definitions of dose limiting toxicities; 6.3.1 Dose modification and dose delay 
The above sections were modified to reflect the change in the CTCAE version to be used 
for data analysis, from version 4.0 to version 4.03. The CTCAE version 4.03 was 
implemented before patients were enrolled to the study. 
• Table 6-4 Criteria for interruption and re-initiation of LGX818 and MEK162 or LGX818 
and MEK162 and LEE011 treatment; 
 
Table 6-4 was amended to provide detailed dose modification guidelines for patients 
undergoing treatment with the dual combination (LGX818 and MEK162) and the triple 
combination (LGX818 and MEK162 and LEE011). 
• 6.3.2 was Section 6.2.6.2 – Follow-up evaluations for appearance of central serous 
retinopathy (CSR) 
The above section was amended to include information on the ophthalmic examination 
schedule for patients without a retinal AE. 


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• 6.3.3 Additional follow-up for hepatic toxicities in patients receiving LEE011 
The above section was amended to provide the specifics of hepatic toxicity monitoring, and 
add additional guidance for the investigation of potential hepatic toxicity. 
• 6.4.1 Permitted concomitant therapy 
The above section was revised to add a subsection with guidance on the use of 
corticosteroids while on study. 
• 6.4.2 Permitted concomitant therapy requiring caution and/or action for LGX818 and 
MEK162 
The above section was revised to include drug-drug interaction risks of clinical relevance. 
• 6.4.2.1 Additional permitted concomitant therapy requiring caution and/or action for 
addition of LEE011 in the triple combination 
The above section was amended to add additional guidance on the use of concomitant 
therapy requiring caution for patients during treatment with the triple combination LGX818 
and MEK162 and LEE011. 
• 6.4.3.1 Additional prohibited concomitant therapy for addition of LEE011 in the triple 
combination 
The above section was amended to add additional guidance on prohibited concomitant 
therapy for patients during treatment with the LGX818/MEK162/LEE011 triple 
combination. 
• Table 7-1 Visit evaluation schedule; 7.1 Study flow and visit schedule. 
The above table was amended in the row for ophthalmologic examination to allow patients 
who 
have 
been 
on 
the 
LGX818/MEK162 
dual-combination 
and 
LGX818/MEK162/LEE011 triple-combination treatment for ≥ 24 months (Cycle 25 Day 1 
onward) without a retinal AE to be evaluated only for visual acuity at each scheduled patient 
visit and at the End of Treatment visit. These patients are also required to have a full 
ophthalmic examination if clinically indicated and at the End of Treatment visit. 
The above table was also amended in the row for tumor evaluation per the Response Criteria 
in Solid Tumors (RECIST) by computed tomography (CT)/magnetic resonance imaging 
(MRI) to allow patients who have been on the LGX818/MEK162 dual- combination and 
LGX818/MEK162/LEE011 triple-combination treatment for ≥ 24 months to have CT/MRI 
scans every 8-12 weeks (± 7 days) instead of every 8 weeks. Also, this row was amended 
to allow patients who have been on either combination treatment for ≥ 24 months and then 
discontinue study treatment for any reason other than disease progression to have CT/MRI 
scans every 8-12 weeks (± 7 days) instead of every 8 weeks. 


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The above table was amended to add the recommendation following the 30-day follow-up 
period and when clinically appropriate for patients to be monitored with physical 
examinations, dermatological examinations and chest CT scans for cutaneous and 
non-cutaneous secondary malignancies for up to 6 months after the last encorafenib dose or 
until initiation of another antineoplastic therapy. 
The above section was amended to reflect the changes in the tumor evaluation schedule 
described as for Table 7-1. 
• 7.1.5.2 Disease progression follow-up period 
The above section was amended for tumor evaluation per RECIST by CT/MRI to allow 
patients 
who 
have 
been 
on 
the 
LGX818/MEK162 
dual-combination 
or 
LGX818/MEK162/LEE011 triple-combination treatment for ≥ 24 months and then 
discontinue study treatment for any reason other than disease progression to have CT/MRI 
scans every 8-12 weeks (± 7 days) instead of every 8 weeks. 
• 7.1.5.3 Survival follow-up period 
The above section has been modified to remove the 18-month follow-up. 
• 7.2.1 Efficacy assessments 
The above section was amended for tumor evaluation per RECIST by CT/MRI to allow 
patients who have been on the LGX818/MEK162 dual-combination treatment or 
LGX818/MEK162/LEE011 triple combination for ≥ 24 months to have CT/MRI scans 
every 8-12 weeks (± 7 days) instead of every 8 weeks until disease progression. The above 
section was also amended for tumor evaluation per RECIST by CT/MRI to allow patients 
who have been on the dual- or triple-combination treatment for ≥ 24 months and then 
discontinue study treatment for any reason other than disease progression to have CT/MRI 
scans every 8-12 weeks (± 7 days) instead of every 8 weeks. The above section was also 
amended to remove the note that all radiological assessments are to be centrally collected 
by an imaging CRO, and to remove the note that such assessments may be assessed centrally 
if deemed necessary. 
• 7.2.2.7 Ophthalmologic evaluation 
The above section was amended to allow patients who have been on the LGX818/MEK162 
dual-combination or LGX818/MEK162/LEE011 triple-combination treatment for ≥ 24 
months without a retinal AE to be evaluated only for visual acuity at each scheduled patient 
visit and at the End of Treatment visit. These patients are also required to have a full 
ophthalmic examination if clinically indicated and at the End of Treatment visit. 


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• 7.2.2.8.2 Electrocardiogram (ECG) schedule for the triple combination 
The above section was amended to remove text around unscheduled PK sample collection 
when an ECG with a QTcF change from baseline > 60 msec or a new absolute QTcF ≥ 501 
msec result is observed. 
• 7.2.3.1.1 Pharmacokinetic blood sample collection and handling 
The above section was amended stop collection of unscheduled PK samples and text was 
removed where this practice was discussed. This includes addition of footnotes in 
Table 7-4 and Table 7-5 denoting collection should be stopped upon the effective date of 
this amendment. 
• 8.1.1 Definitions and reporting 
The above section was modified to reflect the change in the CTCAE version to be used for 
assessment of AEs, from version 4.0 to version 4.03. 
• 9.3 Data collection 
The above section was amended to remove the note that all imaging data to be centrally 
collected by an imaging CRO, and to remove the note that such imaging data may be 
assessed centrally if deemed necessary. 
• 9.4 Database management and quality control 
The above section was amended to remove the note that all imaging data are to be assessed 
centrally. 
• 10 Statistical methods and data analysis 
The above section was amended to indicate the final clinical study report will be completed 
once all patients have completed or discontinued from the study. 
• 10.5.2.1 Adverse events and 10.5.2.2 Laboratory abnormalities 
The above sections were amended to reflect that CTCAE version 4.03 was used in the 
grading of AEs and laboratory abnormalities. 
• Table 14-11 List of P-gp Inhibitors to be used with caution and Table 14-12 List of BCRP, 
OAT1, OAT3, OCT1, OCT2, OATP1B1 and OATP1B3 substrates to be used with caution 
Table 14-11 was combined with Table 14-12 and renamed to List of BCRP substrates, BSEP 
inhibitors, P-gp inhibitors/inducers, and MATE1, P-gp, OAT1, OAT3, OCT1, OCT2, 
OATP1B1 and OATP1B3 substrates to be used with caution. The List of BCRP OAT1, 
OAT3, OCT1, OCT2, OATP1B1 and OATP1B3 substrates to be used with caution was 
updated to add BSEP inhibitors, MATE1 and P-gp inhibitors/inducers (Table 14-11). 


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• Table 14-12 Drugs with a conditional risk of Torsades de Pointes, and a second Table 
14-12 Drugs with a possible risk of Torsades de Pointes; Appendix 4 List of concomitant 
medications prohibited or to be used with caution for dual and triple combination 
Information regarding Torsades de Pointes and Drugs with a possible risk of Torsades de 
Pointes (in 2 tables labelled Table 14-12) were combined and updated and a new table 
(Table 14-12, List of QT prolonging drugs), was added. The new table updates and expands 
the list of QT prolonging drugs and matches the changes made in Section 6.4 on concomitant 
medications. 
Other minor clarification changes and corrections to typographical errors have been made. 
IRB/IEC 
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. 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 protocol amendment. 


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Amendment 8 
Amendment rationale 
The main purpose of this amendment is to address recently observed safety findings from 
patients treated with LEE011 (Ribociclib) in other clinical trials. 
1. Recent data suggests a potential risk of hepatic toxicity (drug induced liver injury [DILI] 
indicated by an increase of transaminases, in isolation or with bilirubin increase, in 
patients treated with LEE011. Updates to monitoring for hepatobiliary toxicities including 
ALT, AST, and total bilirubin have been added. 
2. Updates to monitoring and dose adjustment guidelines for QTcF prolongation in order to 
improve patient safety based on program standard language recommendations have been 
implemented. Specific changes are as follows: 
a. Dose modification guidelines have been changed to more strictly manage QTcF 
prolongation 
b. Additional ECG assessments 
c. Follow-up of electrolyte abnormalities until normalization in the event of QTcF 
prolongation 
d. Mandated review of concomitant medications in the event of QTcF prolongation, also 
updated based on recent metabolism data for LEE011 or MEK162 
e. Mandated review of dosing regimen in the event of QTcF prolongation 
f. Addition of continued ECG monitoring for all cycles in the event of a patient QTcF 
≥ 481 ms at any time before Cycle 7 Day 1 
This amendment also documents a change in study sponsorship from Novartis to Array 
BioPharma. Study design and procedures are not affected by the sponsorship change. 
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. 
• The Protocol Summary is updated to reflect the changes to the inclusion and exclusion 
criteria 
• Section 5.3 Exclusion criteria has been updated with the following: 
• Addition of criteria for the following laboratory values within normal limits or 
corrected to within normal limits with supplements before the first dose of study 
medication: sodium, inorganic phosphate, calcium (corrected for serum albumin) 
• Clarification of QTcF interval criteria on the ECG (ie: unreadable or not interpretable) 
or QTcF >450 ms. All as determined by screening ECG (mean of triplicate ECGs) 
• Addition of symptomatic pericarditis within 12 months prior to starting study drug 
• Addition of any other clinically significant heart disease (e.g. documented congestive 
heart failure, documented cardiomyopathy) 
• Increase in exclusion window from 3 months to 12 months prior to starting study drug 
for unstable angina pectoris and acute myocardial infarction 


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• Addition exclusion window of 12 months prior to starting study drug for clinically 
significant resting bradycardia, history or presence of ventricular tachyarrhythmia, 
complete left bundle branch block, right bundle branch block and left anterior hemi 
block (bifasicular block) 
• Clarification that patients who are currently receiving agents known to cause QT 
prolongation, induce Torsades de Pointes, or that are metabolized predominantly 
through CYP3A4 and have a narrow therapeutic index, and cannot be discontinued 7 
days prior to Cycle 1 Day 1, are excluded 
• Section 6.1.1, added grapefruit hybrids, pummelos, starfruit and Seville (sour) oranges to 
list of items to be avoided due to CYP3A4 mediated interaction 
• Table 6-4 - Dose modification guidelines, has been updated to: 
• Include new guidelines for the management of QTcF prolongation. Dose reduction is 
recommended in case of grade 2 QTc prolongation (QTcF 481-500 ms). For patients 
who experience grade 3 QTc prolongation (QTcF ≥ 501 ms) on at least two separate 
ECGs, local cardiologist consultation is also recommended in addition to dose 
reduction. Patients who experience grade 4 QTc prolongation must discontinue study 
treatment. 
• Section 6.3.3 added to outline Additional follow-up for hepatic toxicities 
• Section 6.4.3.1 updated to reference medications that are known to induce Torsades 
de Pointes 
• Section 7.2.2.8.2 was updated to clarify follow-up guidelines in the event a QTcF value 
of ≥ 481 ms is observed prior to cycle 7 
• Appendix 4 includes new tables listing medications with a risk of Torsades de Pointes 
In addition to these changes, inconsistencies and typographical errors have been corrected 
as needed. 
IRB/IEC 
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. 
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 
protocol amendment. 


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Amendment 7 
Amendment rationale 
• This protocol amendment is based on Urgent Safety Measures (re: Investigator 
Notification letter dated 07Feb2014): 
• A fatal event of intracranial hemorrhage occurred in a 21-year-old patient in a phase Ib 
study of LEE011 in combination with MEK162 [MEK162X2114]. Based on the normal 
laboratory assessments, absence of other known risk factors for intracerebral bleeding 
together with early signs of clinical response to treatment, the investigator suspected 
undetected intracranial metastases as the source of the bleeding. The relationship to study 
drugs cannot be ruled out. While the protocol excludes patients with symptomatic brain 
metastases, brain imaging prior to study entry had not been required and was not 
performed for this patient. As a precautionary measure, this amendment will mandate 
brain imaging for all patients at screening and will exclude patients with brain metastases 
from the triple-combination part of the study. Furthermore, patients with abnormal 
coagulation evaluations at Screening/baseline will be excluded from the triple- 
combination part of the study. 
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 has been updated for the triple-combination part of the 
study to include the following: 
1. Exclusion criterion no. 3 has been updated to exclude patients with brain metastases. 
2. Exclusion criterion no. 7 has been updated to exclude patients with abnormal 
coagulation evaluations: PT/INR >1.5 x ULN or aPTT >1.5 x ULN. 
• Section 6.1.5, Treatment duration has been updated to exclude from treatment beyond 
progression patients in the triple-combination part of the study that appear with new brain 
metastases. 
• Table 7-1, Visit evaluation schedule has been updated to include mandatory brain 
MRI/CT at Screening/baseline for patients in the triple-combination part of the study. 
• Section 7.2.1, Efficacy assessment has been updated to include mandatory baseline brain 
imaging to access CNS disease for the patients in the triple-combination part of the study. 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
1. Urgent Safety Measures (re: Investigator Notification letter dated 07 Feb 2014): 
This amendment is required for patient safety (i.e. necessary to eliminate immediate hazards to 
the trial subjects ICH GCP 3.3.8). Therefore updated exclusion criteria and baseline imaging 
assessments will be implemented prior to IRB/IEC approval, but will be sent for approval as 
well. 


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Amendment 6 
Amendment rationale 
1. Urgent Safety Measures (re: Investigator Notification letter dated 08 Nov 2013): 
• The main objective of this amendment is to modify existing safety monitoring for 
visual toxicities. This is based on a new unexpected non-clinical finding from the 
13-week monkey toxicology study with LGX818. In this study, two monkeys 
treated at a dose of 60mg/kg/day presented retinal changes at the assessment on 
week 12 (please refer to the Investigator Notification letter dated 08 Nov 2013). As 
for this protocol sufficient ophthalmic examinations are already in place to monitor 
for the potential risk of retinal/ocular changes, these examinations and frequency 
of the examinations will not change. However this amendment includes modified 
recommendations for LGX818 dose modifications for visual toxicity and in 
addition, modified definitions of ophthalmologic DLT’s are provided. 
2. Other Changes Implemented under Protocol Amendment 6: 
• In addition, prohibited medications are updated. Since LGX818 is mainly 
metabolized by CYP3A4 (>80%), concomitant use of strong CYP3A4 inhibitors 
would likely significantly increase the exposure of LGX818. Therefore 
concomitant use of strong systemic CYP3A4 inhibitors is prohibited during this 
study. Language in Section 6.4.2 and Section 6.4.3, and Appendix 4 (Section 
14.4) is amended accordingly and a corresponding exclusion criterion was added 
in Section 5.3. 
• Also, this amendment clarifies that any language regarding the triple combination 
of LGX818/MEK162/LEE011 in this protocol (introduced under protocol 
amendment 5) is not applicable to the USA and Singapore, as indicated in the 
applicable Protocol Sections. Any other changes introduced under protocol 
amendment 5, are by this amendment now made applicable to the USA and 
Singapore. Which are as follows: 
a. Table 6-4 under ‘Creatine phosphokinase (CPK)’ clarifying text added: If the 
LGX818 dose administered is > 450mg QD, then the LGX818 dose must be 
reduced to 450mg QD during the MEK162 dosing interruption. If the 
LGX818 dose was reduced to 450mg QD during MEK162 dosing 
interruption, the LGX818 dose must be re-escalated to the previous 
administered dose once MEK162 dosing is restarted. Section 6.3.2 was 
amended accordingly. 
b. Section 1.2.1.2 and Section 1.2.2.2 (and subsections) have been updated with 
data from the most recent Investigator Brochure for LGX818 and Investigator 
Brochure for MEK162, respectively. 
c. Section 6.4.2 was updated for new available data: 1) MEK162 is also an 
inhibitor of CYP2B6. 2) There is a potential for MEK162 to induce CYP3A4. 
3) The solubility of LGX818 and MEK162 is pH dependent. Patients 
receiving concomitant treatments that could potentially modify the gastric pH 
(i.e. PPI) should be instructed to take them at least two hours after the 
administration of LGX818 and/or MEK162. 


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d. Section 7.2.2.2 was corrected for the collection of vital signs at Cycle 2 Day 
15 also for patients enrolled in the Phase II part of the study. 
e. For clarity of presentation, the description in Section 10.4.2.1 of the prior 
distributions for the 5 parameter BLRM has been moved to Appendix 5 
(statistical methodology LGX818 and MEK162 dual combination). 
This amendment occurs while the study drug dual combination of LGX818 and MEK162 is 
enrolling in the Phase II part of the study. In this ongoing study two RP2Ds were declared: 
600mg/45mg and 450mg/45mg (LGX818 QD/ MEK162 BID). The dose escalation part for the 
triple combination LGX818, MEK162 and LEE011 is open for enrollment at participating sites. 
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 1.2.1.1.2 and Section 1.2.1.2 were updated with the new data of the 13-week 
monkey toxicology study. 
• Table 6-3 and Table 6-4 have been amended to include the modified definitions of the 
ophthalmologic DLT and the modified recommendations for LGX818 dose modifications 
for visual toxicity, respectively. Section 6.2.6.2 and Section 6.3.2 have been updated 
accordingly. 
• Section 6.4.2 and Section 6.4.3, have been updated to include the new data on 
concomitant use of strong systemic inhibitors of CYP3A4, which are as per this 
amendment prohibited. Section 6.4.3.1, Table 14-10 and exclusion criterion 17 (Section 
5.3) were updated accordingly, as well was exclusion criterion 18 (Section 5.3) added. 
• For the clarification that any language regarding the triple combination with LEE011 in 
this protocol is not applicable to the USA and Singapore, a statement was added to the 
Protocol Summary and to Section 1, Section 2, Section 3, Section 4, Section 5, Section 6, 
Section 7, Section 10, Section 11.3, Section 14.3, Section 14.4 and Section 14.6. 
• Section 7.2.4.1.3 was updated to clarify that the collection of a fresh tumor biopsy at the 
time of relapse is strongly encouraged if feasible according to the investigator. Section 
7.2.4.1.4 and Section 7.2.4.2.1 were updated to align the collection of the tissue with the 
requirements of the analysis lab. Table 7-5 was updated accordingly. 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
1. Urgent Safety Measures (re: Investigator Notification letter dated 08 Nov 2013): 
This amendment is required for patient safety (i.e. necessary to eliminate immediate hazards to 
the trial subjects ICH GCP 3.3.8). Therefore dose modifications for ocular adverse events and 
updated DLT criteria will be implemented prior to IRB/IEC approval, but will be sent for 
approval as well. 
2. Other Changes Implemented under Protocol Amendment 6: 


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All other changes described in this amendment 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 5 
Amendment rationale 
1. The main rationale for this amendment is to add LEE011 to the LGX818 and MEK162 
combination treatment in order to explore safety and preliminary efficacy of this triple 
combination in patients with BRAF V600-dependent advanced solid tumors. 
Pre-clinical evidence suggests that the addition of LEE011 to the dual combination of 
MEK162 and LGX818, could potentially improve the clinical response in patients 
with BRAF V600-dependent melanoma (see Section 1.2.4.3). Although clinical trials 
with selective BRAF and MEK inhibitors have shown significant activity in patients 
with BRAF mutant melanoma, these patients ultimately relapse and fail to continue to 
respond to these therapies. Therefore, targeting both the RAS/RAF/MEK/ERK and the 
Cyclin D-CDK4/6 pathways downstream may improve and prolong response and be 
an effective strategy to expand therapeutic options for these patients with advanced 
melanoma that have very poor prognosis and constitute a high unmet medical need. 
Therefore the triple combination of LGX818 and MEK162 and LEE011 will be 
evaluated in a dose escalation to determine the MTD and/or RP2D in patients with 
BRAF V600-dependent advanced solid tumors. Once the MTD and/or RP2D is 
declared, the preliminary efficacy of the triple combination will be assessed in patients 
with BRAF V600 mutant advanced melanoma naïve to prior treatment with a BRAF 
inhibitor (arm A). 
The triple combination will be evaluated in parallel and separately from the evaluation 
of the dual combination. 
2. In addition, this amendment was used to clarify that in those patients dosed with a 
LGX818 dose > 450mg QD, the LGX818 dose is recommended to be reduced to 
450mg QD during a MEK162 dosing interruption while maintaining LGX818 dosing 
(as per Table 6-4 for grade 3 CPK, eye disorders - retinopathy and eye disorders – any 
other), to reduce any potential risk of developing adverse events to the patient. This is 
recommended since a dose of 450mg QD LGX818 is the maximum tolerated dose for 
LGX818 as a single agent, and there is an improved tolerability of LGX818 in the 
combination with MEK162 compared to LGX818 as a single agent. Once MEK162 
dosing is restarted, the LGX818 dose can be re-escalated to the previous administered 
dose. 
This amendment occurs while the study drug dual combination of LGX818 and MEK162 is 
enrolling in the Phase II part of the study at the RP2D of 600mg LGX818 QD and 45mg 
MEK162 BID. In this ongoing study two RP2Ds were declared: 600mg/45mg and 450mg/45mg 
(LGX818 QD/ MEK162 BID). 
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. 
• All relevant Sections, Tables and Figures throughout the protocol were updated to include 
the evaluation of the triple combination of LGX818 and MEK162 and LEE011. 


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• Sections 1.2.1.2 and 1.2.2.2 (and subsections) have been updated with data from the most 
recent Investigator Brochures for LGX818 and MEK162, respectively. 
• Sections 1.2.3 (and subsections), 1.2.4.3, 1.2.4.4, 1.3.2, 6.1.1.2, 6.4.2.1, 6.4.3.1, 7.2.2.8.2, 
and Tables 6-2, 6-4, 6-6 were added for the triple combination. 
• Table 6-4 and Section 6.3.2 were amended to include the guidance on the LGX818 dose 
reduction/re-escalation during MEK162 dosing interruption for certain toxicities. 
• Section 6.4.2 was updated for new available data 
• Section 7.2.2.2 was corrected for the collection of vital signs at Cycle 2 Day 15 also for 
patients enrolled in the Phase II part of the study. 
• For clarity of presentation, the description in Section 10.4.2.1 of the prior distributions for 
the 5 parameter BLRM has been moved to Appendix 5. 
• Section 14.6 (Appendix 6) was added to describe the operating characteristics of the 
BLRM and hypothetical dose escalation scenarios of the triple combination. 
• Other minor changes in the protocol text were made for consistency/clarification. 
• The protocol summary has been updated according to the changes in the amended 
protocol. 
IRB/IEC 
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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Amendment 4 
Amendment rationale 
The rationale for this amendment is to allow reduction of the MEK162 dose in case of MEK162 
related toxicities. The current language in this protocol recommends a reduction to the next 
lower, previously tested (i.e. in this study) dose level of the respective study drug. This applied 
only to LGX818 and not to MEK162, since only the LGX818 dose has been escalated and no 
lower dose levels than 45mg MEK162 have been tested in this study. 
Therefore this amendment introduces the modified recommendation: treatment at the next lower, 
previously tested dose level of LGX818 and the next lower dose level of MEK162 (please see 
Table 6-1). Treatment with LGX818 should be maintained at the same dose level if, in the 
judgment of the investigator, the adverse event is considered to be unrelated to LGX818. 
In addition, this amendment introduces a number of further changes and clarifications: 
• For patients considered for enrollment in this study for whom molecular status is not 
known and who have a tumor which is not routinely screened for a BRAF mutation at a 
local laboratory, both fresh and archival tumor tissue can be used for the local assessment 
of the mutational status. As the BRAF mutational status assessment for these cases is 
specifically performed for this study at the local laboratory, both patients giving fresh 
tumor sample and allowing use of archival tumor tissue must sign Molecular pre- 
screening Informed consent prior to this assessment. Therefore the language in the 
protocol was amended to require Molecular pre-screening Informed consent to be signed 
for allowing both collection of fresh tumor sample and use of archival tumor tissue. 
Previously this was required only for patients from whom fresh tumor sample was 
collected. 
• Minimal criteria to allow dosing beyond progression were added: it was clarified that 
dosing beyond progression of disease is not allowed in situations where the patient has a 
rapid progression of disease and needs urgent alternative medical intervention, if patients 
have worsening of clinically relevant laboratory values or if patients have a clinically 
relevant decline in performance status at time of progression. 
• The early tumor assessment on C1D28 has been removed from the Phase II part of the 
protocol in order to reduce the amount of irradiation patients enrolled in this part of the 
study would receive and for consistency with the tumor assessment schedule of future 
studies involving MEK162 and LGX818. 
• As supported by additional data now available, the new MEK162 tablet variants as 
described in this protocol, no longer need to be administered to the patients under 1-hour 
fasting periods prior, and after dosing of the evening MEK162 doses. Therefore language 
referring to this fasting has been removed from the protocol. 
• The frequency of physical examinations, vital signs and performance status assessments 
was reduced and the collection of several clinical chemistry laboratory parameters was 
removed for the Phase II part of the study, as sufficient safety data were collected during 
the Phase Ib part of the study. 
• In order to assess the potential impact of demographic differences (e.g. Japanese vs 
Caucasian) on the PK of the LGX818 and MEK162 combination, the protocol has been 


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modified to allow PK samples to be collected from additional patients enrolled in the 
Phase II part. 
• The time points and requirements for the fresh tumor biopsy and skin biopsy collection 
were clarified and further specified. 
The current study began recruitment on 28-May-2012. As of 16-April-2013, 35 patients with 
advanced solid tumors with BRAF mutations have been enrolled and treated for at least 28 days. 
This amendment occurs while the study drug combination is being evaluated at the seventh dose 
cohort (800mg LGX818 QD and 45mg MEK162 BID) and expanded dose level cohort six of 
450mg LGX818 QD and 45mg MEK162 BID. In parallel, recruitment to the Phase II part of 
the study started on 18-Apr-2013 with the RP2D of 600mg LGX818 QD and 45mg MEK162 
BID. 
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. 
• Sections 1.2.1.1.1 and 6.4.2 were updated with newly available data. Table 14-12 was 
updated accordingly. 
• Sections 4.1 and 7.1.1 were amended with the new requirements for signing of Molecular 
pre-screening ICF. The Molecular pre-screening ICF was corrected accordingly. 
• Language referring to fasting for the new MEK162 tablet variants has been removed from 
Section 6.1.1. 
• Section 6.1.5 was amended to included cases in which treatment beyond progression is not 
allowed. 
• Section 6.3.2 and Table 6-3 have been amended to revise the wording on dose level 
reduction. 
• The Visit Names/Numbers for the D28 visits were removed from Table 7-1 to be 
consistent with the clinical data base visit numbering. 
• Section 7.2.1 was amended to indicate that the C1D28 tumor imaging assessment is not 
required for the patients enrolled in the Phase II part of the study. Section 7.1 and Table 7- 
1 were updated accordingly. 
• Sections 7.2.2.1, 7.2.2.2, 7.2.2.3 and 7.2.2.5.2 were amended to reduce the frequency of 
physical examination, vital signs and performance status assessments, and to remove the 
collection of chloride, urea or BUN, uric acid, total cholesterol, triglycerides, HDL, LDL, 
TSH, T3 and T4 from the clinical chemistry laboratory assessment for patients enrolled in 
the Phase II part of the protocol. Table 7-1 was revised accordingly. 
• Sections 7.2.3 and 7.2.3.1.1 were amended to include language that collection of PK 
samples from additional patients than previously specified, is allowed if required as per 
instruction from the Sponsor. Tables 3-1, 7-1, 7-4 and 7-5 were updated accordingly. 
• Sections 7.2.4.1.2, 7.2.4.1.3 and 7.2.4.2 were amended to clarify and further specify the 
time points and requirements under which fresh tumor and skin biopsies should be 
collected. Tables 7-1 and 7-5 were revised accordingly. 


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• Sections 7.2.4.4 and 7.2.4.5 were updated to clarify which samples collected during the 
study, are meant to be stored for 15 years for optional additional exploratory biomarker 
assessments and to include further potential use of all remaining study samples. 
IRB/IEC 
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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Amendment 3 
Amendment rationale 
The production of the original MEK162 tablet that is currently used in this study will cease. 
Two new MEK162 tablet variants have been developed. One variant is a modified formulation 
of the MEK162 drug product (hence forth referred to as “MEK162 smaller tablet”) and the other 
variant has the same formulation but contains drug substance from a new manufacturer (hence 
forth referred to as “new MEK162 tablet variant”). 
Two relative bioavailability studies in humans are currently ongoing in order to compare 
a) the MEK162 smaller tablet with the original MEK162 tablet (CMEK162X2108 study) and 
b) the new MEK162 tablet variant with the original MEK162 tablet (CMEK162A2101 study). 
Based on the results of these two relative bioavailability studies, the MTD/RP2D of the 
LGX818 and MEK162 combination may need to be established with one or both of the two 
new MEK162 tablet variants (for further details please see Section 6.2.3). This amendment will 
introduce this possibility. 
If it is decided based on the results of the two relative bioavailability studies, that the 
MTD/RP2D can be determined using the original MEK162 tablet, then enrollment in the 
CMEK162X2110 study will continue in the dose escalation or the Phase II part will start with 
one or both of the two new MEK162 tablet variants, as applicable at that time. 
• Since food interaction studies with the two new MEK162 tablet variants have not yet been 
performed at the time of this amendment, these new tablet variants would need to be 
administered to the patients under 1-hour fasting periods prior, and after dosing of the 
evening MEK162 doses. 
In addition, this amendment was used to make a few changes for clarification (please see below 
Changes to the protocol for details). 
The current study began recruitment on 28-May-2012. As of 05-Nov-2012, 20 patients with 
advanced solid tumors with BRAF mutations have been enrolled. This amendment occurs while 
the study drug combination is being evaluated in the fourth dose cohort. 
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 5.2 has been updated to clarify the collection of mandatory fresh tumor biopsies at 
Screening/baseline for patients to be enrolled in the Phase II part. Section 7.2.4.1.1 and 
Table 7-1 were amended accordingly. 
• Section 6.2.3 has been updated to include the possibility to establish the MTD/RP2D with 
the MEK162 smaller tablet and/or new MEK162 tablet variant if needed. Sections 10.1.1, 
10.3.1 and 10.4.2.1 have been updated accordingly. 
• Section 6.1.1, Section 6.6.1 and Section 6.6.2 have been updated to include instructions on 
dose administration of, and (label) information on the two new MEK162 tablet variants. 


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• Sections 7.1, Section 7.2.1 and Table 7-1 have been updated to clarify the wording on 
imaging assessments. Sections 9.3 and 9.4 have been updated to accurately describe the 
process of central reviewing of the imaging assessments. Section 10.4.4 and Section 10.5.1 
have been amended accordingly. 
IRB/IEC 
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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Amendment 2 
Amendment rationale 
The main rationale of the amendment is to introduce a third arm in the Phase II part of the study 
to enroll 40 patients with locally advanced or metastatic BRAF V600 mutant melanoma who 
are naïve to previous treatment with a selective BRAF inhibitor. LGX818 has shown in the first 
in human Phase I single agent CLGX818X2101 study, clinical antitumor activity at all dose 
levels tested (50 mg/day to 300 mg/day) in patients with metastatic BRAF V600 mutant 
melanoma who did not receive prior treatment with a selective BRAF inhibitor. As of 03 July 
2012, signs of clinical activity have been observed in 20 out of the 21 enrolled patients naïve 
for prior selective BRAF inhibitor treatment, with reductions in tumor volume of 8.3% to 100% 
(including 11 PR (of which 8 confirmed)), observed after initiation of LGX818 single agent 
treatment. In addition, MEK162 has demonstrated clinical activity in the human phase II single 
agent CMEK162X2201 study in patients with BRAF mutant metastatic melanoma (Ascierto 
2012). Recent data from the phase Ib/II combination study of the BRAF inhibitor Dabrafenib 
and MEK inhibitor Trametinib also show that patients with BRAF mutated melanoma clinically 
benefit from a BRAF/MEK inhibitor combination with an improved durability of response over 
single agent therapy (Weber 2012). The anticipated sample size of n = 40 patients was chosen 
in order to ensure desirable statistical properties (correct declaration of activity/ inactivity) with 
respect to the primary analysis. 
Additionally, this amendment will introduce the possibility to continue to treat patients beyond 
progression of disease. The recent overall survival data from the BRIM2 and BRIM3 clinical 
trials of the selective BRAF inhibitor Vemurafenib show that patients with BRAF mutated 
melanoma may clinically benefit from continued treatment beyond progression (Sosman 2012, 
Chapman 2011). This amendment will therefore allow that in special circumstances, such as 
cystic lesions, mixed responses, or new brain metastases treatable with stereotactic radiotherapy 
or surgery, patients to continue dosing with LGX818 and MEK162, if it is considered to be of 
benefit for the patient by the investigator, and in agreement with the Sponsor. 
Moreover, collection of fresh tumor biopsies at Screening/baseline for all patients enrolled in 
the Phase II part, will be mandatory as per this amendment (unless sufficient fresh tumor tissue 
was collected during local molecular pre-screening which can be submitted to the Sponsor- 
designated laboratory at Screening (see Section 7.2.4). Clinical activity of BRAF inhibitors is 
substantial in terms of response rate. However, not all patients respond and some patients show 
progression of disease after relatively short time periods (Flaherty 2010, Chapman 2011, 
Sosman 2012). In order to fully characterize the tumor, a comprehensive genomic analysis of 
the tumor will be performed at baseline to better understand the genomic profile of the patient's 
tumors and potentially identify predictive markers of efficacy. As a result, characterization of 
select baseline gene mutation status in tumor tissue for the Phase II part will now be assessed 
as a secondary endpoint. 
A number of additional changes and clarifications are introduced in this amendment: 
• All patients enrolled in the Phase II part of the study will be followed for survival more 
frequently: every three months instead of every four months. 


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• The recommended dose modifications for Grade 2 and 3 eye disorders have been revised. 
The ocular toxicity profile of MEK162 is becoming better understood and investigators 
are gaining experience in assessing and managing these toxicities. Emerging data from 
several ongoing trials with MEK162 demonstrate that the events were low grade and 
appear to be reversible and manageable in all patients. In most cases, the events are 
transient in nature and resolve either without stopping treatment, upon dose reduction, or 
upon interruption of treatment and subsequent continuation at the same dose of MEK162. 
Based on these growing safety data from the clinical studies with MEK162, it is 
reasonable to consider maintaining the treatment of LGX818 and MEK162 for Grade 2 
CSR (central serous retinopathy)/CSR-like events, and also to allow dose reduction of 
MEK162 for Grade 3 CSR/CSR-like events. As result the DLT criteria for Grade 2 and 3 
Eye disorders have been revised accordingly. 
• The recommended dose modifications for CTCAE Grade 3 and 4 CPK have been revised. 
Blood creatine phosphokinase (CPK) elevations are mostly asymptomatic and not 
clinically significant. Therefore and based on the growing safety data from the ongoing 
clinical studies with MEK162, it is reasonable to review and consider to not dose modify 
LGX818 and MEK162 treatment in asymptomatic cases of Grade 3 CPK elevations and to 
recommend dose reduction for symptomatic Grade 3 blood CPK and for all Grade 4 blood 
CPK. As result the DLT criteria for CTCAE Grade 3 and 4 CPK have been revised 
accordingly. 
• The CYP inhibitors/inducers/substrates lists were updated according to the new lists 
published by FDA. Caution for co-medications that are UGT1A1 substrates was added 
since LGX818 was found to be an inhibitor of UGT1A1 in vitro. In addition, caution for 
co-medications that are substrates of renal transporters OAT1, OAT3 and OCT2 and 
hepatic transporters OATP1B1 and OATP1B3 was added because LGX818 was found to 
inhibit OAT1, OAT3, OCT2, OATP1B1 and OATP1B3. 
• PK samples will be collected for the first 10 patients treated in each arm 2 and 3 in the 
Phase II part of the study. Previously, PK samples were collected in Phase II arm 2 from 
those patients from whom a fresh tumor biopsy could be collected (i.e. at least 15 
patients). As per this amendment a fresh tumor biopsy at Screening/baseline is mandatory 
for all patients in the Phase II part, it was redefined which patients treated in the Phase II 
arms 2 and 3, will be selected to provide PK samples. 
• To redefine the time of end of study (LPLV), the period of survival follow-up was 
amended to follow all patients enrolled in the Phase II part of the study for survival until 
death, or until all patients have completed SEC and have been followed for at least 18 
months after their first dose of study treatment, or have been lost to follow-up or withdrew 
consent, whichever occurs first. Previously patients were followed for survival until death 
or up to 18 months after LPLT, whichever occurs first. 
• Clarifications throughout the protocol. 
The current study began recruitment on 28May2012. As of 12July2012, six patients with 
advanced solid tumors with BRAF mutations have been enrolled and have completed the first 
dose cohort. This amendment occurs while the study drug combination is being evaluated in the 
second dose cohort. 


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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 1.2.1.1.1 and 1.2.2.1.2 has been updated to include more recent data on non-clinical 
pharmacokinetics of LGX818 and MEK162. 
• Section 1.2.1.2 has been updated to include more recent clinical experience with LGX818. 
• Sections 2.1, 3, 4.1 (including Figure 4-1), 5.1 and 5.2 Inclusion Criterion 2 have been 
amended to include the additional arm 3 in the Phase II part of the study and the objectives 
and endpoints associated with this population. Sections 10.4, 10.4.1, 10.4.2.2 and 10.8 have 
been updated accordingly. 
• Sections 4.1, 6.1.5 and 7.1.3 were amended to include the possibility to continue treatment 
with LGX818 and MEK162 beyond progression of disease under certain circumstances. 
• Section 5.2 Inclusion Criterion 8 was added to only allow patients to enroll in the Phase II 
part of the study that can provide a fresh tumor biopsy at Screening/Baseline. As 
consequence a secondary objective has been added in Table 3-1 to include the data analysis 
on these tumor samples. Sections 7.2.4 and 10.5.4.3.2, and Table 7-1 have been updated 
accordingly. 
• Section 6.3.2 Table 6-3: recommended dose modifications for ‘creatine phosphokinase’ and 
‘eye disorders’ have been amended. Table 6-2 Criteria for defining DLTs and Section 
6.2.6.2 have been updated accordingly. 
• Section 6.4.2 and Appendix 4 Tables 14-9 and 14-12, were updated with newest data on 
permitted drugs to be used with caution. 
• Section 7.1.5.3 was revised to introduce survival follow-up phone calls every 3 instead of 
every 4 months. Table 7-1 was updated accordingly. 
• Section 7.1.5.3 was revised to redefine the period of survival follow-up. Sections 7.1.5.2 
and 4.3 were updated accordingly. 
• Section 7.2.2.5.2 was updated to clarify that if total CPK is elevated ≥ CTCAE Grade 2, 
then isoenzymes in blood and myoglobin in blood and urine, should be weekly measured 
until resolved to ≤ CTCAE Grade 1. 
• Section 7.2.3.1.1 was updated to add PK sample collection in Phase II arm 3 and was revised 
to collect PK samples in Phase II arms 2 and 3 from the first 10 patients treated in each arm, 
instead of from those patients who can provide fresh tumor biopsies. 
• Sections 7.2.4.1.1, 7.2.4.1.2, 7.2.4.1.3 and 7.2.4.3, and Table 7-5 have been updated to 
clarify the tumor tissue analysis, the collection time point for the fresh tumor biopsy at 
C1D16 and relapse, and the collection time point for the whole blood sample. 
• Section 13 was updated with new references added. 
• Other minor changes/corrections in the protocol text were made for consistency and/or 
clarifications. 
• The protocol summary has been updated according to the changes in the amended protocol. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 


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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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Amendment 1 
Amendment rationale 
This amendment addresses the enhanced safety measures to be implemented in order to 
minimize risks to patients to be treated in this study, as result of two Investigator Notification 
letters (Case PHHO2012DE003954 - acute liver failure with a fatal outcome, Case 
PHHO2012CH005184 - decreased ejection fraction, heart failure, myocarditis, and tachycardia) 
issued by the Sponsor for patients treated with MEK162 at a 60mg BID dosing schedule in the 
CMEK162X2201 study. 
PHHO2012DE003954 is describing a case of liver failure with fatal outcome. The investigator 
considered that the liver failure was related to the study drug. However other differential 
diagnoses such as muscular toxicity and /or thrombotic/vascular/ hepatic events may be 
considered in this case. This is the only fatal liver failure case reported in a total of more than 
450 subjects/patients that have received at least 1 dose of MEK162 up to date. 
PHHO2012CH005184 is describing a case of reduced ejection fraction, symptoms of 
congestive heart failure, myocarditis and tachycardia. The events were considered suspected to 
the study drug by the investigator. However also other differential diagnoses may be considered 
in this case. The toxicities stabilized after study treatment discontinuation. This is the only case 
of cardiac failure/myocarditis reported so far suspected to be related to MEK162. 
The following will be implemented: 
• Increase of the frequency of liver transaminase and function test monitoring. 
• Revision of dose modification guidelines for patients with elevated transaminase levels, 
bilirubin levels and/or other liver function tests. 
• Increase of the frequency of cardiac monitoring. 
In addition, this amendment was used to correct a typo in Exclusion Criterion 7 and to make a 
few other minor corrections for consistency. This amendment occurs while several sites have 
received HA and IRB approval for the original protocol. 
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: in Exclusion Criterion 7 ‘directly measured CrCl ≥ 50% LLN’ was corrected 
to ‘directly measured CrCl < 50% LLN’. 
• Section 6.3.2 Table 6-3: recommended dose modifications for ‘Bilirubin’, ‘AST or ALT’ 
and ‘AST or ALT and Bilirubin’ have been amended. 
• Section 7.2.2.5.2: CPK was added to the clinical chemistry panel as a parameter to be 
measured. 
• Section 7.2.2.5.2: Additional liver function test (LFT = AST, ALT, alkaline phosphatase 
and bilirubin (total, indirect and direct)) measurements have been added at Days 8 and 22 
of Cycle 2 and Day 15 of Cycle 4. Table 7-1 has been amended accordingly. 


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• Section 7.2.2.8.2: Additional ECHO or MUGA evaluations have been added at Day 1 of 
Cycle 2, Day 1 of every third cycle until Cycle 11 and Day 1 of every fourth Cycle thereafter. 
Table 7-1 has been amended accordingly. 
The changes in this protocol amendment should be considered as substantial, in Member States 
of the European Union and European Economic Area (Directive 2010/C80/01/EC). 
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 
[Any language regarding the triple combination of LGX818/MEK162/LEE011 in this 
Section is not applicable to the USA and Singapore] 
Study title: A Phase Ib/II, multicenter, open-label, dose-escalation study of LGX818 in 
combination with MEK162 in adult patients with BRAF V600 - dependent advanced solid 
tumors 
Study phase: Ib/II 
Study objectives: 
Primary objectives: 
Phase Ib: 1) To estimate the MTD(s) and/or RP2D(s) of oral LGX818 in combination with oral 
MEK162 in patients with BRAF V600-dependent advanced solid tumors. 2) To estimate the 
MTD(s) and/or RP2D(s) of oral LGX818 and MEK162 in combination with oral LEE011 in 
patients with BRAF V600-dependent advanced solid tumors. 
Phase II: 1) To assess clinical efficacy of the LGX818 and MEK162 dual combination in the 
Phase II populations: BRAF V600 mutant metastatic colorectal cancer (mCRC) patients (arm 
1), BRAF V600 mutant metastatic melanoma patients who have progressed after prior selective 
BRAF inhibitor treatment (arm 2) and BRAF V600 mutant metastatic melanoma patients who 
are naïve to previous treatment with a selective BRAF inhibitor (arm 3). 2) To assess clinical 
efficacy of the LGX818 and MEK162 and LEE011 triple combination in the Phase II population: 
BRAF V600 mutant metastatic melanoma patients who are naïve to previous treatment with a 
selective BRAF inhibitor (arm A). 
Secondary objectives: 
Phase Ib + II: To characterize the safety and tolerability of LGX818 and MEK162 in 
combination and LGX818 and MEK162 and LEE011 in combination. 
Phase Ib: 
• To determine the single and multiple dose PK profile of the LGX818 and MEK162 
dual combination and LGX818 and MEK162 and LEE011 triple combination. 
• To assess preliminary clinical anti-tumor activity of the LGX818 and MEK162 dual 
combination and LGX818 and MEK162 and LEE011 triple combination. 
Phase II: 
• To further assess clinical efficacy of the LGX818 and MEK162 dual combination in 
the Phase II populations, and of the LGX818 and MEK162 and LEE011 triple 
combination in the Phase II population. 
• To characterize baseline molecular status of molecules relevant to RAF/MEK/ERK 
and EGFR/PI3K/AKT signaling in tumor tissue. 
Study population: The dose escalation for both the dual and triple combination, will be 
conducted in adult patients with locally advanced or metastatic melanoma, mCRC or any other 
solid tumor upon agreement with the Sponsor, harboring the BRAF V600E mutation, or any 
other BRAF V600 mutation, whose disease has progressed despite previous anti-neoplastic 


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therapy or for whom no further effective standard therapy is available. Once MTD/RP2D has 
been determined for the dual combination, patients with BRAF V600 mutant mCRC for whom 
no further effective standard therapy is available will be enrolled in arm 1 of the Phase II part 
of the study. Patients with locally advanced or metastatic BRAF V600 mutant melanoma who 
have progressed after previous treatment with a selective BRAF inhibitor will be enrolled in the 
Phase II arm 2. Patients with locally advanced or metastatic BRAF V600 mutant melanoma 
who are naïve to previous treatment with a selective BRAF inhibitor will be enrolled in the 
Phase II arm 3. Once MTD/RP2D has been determined for the triple combination, patients with 
locally advanced or metastatic BRAF V600 mutant melanoma who are naïve to previous 
treatment with a selective BRAF inhibitor will be enrolled in the Phase II arm A. 
Patients must be at least 18 year with a performance status ≤ 2 and have adequate hematologic, 
renal, and hepatic function. 
Number of patients: Dual combination: approx. 127 (at least 18 in the dose escalation and 
28+41+40 respectively in arms 1, 2 and 3 of the Phase II). Triple combination: approx. 52 (at 
least 12 in the dose escalation and 40 in arm A of the Phase II part). 
Overview of study design: This is a multi-center, open-label, dose finding, Phase Ib dose- 
escalation study to estimate the MTD(s) and/or RP2D(s) for the combinations of LGX818/ 
MEK162 and LGX818/ MEK162/ LEE011, followed by a Phase II part to assess the clinical 
efficacy and to further assess the safety of the combination in selected patient populations. Oral 
LGX818 and MEK162 will be administered on a continuous schedule, oral LEE011 will be 
administered continuously on a 3 weeks on, 1 week off schedule. Patients will be treated until 
progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, 
whichever occurs first. Continued treatment beyond progression of disease will be allowed 
under certain circumstances. A cycle is defined as 28 days. 
The dose-escalation part of the trial will be conducted in adult patients with BRAF V600- 
dependent advanced solid tumors and is expected to enroll at least 18 patients for the dual 
combination and at least 12 patients for the triple combination. The dose escalation will be 
guided by a Bayesian logistic regression model (BLRM). At each decision time point, the 
adaptive BLRM provides the upper boundary for the combinations that meet the escalation with 
overdose control (EWOC) criteria. Safety and tolerability data, PK, PD, and efficacy, as well 
as the recommendations from the Bayesian model are used to determine the dose combination 
for the next cohort(s) at a dose escalation teleconference. Provisional dose levels are given in 
Table 6-1 and Table 6-2. Various dose pairs will be explored until the MTD is determined 
and/or until a consensus between the Sponsor and Investigators is reached and it is considered 
that there is no benefit of further increasing the dose. At least 6 patients eligible for the dose 
determining set (DDS) must be treated at the dose(s) declared to be the MTD/RP2D. 
Following MTD/RP2D declaration of the dual combination, patients will be enrolled in three 
Phase II arms. Phase II arm 1 will consist of 28 patients with non-resectable advanced BRAF 
V600 mutant mCRC for whom no further effective standard therapy is available. The Phase II 
arm 2 will consist of 41 patients with locally advanced or metastatic BRAF V600 mutant 
melanoma who have progressed after previous treatment with a selective BRAF inhibitor. 
The Phase II arm 3 will consist of 40 patients with locally advanced or metastatic BRAF V600 
mutant melanoma who are naïve to previous treatment with a selective BRAF inhibitor. 


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Following MTD/RP2D declaration of the triple combination, patients will be enrolled in one 
Phase II arm (arm A) which will consist of 40 patients with locally advanced or metastatic 
BRAF V600 mutant melanoma who are naïve to previous treatment with a selective BRAF 
inhibitor. 
All patients will be followed for 30 days for safety assessments after study drugs discontinuation. 
Patients enrolled in the Phase II parts of the study who discontinue study treatment for any 
reason other than disease progression will be followed up for progression of disease. All patients 
enrolled in the Phase II parts of the study will be followed for survival. 
Note: As of protocol amendment 10, patients who remain on study treatment will have 
assessments performed as per local standard-of-care practice. In addition, post- 
treatment disease progression follow-up (if applicable) and/or survival follow-up 
(including documentation of subsequent antineoplastic therapies) will no longer be 
performed for any patient in the Phase II part of the study. 
Statistical considerations: A BLRM employing the EWOC principle will be used during the 
escalation phase for selection of doses to investigate and for estimation of the MTD. Each cohort 
will consist of newly enrolled patients. Estimation of the MTD during the escalation phase 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 MTD is defined as the highest drug dosage not causing in 
the first cycle of treatment medically unacceptable, dose-limiting toxicity (DLT) in more than 
35% of the treated patients. The corresponding statistical methodology is described in Section 
10.4.2. 
The Sponsor and investigators will decide on next dose levels and dosing schedule(s) to be 
explored at the dose escalation teleconference. Dose escalation decisions will be based on a 
clinical synthesis of all relevant available data and not solely on DLT information. The Sponsor 
will prepare minutes from these meetings. 
During the Phase II part of the dual combination, depending on the observed DLT rate, the 
BLRM will be re-run to confirm that the current dose combination still satisfies the overdose 
criteria. In the Phase II parts of the study, a Bayesian design will be used in order to estimate 
the true DCR for the dual-combination arm 1 and the true ORR for the dual-combination arms 
2 and 3 populations and for the triple-combination arm A, respectively. 


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♦ 
1 
Background 
[Any language regarding LEE011 or CDK4/6 signaling in this Section is not applicable to 
the USA and Singapore] 
1.1 
 Overview of disease pathogenesis, epidemiology and current 
treatments 
1.1.1 
The RAF/MEK/ERK pathway, BRAF-mutations and cyclin-dependent 
kinases 4 and 6 in solid tumors 
Growth factor-mediated proliferative signals are transmitted from the extracellular environment 
to the nucleus through several pathways, including the RASIRAF/MEK/ERK pathway (Roberts 
2007). This pathway comprises an evolutionarily conserved signaling cascade activated by the 
RAS small guanidine ti·iphosphatase (GTPase), which in tum activates RAF, which in tum 
phospho1ylates and activates MEK, which in tum activates exti·acellular signal-regulated kinase 
(ERK). ERK phospho1ylation of a variety of ti·anscriptional factors regulates several key 
cellular activities including proliferation, differentiation, Inigration, survival and angiogenesis. 
Abeffant signaling through this pathway has been shown to lead to unconsti·ained cell growth 
and cell transfo1mation (Yoon 2006; Scholl 2005) and is a characteristic feature of many cancers. 
fuappropriate activation of the RAS pathway can occur through several distinct mechanisms, 
including activating mutations in RAS and BRAF (Lea 2007), activated growth factor signaling 
(Nakazawa 2005), and cytokines and stress response signals (Mccubrey 2000; Chang 2003) 
(Figure 1-1). 
Figure 1-1 
Overview of Ras-Raf-ERK-MEK pathway (adopted from Cho 2009) 
Growtch factors and 
.... differentiation factors 
 -,R-ec-eptor 
I 
 
 
- 
. 
_J 
Raf 
ActiYating 
, 
I 
1\1 utatious 
 
 
(MAPKK) 
l 
(MAPK) 
ERK 
• 
 
L ----------------------------------- Other substrat"es 
 
 
 


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Recently activating mutations in the gene encoding the serine–threonine protein kinase B-RAF 
(BRAF) were identified in large-scale screens in human cancers (Davies 2002). Ninety percent 
of reported BRAF mutations result in a substitution of glutamic acid for valine at amino acid 
600 (V600E mutation) which leads to a 500-fold increase in its activity compared to the wild 
type protein kinase (Wan 2004). Somatic mutations of BRAF occur in 60% of malignant 
melanomas and in 8-15% in colorectal, (Rajagopalan 2002), in 30% of serous borderline 
ovarian cancer (Singer 2003), in 40-70% of papillary thyroid carcinomas (Brose 2002; Cohen 
2003; Nikiforova 2003; Fukushima 2003) and in 7-8% of all solid tumors (Brower 2010), 
implicating activating oncogenic mutations of BRAF as critical promoters of malignancy. 
Interestingly, BRAF and RAS mutations are restricted to the same tumor types usually in a 
mutually exclusive fashion, suggesting that these genes are on the same oncogenic signaling 
pathway and that RAS acts to activate BRAF in these mutations to these tumors (Davies 2002) 
(Table 1-1). 
Table 1-1 
Incidence of BRAF- mutations in human cancers 
Cancer 
Mutation incidence % BRAF 
Melanoma 
40-60 
CRC 
8-15 
Pancreatic 
5 
NSCLC 
2-5 
BTC 
25 
Ovarian (serous) 
30 
PTC 
40-70 
In the mammalian cell cycle, entry into S phase is achieved by cyclin-dependent kinases 4 and 
6 (CDK4/6). D-cyclins are the positive regulators of these kinases, while the p16 protein 
encoded by the INK4a gene functions as their major inhibitor. Signal transduction pathways 
including MAPK and PI3K increase cell proliferation upon mitogen stimulation by upregulating 
the expression of D-cyclins, which in turn activate the kinases. A wide range of human tumors 
harbor genetic aberrations that increase the activity of CDK4/6. These genetic aberrations 
include translocation, amplification and overexpression of D-cyclins, amplification of CDK4/6 
kinases, a mutation of CDK4 resistant to p16 binding and inactivation of p16 (Lundberg 1998). 
Agents that inhibit the activity of CDK4/6 kinases may be able to stop the proliferation of these 
cancers and thereby function as effective anti-cancer drugs. 
1.1.2 
Malignant Melanoma 
Malignant melanoma is one of the most aggressive human malignancies. Its incidence has 
rapidly increased throughout the world in the last few decades (in the order of 3-7% per year 
for fair skin Caucasian population) (Diepgen 2002), faster than that of all solid tumors, 
constituting a significant and growing health burden. It is estimated that 68,130 men and women 
will be diagnosed with, and 8,700 men and women will die of, melanoma of the skin in 2010 in 
the United States (Altekruse 2010). Although the majority of early stage patients can be treated 
with surgical resection, and have excellent survival rates (approximately 90% at 5 years), many 
will develop disseminated disease. The prognosis for patients with distant metastasis is, by 
contrast, very poor with survival rates ranging from 6.7% to 8% at 5 years, and a median 
survival of 6 to 9 months (Jemal 2009). 


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Currently, the existing therapeutic options for patients with melanoma comprise 4 therapies 
approved by the Food and Drug Administration (FDA): dacarbazine (DTIC), interleukin-2 (IL- 
2) ipilimumab (anti-CTLA-4) and vemurafenib (BRAF inhibitor). Single agent therapy with 
dacarbazine (DTIC), a cytotoxic chemotherapy, is generally well tolerated, but results in overall 
response rate of 10% and no survival benefit for patients with metastatic disease (median PFS 
of 2-3 months and OS of 6-10 months) (Anderson 1995; Chapman 1999; Serrone 2000). 
Immunotherapy with high-dose IL-2 was approved based on its ability to produce durable 
response in a small subset of patients (5 to 10%) with metastatic melanoma (Atkins 1999). 
Ipilumumab (Yervoy® Bristol-Myers Squibb) was approved by the FDA (25 March 2011) for 
the treatment of unresectable or metastatic melanoma based on a phase 3 randomized, double- 
blind study (MDX010-20) of 676 patients that demonstrated longer OS for patient treated with 
ipilimumab compared to tumor vaccine (median OS of 10 months vs 6 months, respectively). 
The best ORR was 10.9% in the ipilumumab arm compared to 1.5% in the tumor vaccine arm 
(Hodi 2010). The selective BRAF inhibitor PLX4032 (vemurafenib/Zelboraf® (Roche)), was 
approved by the FDA (17 August 2011) for the treatment of patients with unresectable or 
metastatic melanoma with the BRAF V600E mutation. In a phase 3, open-label, randomized 
study (BRIM3 trial) of 675 patients, the patients receiving PLX4032 experienced longer mPFS 
and OS compared to those randomized to DTIC (Chapman 2011). ORR was 48.4% vs 5.5% 
with a median PFS of 5.3 months vs 1.6 months, and an OS at 6 months of 84% vs 64% for 
PLX4032 and DTIC respectively. 
Preliminary results from a phase 1/2 study with the selective BRAF inhibitor GSK2118436 
(GlaxoSmithKline) were presented at ASCO 2010 (Kefford 2010). The drug was well tolerated 
with main toxicities as follows: cutaneous events (including 15% of SCC), headache, 
nausea/vomiting, and fatigue. Responses (PR) were observed in 63% of the patients with V600 
BRAF mutant melanoma receiving ≥ 150 mg bid. Clinical trials with the selective allosteric 
MEK1/2 inhibitor, GSK1120212 have also shown promising activity in patients with BRAF 
mutant melanoma (Infante 2010; Kim 2011). In the phase 2 study, patients receiving 
GSK1120212 and previously treated with chemotherapy and/or immunotherapy had an ORR 
of 25% and a mPFS of 4 months. However, only minimal activity was observed in patients 
previously treated with a selective BRAF inhibitor (ORR 5%) (Kim 2011). Main toxicities 
included rash, diarrhea and central serous retinopathy. Two phase 3 randomized studies are 
currently ongoing in patients with BRAF mutant melanoma: NCT01227889 comparing 
selective BRAF inhibitor GSK2118436 to DTIC, and NCT01245062 comparing MEK inhibitor 
GSK1120212 to chemotherapy. 
Although clinical trials with selective BRAF inhibitors PLX4032 and GSK2118426, have 
shown significant activity in patients with BRAF mutant melanoma, these patients ultimately 
relapse with a median PFS of 6 to 7 months, and up to 50 % fail to respond to these therapies 
(Flaherty 2010; Kefford 2010; Chapman 2011; Ribas 2011). These results strengthen the 
importance of exploring new selective BRAF inhibitors, as single agent or in combination, to 
expand therapeutic options for patients with advanced melanoma that have very poor prognosis 
and constitute a high unmet medical need. 


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1.1.3 
Metastatic Colorectal Cancer (mCRC) 
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and second leading 
cause of cancer death in the United States and in the European Union. In 2009, an estimated 
150,000 new cases and 50,000 deaths from CRC in the US have occurred (Engstrom 2009). In 
the last decade, substantial advances in the treatment of metastatic CRC have resulted in an 
improvement in overall survival from 10-12 months to more than 20 months (Grothey 2004). 
This improvement has occurred with the addition of irinotecan, oxaliplatin, bevacizumab, 
cetuximab and panitumumab to the standard treatment with 5-fluorouracil (5 FU)/ leucovorin. 
However, because many patients eventually develop resistance to these agents, new agents to 
treat resistant tumors are an important area of investigation. The anti-EGFR monoclonal 
antibodies panitumumab and cetuximab were initially evaluated as monotherapy in patients 
with EGFR-expressing tumors after they became resistant to standard chemotherapy. 
Subsequent investigations discovered that oncogenic activation of signaling pathways 
downstream of the EGFR, such as mutations of KRAS and BRAF, play an important role in the 
progression of colorectal cancer. There is accumulating evidence that BRAF mutations, which 
may be present in up to 15% of patients with CRC have emerged as important predictive 
markers of resistance to the anti-EGFR monoclonal antibodies (Karapetis 2008; Amado 2008). 
BRAF mutation is also a negative prognostic marker in patients with metastatic CRC and this 
effect, in contrast to KRAS mutations, seems not to be restricted to the outcome of cetuximab 
treatment (Tol 2010). Therefore, patients with BRAF-mutation-related CRC have fewer 
treatment options. The highly selective BRAF inhibitor PLX4032 has shown some clinical 
activity in BRAF-mutant mCRC, albeit more modest than that observed in BRAF mutation- 
related melanoma (1/19 PR and 4 minor responses, mPFS 3.7 months); however, these findings 
confirm that BRAF mutation is a therapeutic target in mCRC strengthening the importance of 
evaluating the clinical activity of new selective and potent BRAF inhibitors in this indication 
(Kopetz 2010). 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of LGX818 
NVP-LGX818 is a ((S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido) phenyl)-1- 
isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate. 
LGX818 
(also 
known as encorafenib, PF-07263896, ONO-7702, and W0090) is a highly selective ATP- 
competitive small molecule RAF kinase inhibitor, which suppresses the RAF/MEK/ERK 
pathway in tumor cells expressing BRAFV600E. Similar to other selective small molecule RAF 
kinase inhibitors, LGX818 inhibits CRAF (IC50 = 0.30 nM), BRAF (IC50 = 0.47 nM) as well as 
BRAFV600E (IC50 = 0.35 nM) in cell-free assays, however, this class of inhibitor does not 
inhibit RAF/MEK/ERK signaling in cells expressing wild-type BRAF. In the human melanoma 
cell line A375 (BRAFV600E), LGX818 potently inhibits phospho-MEK (EC50 = 2 nM) and 
phospho-ERK (EC50 = 3 nM) and proliferation (EC50 = 4 nM), resulting in cell cycle arrest and 
apoptosis. Given the high-degree of selectivity against other kinases, LGX818 has no 
antiproliferative activity in tumor cell lines that express wild-type BRAF and is highly selective 
for BRAF V600E/D/K containing cell lines, with the greatest sensitivity observed in BRAF 
mutant melanoma and CRC lineages. 


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The narrow kinase profile and potent anti-proliferative activity of LGX818 translates into a very 
wide therapeutic index in vivo. LGX818 has been evaluated in multiple human tumor xenograft 
models grown in nude mice. Similar to the in vitro profile, the antitumor activity was restricted 
to tumors expressing BRAFV600E, while there was no anti-tumor effect in xenograft models 
expressing wild-type BRAF. Preclinical in vivo data suggest that LGX818 has a wide 
therapeutic index and that regression of BRAFV600E human melanoma tumor xenografts is 
associated with a strong and sustained inhibition of the RAF/MEK/ERK pathway. 
For further details on clinical and non-clinical experience, please refer to the current LGX818 
Investigator’s Brochure. 
1.2.1.1 
Non-clinical experience 
1.2.1.1.1 Non-clinical pharmacokinetics and metabolism 
Plasma pharmacokinetics of LGX818 has been investigated following single oral and IV dose 
in mouse, rat, dog and monkeys. LGX818 exhibited a low plasma clearance (CL) in the rat and 
mouse and a moderate to high plasma clearance in the monkey and dog. Volume of distribution 
at steady state (Vss) was low in the rodents and moderate in the non-rodent species examined 
(0.1 - 2.6 L/kg). This was in agreement with the observed in vitro plasma protein binding where 
LGX818 showed high binding to plasma proteins in the mouse and rat and low to moderate 
binding to dog, monkey and human plasma proteins. Good bioavailability (F) was observed in 
the mouse, rat, and dog (~50%) and was low in the monkey at low doses (~5%). Moderate 
absorption and bioavailability (~ 40%) was also observed in the rat ADME study following oral 
administration of a suspension of [14C] LGX818. 
The predominant route of excretion of [14C] LGX818 in rats was via fecal excretion while the 
urinary excretion was a minor route of elimination. LGX818 was eliminated in the rat mainly 
through oxidative metabolism and to a much smaller extent, through parent drug excretion. The 
major circulating component in rat plasma was LGX818 with only a minor fraction of 
metabolites. 
LGX818 is a relatively potent reversible inhibitor of CYP2B6 (IC50 ~ 1 µM), CYP2C9 (IC50 ~ 
5 µM), and CYP3A4/5 (IC50 = 8 µM) and a weak (IC50 ≥ 20 µM) reversible inhibitor of 
CYP1A2, CYP2C8, CYP2C19 and CYP2D6. LGX818 is also a time-dependent inhibitor of 
CYP3A4 (KI = 20.5 µM and Kinact = 0.0527 min -1). Furthermore, LGX818 was identified to 
potentially induce CYP3A4 based on an in vitro PXR reporter gene assay at high concentrations 
(≥ 10 -50 µM), likely achievable at doses greater than 800 mg in humans based on predicted 
human PK data. LGX818 is also a UGT1A1 inhibitor with in vitro IC50 ranging from 4 to 7 
uM. LGX818 is a substrate of P-glycoprotein with a high apparent passive permeability. It is a 
weak inhibitor of BCRP (IC50 = 10-25 µM). LGX818 is a potent inhibitor of the renal 
transporters, OCT1, OAT1, OAT3 and OCT2 (with IC50s at 4.2, 0.93 and 2.05 µM, respective) 
and hepatic transporters OATP1B1 and OATP1B3 (IC50 values of 5.35 µM and 6.16 µM, 
respectively). It is therefore advised that substrates for CYP2B6, CYP2C9, CYP3A4/5, OAT1, 
OAT3, and OCT2, OCT1, OATP1B1 and OATP1B3 with a narrow therapeutic index be taken 
with caution with LGX818 (see Appendix 4). 


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LGX818 is metabolized by CYP3A4, CYP2D6 and CYP2C19. The primary CYP responsible 
for this metabolism is CYP3A4 (>50%); it is therefore advised that strong inhibitors of CYP3A4 
(see Appendix 4), be taken with caution. 
1.2.1.1.2 Safety pharmacology and toxicology 
LGX818 was evaluated in rats and Cynomolgus monkeys in toxicology studies ranging from 1 
to 4 weeks in duration. Overall LGX818 was well tolerated at doses at which tumor regression 
was observed. Significant toxicities were mainly observed in the female rat at the highest dosage 
of 400 mg/kg/day, a dose well above the maximum dose level to be evaluated in this phase Ib/II 
study. 
Preclinical cardiovascular safety pharmacology data did not indicate a clinical risk for QTc 
prolongation based on the findings of the hERG assay and ECG evaluation in the GLP 4-week 
monkey study. Also, there were no clinical signs in the 4-wk GLP rat and monkey studies that 
would indicate an effect on the CNS or respiratory system. 
In a 13-week monkey toxicology study with LGX818, two monkeys treated at a dose of 
60mg/kg/day presented retinal changes at the assessment on week 12. These non-clinical 
findings suggest a potential risk of retinal changes with LGX818. 
Rat studies 
The 4-week GLP toxicology study in rats was performed at daily doses of 20 mg/kg, 100mg/kg, 
and 400mg/kg. There were findings associated with the pharmacologic activity of a BRAF 
kinase inhibitor activation of the RAF/MEK/ERK pathway. These included hyperplasia and 
hyperkeratosis in the skin (plantar surface of feet) and non-glandular stomach in rats which was 
apparent at all dose levels in rats and presented with recovery 4 weeks after stopping treatment. 
Additional toxicity was observed in the 4-week GLP rat study in the testes/seminiferous tubules 
and epididymides that included an absence of the later stages of spermatid maturation. This 
finding did not appear to be reversible in affected tubules, but there were normal tubules present 
in recovery rats. There was significant mortality/morbidity in the female rats at the highest dose 
(400 mg/kg/day). In these early death rats (around Day 10), significant lesions were seen in the 
kidneys, liver, stomach, esophagus, bone marrow, spleen, thymus, lymph nodes, pancreas, 
adrenal glands, and parathyroid glands. However, in the 4 female rats that survived the recovery 
there were no histopathologic findings. Toxicity was more pronounced in females, where 
plasma exposure was noted to be approximately double that of males. One male rat at the 
highest dose of 400 mg/kg/day was also euthanized on Day 10, but the remaining male rats 
survived to their scheduled necropsy. 
The dose of 100 mg/kg/day was tolerated in the rat and considered the appropriate dose for 
calculation of the initial starting dose in the first-in-man clinical trial. 
Monkey studies 
The studies in monkeys were performed at daily doses of 5, 20 and 100 mg/kg. All doses were 
well tolerated. At the highest dose of 100 mg/kg/day, the only toxicity observed was an increase 
in diarrhea and body weight loss, which was believed to be related partially to the vehicle. There 
were no histopathologic findings in the monkeys at this highest dose. 


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1.2.1.1.3 Genotoxicity study 
The GLP AMES and Chromosomal Aberration assays indicate that LGX818 is not genotoxic. 
No in vivo genotoxicity studies have been conducted at this stage of development. 
1.2.1.2 
Clinical experience 
Clinical safety 
LGX818 is being tested in a first in human Phase I dose escalation ([CLGX818X2101]) study 
in patients with locally advanced or metastatic BRAF mutant melanoma as micro-emulsion 
(ME) and capsule formulation (CPS). As of 7 January 2013, 68 patients have been enrolled in 
the study. 54 Patients were treated in the dose escalation and 14 patients in the dose expansion. 
Patients were treated with LGX818 capsules (CPS) or micro-emulsion (ME) at 50 mg/day and 
100 mg/day, and with LGX818 (CPS) at 150 mg/day, 200 mg/day, 300 mg/day, 450 mg/day, 
550 mg/day, 700 mg/day, 75 mg BID, 100 mg BID and 150 mg BID. 
In general LGX818 was well tolerated with mainly cutaneous adverse events reported. As per 
the cut-off date of 7 January 2013 seven dose limiting toxicities (DLTs) have been observed, 
all were grade 3 events and reversible: 5 DLTs occurred in the once daily dosing regimen 
(Palmar-plantar erythrodysaesthesia syndrome at 100 mg (with microemulsion)), pain in 
extremity at 300 mg, fatigue at 550 mg, diarrhea, headache and rash at 700 mg, and insomnia 
and asthenia at 700 mg) and 2 DLTs occurred in the twice daily regimen (facial paresis and 
confusional state at 100 mg BID, and neuralgia and musculoskeletal pain in shoulder at 150 mg 
BID). 
The most frequently reported LGX818-related AEs regardless of CTCAE Grade occurring in ≥ 
10% of patients overall (as per 7 January 2013) were: hyperkeratosis 25/54 (46%), 
Palmarplantar erythrodysaesthesia syndrome 25/54 (46%), keratosis pilaris 20/54 (37%), 
pruritus 20/54 (37%), alopecia 17/54 ( 32%), dry skin 17/54 ( 32%), arthralgia 16/54 (30%), 
fatigue 16/54 (30%), pain in extremity 15/54 (28%), nausea 13/54 (24%), asthenia 12/54 (22%), 
decreased appetite 12/54 (22%), melanocytic naevus 12/54 (22%), myalgia 12/54 (22%), 
xerosis 12/54 (22%), erythema 11/54 (20%), hair texture abnormal 10/54 (19%), headache 9/54 
(17%), skin papilloma 9/54 (17%), dermal cyst 8/54 (15%), rash erythematous 8/54 (15%), 
insomnia 7/54 (13%), musculoskeletal pain 7/54 (13%), alanine aminotransferase increased 
6/54 (11%), and hypotrichosis 6/54 (11%). 
Different types of rash included erythema (20%), rash erythematous (15%), rash (9%), 
dermatitis acneiform (9%), eczema (9%) rash maculopapular (9%), rash follicular (6%), rash 
macular (6%), rash papular (4%), dermatitis exfoliative (2%), exfoliative rash (2%), livedo 
reticularis (2%), rash pruritic (2%), and rosacea (2%). At the cut-off date, 2 patients had a 
keratoacanthoma and 2 patients had a squamous cell carcinoma (SCC), related to the study drug. 
The MTD for LGX818 has been declared at 450 mg QD. This dose is well tolerated and is the 
recommended phase II dose (RP2D). 
As of 7 January 2013, preliminary efficacy results are available for the 54 patients (26 BRAF 
inhibitor-naïve and 28 BRAF inhibitor-pretreated) enrolled in the dose escalation phase (all 
dose levels pooled). Among the 26 BRAF inhibitor-naïve patients, 16 (62%) had a partial 
response (PR) [14 confirmed PR (54%)], and 7 (27%) had stable disease; in the 24 naïve patients 


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with at least 1 post-baseline tumor assessment all had a tumor reduction (decrease of 6% to 
100%). Out of the 28 BRAF inhibitor-pretreated patients, 3 (11%) had a PR [2 confirmed PRs 
(7%)], and 10 (36%) had stable disease, which includes the unconfirmed PRs. 
While retinal changes were observed in two monkeys treated at a dose of 60mg/kg/day at the 
assessment on week 12, no cases of retinal toxicity were reported in patients who received 
LGX818 monotherapy or in combination with any other compounds except for MEK162, a 
drug known to be associated with a risk of retinal changes. In addition, as of November 2013 it 
is noteworthy that uveitis, a suspected class effect of BRAF inhibitors (according to the 
vemurafenib and dabrafenib prescribing information), has been reported in 2 patients treated 
with LGX818 monotherapy and in combination with MEK162, one each respectively. 
For further details, please refer to the current LGX818 Investigator’s Brochure. 
Clinical pharmacokinetics 
As of 7 January 2013, patients with locally advanced or metastatic BRAF mutant melanoma 
received escalating doses of LGX818. Oral doses of 50 mg, 100 mg (both capsule and 
microemulsion), 150 mg, 200 mg, 300 mg, 450 mg, 550 mg or 700 mg were administered once 
daily and oral doses of 75 mg, 100 mg and 150 mg were administered twice daily. The 
pharmacokinetics was investigated after a single dose (Day 1) and multiple doses (Day 15) in 
Cycle 1. Trough samples were collected on Day 1 of Cycle 2 to 10. In the expansion phase, an 
additional C1D8 PK profile was collected from 0 to 8 hr. As this study is on-going, all data 
presented are considered preliminary. The capsule and microemulsion formulations of LGX818 
produced similar PK profiles. The median Tmax was around 2 hr for capsule formulation and 
0.5-2 hr for the microemulsion formulation. The half-life of LGX818 was approximately 3 
hours. From 50 mg to 700 mg QD Cmax and AUC increased in an approximately dose- 
proportional manner with increasing dose. The BID regimen resulted in a smaller 
Cmax/Ctrough ratio as expected compared to QD regimen. At the same total daily dose per day, 
the total AUC under BID regimen appears to be similar to the QD regimen. With QD or BID 
dosing, the Day 15 exposures were consistently lower (30-60%) than the Day 1 exposures 
within subjects, probably due to induction of CYP enzymes. AUC and Cmax ratios at steady 
state (Day 15) relative to Day 1 did not appear to change with dose. The trough concentration 
on and after Cycle 2 Day 1 did not show a trend of further decline, suggesting that C1D15 was 
close to or at steady state. So far limited data on C1D8 PK showed that Cmax and AUC were 
similar on C1D8 and C1D15 with a small decrease. At the above doses tested, the average 
concentrations of LGX818 reached or exceeded the predicted efficacious concentrations based 
on preclinical xenograft models (0.135 µg/mL). 
For further details, please refer to the current LGX818 Investigator’s Brochure. 
1.2.2 
Overview of MEK162 
MEK162 (also known as binimetinib, PF-06811462, ARRY-438162, ONO-7703, and W0074), 
is an oral, ATP non-competitive, highly selective inhibitor of MEK1/2 that has nanomolar 
activity against purified MEK enzyme (IC50 = 12 nM) and inhibits both basal and induced 
levels of ERK phosphorylation in numerous cancer cell lines with IC50s as low as 5 nM. 
MEK162 is especially potent at inhibiting the cell proliferation of mutant BRAF and RAS 


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human cancer cell lines in vitro. In vivo, MEK162 has demonstrated dose-dependent tumor 
growth inhibition in various subcutaneous tumor transplants harboring BRAFV600E or RAS 
mutations, including HT29, MIA PaCa2, A549, LoVo, Calu6, DU145 and COLO 205. These 
data suggest that MEK162 may provide a potential therapeutic benefit in cancer indications, 
harboring these mutations. MEK162 is currently being investigated in Phase I clinical testing 
and has been well tolerated up to a maximum tolerated dose (MTD) of 60mg BID in cancer 
patients. 
For further details on clinical and non-clinical experience, refer to the current MEK162 
Investigator’s Brochure. 
1.2.2.1 
Non-clinical experience 
1.2.2.1.1 Pharmacology studies 
The biological activity of MEK162 has been evaluated in vitro (enzymatic and cell culture) and 
in vivo mouse xenograft studies. 
In vitro efficacy studies 
In biochemical studies, MEK162 has been shown to be a potent and highly selective inhibitor 
of MEK. In cellular assays, MEK162 has been shown to markedly inhibit the phosphorylation 
of ERK in human cell lines as well as human whole blood. In human MALME-3M melanoma 
cells and in HT29 colorectal cancer cells, MEK162 significantly inhibited proliferation and 
viability, respectively. The ability of MEK162 to inhibit cancer cell growth in culture was 
evaluated using a standard 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4- 
sulfophenyl)-2H-tetrazolium (MTS) assay. In the human HT-29 colorectal cell viability assay, 
the IC50 of cell growth was observed at a concentration of 163 nM MEK162. In the human 
melanoma Malme-3M cell proliferation assay, the IC50 of cell growth was observed at a 
concentration of 30 nM MEK162. 
In vivo efficacy studies 
In vivo studies were performed to evaluate the activity of MEK162 with respect to inhibiting 
tumor growth and tumor ERK phosphorylation. In the HT29 and in the COLO 205 colon 
carcinoma models, dose-dependent inhibition of tumor growth (up to 75% tumor growth 
inhibition TGI) was observed at doses ranging from 3 to 30 mg/kg, QD, by mouth (PO) for 21 
days. In the sensitive COLO 205 colon carcinoma model, MEK162 treatment resulted in 84% 
TGI with significant tumor regressions at a dose of 30 mg/kg. In the BxPC3 pancreatic 
carcinoma model (which does not harbor either RAS or RAF mutations, but harbors MAP2K4 
mutation), significant tumor regressions (59%) were seen at doses of 30 mg/kg. In the BxPC3 
pancreatic carcinoma model (which does not harbor either RAS or RAF mutations, but harbors 
MAP2K4mutation), ~70% TGI and 13% PRs were seen at doses of 30 mg/kg, QD, PO for 21 
days. Consistent with the mechanism of action for MEK162, TGI correlates with decreased 
phospho-ERK levels in tumor xenografts. 
Overall, MEK162 has demonstrated potent activity against MEK1/2 and broad anti- 
proliferative activity in vitro and in vivo. 


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1.2.2.1.2 Non-clinical pharmacokinetics and metabolism 
Pharmacokinetic (PK) studies were conducted with MEK162 in rats, dogs and monkeys. After 
oral administration, the AUC and Cmax values for MEK162 increased in a nearly dose- 
proportional manner in rats and monkeys. The mean bioavailability was lowest in monkeys, 
higher in dogs, and highest in rats at equivalent doses (range across species: 13% to 72%). 
Following intravenous (IV) administration, the plasma clearance (CL) values were low-to- 
moderate (range: ~2 to 8 mL/min/kg) and tended to increase across species such that monkey > 
dog > rat. Mean plasma t1/2 values showed a similar trend where monkey > dog > rat 
(range: ~2 to 9 hrs). The volume of distribution at steady state (Vss) values ranged from 0.189 
to 1.57 L/kg. 
In vitro experiments in Caco-2 and LLC-PK1 cells indicated that MEK162 had moderate 
membrane permeability and may be a substrate for active efflux. MEK162 was determined to 
be a substrate for both BCRP and P-gp transporters. MEK162 exhibited high plasma protein 
binding in vitro (> 95%) and is predicted to have good stability with respect to hepatic 
metabolism. Nonclinical in vitro and in vivo data indicate that main pathways of metabolism 
for MEK162 including oxidation by CYP2C19 and CYP1A2 and glucuronidation by UGT1A. 
In human plasma, major entities include glucuronides of MEK162, as well as the primary active 
metabolite, AR00426032, which is equipotent to MEK162. Formation of AR00426032 that has 
been monitored in clinical studies was found to be mediated primarily by CYP1A2 with minor 
contributions from other cytochrome P450 enzymes (CYPs). MEK162 did not significantly 
inhibit (IC50> 25µM) the major CYP isoforms. MEK162 was not a time-dependent inhibitor 
of CYP3A. 
Based on results from the rat ADME study, the absorption of MEK162 was approximately 50% 
of dose and bioavailability was 47%. Following oral dosing at 4 mg/kg to rats, fecal and urinary 
excretion accounted for 69.4% and 23.1% of total radioactivity, respectively. Unchanged 
MEK162 accounted for approximately 5% of dose in urine and 22% of dose in feces. In addition, 
the glucoronide conjugate M10.9 accounted for 13% of dose in urine and metabolite M4 (loss 
of ethane diol) accounted for 34% of dose in feces. Overall, MEK162 is mainly excreted 
through urine and feces as unchanged parent drug, glucoronide conjugates and M4. 
Following single- and repeat-dose administration of MEK162 to Sprague-Dawley rats for up to 
6 months, females were found to have approximately 2-fold higher exposure than males at 
equivalent doses. The values for Cmax and area under the plasma concentration-time curve for a 
dosing interval from time 0 extrapolated to infinity (AUCinf) increased with dose, although the 
increase in exposure was less than dose proportional. Cynomolgus monkeys receiving MEK162 
for 28 days or 9 months showed no consistent differences in exposure between females and 
males. There were no significant changes in exposure versus day. 
1.2.2.1.3 Safety pharmacology and toxicology 
The toxicological evaluations of MEK162 include single-dose, and 28-day and 6-month 
repeat-dose studies in Sprague Dawley rats and 28-day and 9-month repeat-dose studies in 
cynomolgus monkeys, all of which were conducted in accordance with international regulatory 
guidelines for nonclinical toxicity studies and in adherence to current GLP guidelines. These 
studies were supplemented with local tolerance, 9 safety pharmacology studies (hERG channel 


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assay 
and 
behavioral, 
cardiovascular, 
renal, 
pulmonary 
and 
2 
gastrointestinal 
function/tolerability studies as well as 2 non-GLP studies evaluating wound healing and 
immune function) and 3 developmental toxicity studies in the rat and the rabbit. 
In all of the GLP toxicology studies conducted, there was no significant effect of MEK162 on 
vital signs, coagulation parameters, complement, organ weights or urinalysis parameters in 
doses up to 100 mg/kg in rats and 10 mg/kg in monkeys. Administration of MEK162 to rats by 
oral gavage was associated with skin lesions (inflammation/scabbing), microscopic findings of 
soft tissue mineralization (which did not occur with the 26-week dosing regimen) and reversible 
minimal to mild clinical pathology changes. 
Safety pharmacology studies were conducted to assess the effects of MEK162 on key organ 
systems (cardiovascular, respiratory, neurobehavioral, renal and gastrointestinal function). Rats 
received single oral doses of 10, 30 or 100 mg/kg and monkeys were given single oral doses of 
1, 3 and 10 mg/kg. There were no significant in vivo safety findings at doses up to 100 mg/kg 
in rats and 10 mg/kg in monkeys in any of these studies. 
1.2.2.1.4 Genotoxicity study 
MEK162 is not genotoxic in vitro and in vivo, based on the results of 3 genotoxicity assays (in 
vitro bacterial mutagenicity, mouse lymphoma assay and in vivo mouse micronucleus assay). 
1.2.2.2 
Clinical experience 
As of the data-cut-off date of 07 Jan 2013, a total of 686 patients and healthy volunteers have 
received at least one dose of MEK162, either as a single agent or in combination with paclitaxel, 
PI3K, RAF l or IGF-1R inhibitors and have been evaluated for safety, including 90 healthy 
volunteers, 164 patients with rheumatoid arthritis and 432 patients with advanced cancer. 
MEK162 has been evaluated in 3 completed studies in healthy subjects (single ascending dose, 
multiple ascending dose, single-dose relative bioavailability and food effect) and 2 completed 
studies in patients with rheumatoid arthritis (a Phase I multiple ascending dose study and a 
Phase II study, both in combination with methotrexate). 
The experience with MEK162 as a single agent in oncology patients includes 3 ongoing studies 
with a total of 216 patients enrolled as of the cut-off date. These are 2 Phase I studies: [ARRAY- 
162-111] in patients with solid tumors with an expansion phase in biliary and colorectal cancer, 
(in this study a dose range from 30 to 80 mg BID has been explored), and [CMEK162X1101] 
in Japanese patients with solid tumors and an expansion in patients with RAS or BRAF 
mutations, and one Phase II study: [CMEK162X2201] in patients with advanced melanoma, 
(45 mg and 60 mg BID dose levels have been explored). 
The experience with MEK162 in cancer patients in combination studies comprises 7 ongoing 
Phase I studies as of the cut-off date. 
For detailed information regarding clinical studies with MEK162, refer to the MEK162 
Investigator’s Brochure. 


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1.2.2.2.1 Clinical safety and efficacy 
Frequently reported AEs suspected to be related to study drug in single agent studies for 
advanced cancer are dermatitis acneiform, diarrhea, peripheral edema, increased blood CK, 
nausea, fatigue, rash and vomiting. Most of these AEs were Grade 1 or 2 with less than 5% of 
cases Grade 3-4, with the exception of elevation of blood CK. 
Other less frequent but clinically relevant toxicities include left ventricular ejection fraction 
(LVEF) decrease and increase of liver enzymes. Four patients had Grade 2 LVEF decrease, and 
one patient had Grade 3 LVEF decrease. Most of the liver enzyme increases were Grade 1 or 2. 
Grade 3 or 4 liver enzyme elevations were reported in 2/106 (1.8%) patients with AST elevation 
and 1/106 (0.9%) patient with ALT elevation. No Grade 3-4 elevation of bilirubin was reported. 
In combination studies, the most frequently reported AEs suspected to be related to study drug 
were diarrhea, CK elevation, dermatitis acneiform/rash, nausea/vomiting and fatigue. 
CMEK162X2201 
[CMEK162X2201] is a phase II study assessing the safety and efficacy of MEK162 in patients 
with locally advanced and metastatic BRAF and NRAS mutated melanoma. As of the cut-off 
date, a total of 106 patients have received at least 1 dose of MEK162. Initially, the study 
explored the 60 mg BID dose, but due to the occurrence of 2 unexpected suspected severe 
adverse events (one case of fatal acute liver failure and another case of decreased ejection 
fraction), subsequent patients received 45 mg BID, which was the dose selected as the 
recommended Phase II dose. Thus, from the 106 patients who received at least 1 dose of 
MEK162, 25 patients were treated with 60 mg BID MEK162 and 81 patients were treated with 
45 mg BID MEK162. At the time of the cut-off, 93 (87.7%) patients have discontinued 
treatment with 22 (21%) having discontinued due to an AE; 13 (12.3%) patients are still ongoing. 
The most frequently treatment-related occurring events (≥ 20%) were dermatitis acneiform, 
diarrhea, peripheral edema, increase in CK levels, nausea, fatigue and rash. The most common 
treatment-related Grade 3-4 AEs were CK increased (20/106), dermatitis acneiform (4/106) and 
diarrhea (3/106). CSR-like events were reported by 40/106 (38%) patients regardless of 
relationship to MEK162 including Grade 3-4 events in 3/106 (3%) patients. These events 
included retinopathy, blurred vision, retinal edema, generalized eye disorder, vitreous floaters, 
retinal detachment, retinal pigment epitheliopathy, and visual impairment. Most CSR-like 
events were Grade 1, transient in nature and resolved without treatment modification, after dose 
reduction, or after interruption of treatment. Cardiac events regardless of relationship to 
MEK162 were reported by 4/106 (4%) patients. All were Grade 3-4. Three reports of syncope 
(1 related to MEK162) were recorded. A serious and possibly drug related adverse event of 
ventricular ejection fraction decreased, heart failure, myocarditis and tachycardia was reported 
at a starting dose of 60 mg BID. No other case of decreased LVEF was reported. 
As of 7-Jan-2013, in the [CMEK162X2201] study, among the 35 patients evaluable for efficacy 
with mutant BRAF melanoma treated with MEK162 at 45mg BID, 2 confirmed and 6 
unconfirmed partial responses (23%) and 14 patients with stable disease were recorded. In this 
group 63% of the patients achieved disease control. In the 35 patients evaluable for efficacy 
with NRAS mutant melanoma treated at 45 mg BID, 6 confirmed and 2 unconfirmed partial 


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responses (23%) and 15 patients with stable disease were recorded. Sixty six % of the patients 
achieved disease control. 
1.2.2.2.2 Clinical Pharmacokinetics 
In healthy subjects and patients with rheumatoid arthritis, the analysis of PK data was done 
using model independent (NCA) methods only. These analyses suggested that absorption was 
rapid, that there was extensive distribution and that the apparent terminal half-life was short. 
Contrary to expectation, given the short half-life, accumulation greater than that predicted by 
linear PK was observed. Overall when given BID, accumulation was around 1.5 to 1.7 fold. 
This apparent non-linearity in the PK of MEK162 may have been related to a combination of a 
relatively high LLOQ of the assay used (5 ng/mL) and the schedule of blood collection for PK 
used. In order to overcome these limitations and to fully characterize the PK of MEK162 in 
cancer patients a model based analysis was conducted using a population PK method. For this 
analysis, information from 130 subjects from two clinical studies, [CMEK162X2201] and 
[ARRAY-162-111], were used. Dose levels range from 30 mg BID to 80 mg BID. 
MEK162 PK was best described by a two compartment disposition model with first-order 
elimination and first-order absorption with a lag time. The estimated between subject variability 
on apparent clearance (CL/F) was moderate (44%) and very high (~150%) for the apparent 
central volume of distribution (Vc/F) and apparent peripheral volume of distribution (Vp/F). 
The covariate effect of dose on relative bioavailability was identified as significant (at an α = 
0.001 significance level). Relative to the 45 mg dose, the bioavailability of the 30 mg dose level 
was 120%; while the relative bioavailability of 60 mg and 80 mg doses were 88% and 77%. 
This dose dependence was not seen using model independent methods but most likely 
represents either solubility limited absorption of MEK162 or the impact of P-gp or a 
combination of the two. Based on the PK parameters estimated in this analysis when 
administered BID, MEK162 steady state is reached around Day 15 and the accumulation is 
around 1.7 fold, which is consistent with observation. 
For further information refer to the current MEK162 Investigator’s Brochure. 
1.2.3 
Overview of LEE011 
LEE011 (also known as ribociclib) is an orally bioavailable, small molecule inhibitor of 
CDK4/6. LEE011 exhibits highly specific inhibitory activity against CDK4/cyclinD1 and 
CDK6/cyclinD3 complexes, with concentration resulting in 50% inhibition (IC50) values of 10 
nM and 39 nM, respectively, in isolated enzyme assays. It is inactive against the majority of 
other kinases. It is currently being tested in a clinical trial [CLEE011X2101] in adult cancer 
patients. 
For further details on clinical and non-clinical experience, please refer to the current LEE011 
Investigator’s Brochure. 
1.2.3.1 
Pharmacology of LEE011 
LEE011 inhibits the growth of many tumor cell types in vitro and in vivo, including mantle cell 
lymphoma, liposarcoma, rhabdoid tumors, neuroblastoma, and carcinomas of the esophagus, 
breast, lung and pancreas. Regardless of the various genetic aberrations that may be present in 


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the cancer cells, the anti-tumor activity of LEE011 requires the presence of functional 
retinoblastoma protein (Rb). 
LEE011 has demonstrated tumor growth suppression in multiple melanoma xenograft models 
including BRAF wild type and mutant ones as a single agent. Tumor regression was achieved 
in two models while tumor stasis was observed in five models. In primary V600E BRAF 
mutated melanoma models, LEE011 in combination with LGX818 (a potent and selective RAF 
inhibitor), produced significant delay in tumor re-growth. In mouse models resistant to LGX818, 
LEE011 demonstrated tumor growth inhibition as single agent and in combination with 
LGX818, showed enhanced growth inhibition. 
1.2.3.1.1 Nonclinical pharmacokinetics (PK) and metabolism of LEE011 
The PK of LEE011 was investigated in four different species: mouse, rat, dog and monkey. 
After oral administration to rats, LEE011 was moderately absorbed (48 to 84%), with 
bioavailability ranging between 10% and 65% across animal species. Maximum serum drug 
concentration (Cmax) was observed between 2 and 4 hours post-dose. Terminal half-life (T1/2) 
of LEE011 was moderate in rodents and monkeys (2 to 7 h), and was comparatively longer (18 
h) in dogs. 
The binding of LEE011 to plasma proteins was moderate (unbound fraction in plasma for 
humans is 30 ± 2%). 3H-LEE011 and its metabolites were extensively distributed into the organs 
and tissues of rats including choroid, ciliary body and meninges with the exception of the brain. 
The highest radioactivity concentrations were found in tissues such as pituitary gland, pineal 
gland, spleen, kidney and adrenal medulla with remarkably high exposure in the thyroid gland. 
Distribution of LEE011 and/or its metabolites into melanin-containing structures was seen in 
pigmented rats. 
Oxidative metabolism of LEE011 is dominated by CYP3A4 with a minor contribution by 
flavin-containing monooxygenase 3 (FMO3). In vitro studies indicate LEE011 is a reversible 
inhibitor of CYP1A2 (Ki = 16 μM), CYP3A4 (Ki = 35 μM), and CYP2E1 (IC50 = 62μM). 
LEE011 is also a time-dependent inhibitor of CYP3A4 (KI = 5.06 μM, kinact = 0.0245 min-1). 
LEE011 was identified as inhibitor of the efflux transporter MDR1 (IC50 = 143μM) and MXR 
(IC50 = 24μM). LEE011 could affect substrates of the MDR1 transporter, depending on the 
LEE011 dose and intestinal concentration. LEE011 inhibited the human bile salt export pump 
(BSEP) transporter (IC50 = 4.7 μM). 
PK data from the ongoing phase I study ([CLEE011X2101]) show that the plasma Cmax of 
LEE011 at steady state after 600 mg QD dosing in humans ranges from 943-5860 ng/mL 
(arithmetic mean = 2940 ng/mL or 5.32 µM), which is well below the above mentioned Ki or 
IC50s for reversible inhibition of CYPs and transporters. The major DDI risk identified for 
LEE011 is its time-dependent inhibition of CYP3A4, which could increase exposures of major 
CYP3A4 substrates. 
LEQ803 (N-demethylation) is a major metabolite in the rat and monkey, the main metabolite 
in humans and the only metabolite in dogs. This metabolite was found to interact with hERG 
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In rat ADME studies, LEE011 was predominantly excreted with bile. The elimination of 
unchanged drug was limited. A minor proportion of the administered dose is excreted in urine. 
The bulk of the administered dose (87.3%) was excreted within 24 hours post-dose. 
Overall, the elimination of LEE011 may potentially be affected by co-administered drugs that 
inhibit or induce CYP3A4. LEE011 may inhibit the metabolism/transport of sensitive substrates 
of CYP3A4, CYP1A2, and BSEP. 
1.2.3.1.2 Safety pharmacology and toxicology of LEE011 
In vitro, LEE011 did not show mutagenic or phototoxic potential. 
Safety pharmacology studies did not reveal any effects on CNS or respiratory functions. In the 
dog telemetry study, prolongation of the average QT and QTc was observed with the potential 
to induce PVCs at higher exposure levels. NVP-LEE011 and LEQ803 likely contributed to the 
QT prolonging effects seen in vivo. 
In rats and dogs, LEE011 induced bone marrow hypocellularity, lymphoid depletion, atrophy 
of the skin and intestinal mucosa, decreased bone formation and testicular atrophy. These are 
consistent with the mechanism of action of LEE011. In addition, an increased number of ovarian 
corpora lutea was observed in a single female dog at the highest dose tested. The liver, bile 
system and gall bladder (proliferative changes, cholestasis, sand-like gallbladder calculi, and 
inspissated bile) were identified as additional target organs of toxicity which are not likely 
related to the primary pharmacology of LEE011. Correlating hematological and/or 
biochemistry changes were seen for the effects described in the bone marrow, lymphoid system 
and liver. All the described changes were fully reversible in rats and dogs. 
Based on its mechanism of action and preclinical toxicology studies, the major potential 
toxicities for LEE011 include myelosuppression, hepatic toxicity, and prolongation of the QT 
interval. The risk of these toxicities may be amplified by concomitant administration of strong 
inhibitors of CYP3A4. 
Please refer to the current LEE011 Investigator’s Brochure for additional details. 
1.2.3.2 
Clinical Study with LEE011 
As of 4 February 2013, 56 patients have been treated with single agent LEE011 in the first-in 
human phase I study [CLEE011X2101] in which LEE011 is administered orally, once daily for 
21 days followed by a 1 week rest (28-day cycle). Doses tested include 50 mg (n=4), 70 mg 
(n=2), 140 mg (n=4), 260 mg (n=4), 280 mg (n=4), 350 mg (n=5), 400 mg (n=5), 600 mg (n=4), 
900 mg (n=13), 750 mg (n=8), and 1200 mg (n=3). In all, 8 DLTs have been observed. DLTs 
include grade 3 mucositis (n=1) in the 50 mg cohort, grade 3 pulmonary embolism (n=1) in the 
280 mg cohort, grade 3 hyponatremia (n=1) and prolonged grade 3/4 neutropenia (n=1) in the 
400 mg cohort, grade 4 thrombocytopenia (n=1) in the 750 mg cohort, grade 3 asymptomatic 
QTc prolongation with grade 3 neutropenia (n=1) in the 900 mg cohort and grade 4 febrile 
neutropenia (n=1) and grade 4 thrombocytopenia (n=1) in the 1200 mg cohort. The grade 3 
mucositis observed in the 50 mg cohort was later determined to be due to herpes simplex virus 
(HSV) infection. A DLT related to mucositis has not been observed since. Four cases of Grade 
1 or 2 mucositis have been observed in doses up to 350 mg; mucositis has not been observed at 
higher doses. The grade 3 pulmonary embolism was observed in a patient with NSCLC who 


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had diffuse bilateral lung disease and a central venous catheter. The grade 3 hyponatremia was 
asymptomatic and readily corrected with saline infusion. Grade 3 or 4 neutropenia and/or 
thrombocytopenia not meeting DLT criteria were seen in increasing frequency starting from 
600 mg up to 1200 mg. Asymptomatic grade 1 or 2 QTc prolongation were observed in 
increasing frequency starting at 600 mg up to 1200 mg; 1 patient (25%) in the 600 mg cohort, 
2 patients (25%) in the 750 mg cohort, 4 patients (31%) in the 900 mg cohort, and 3 patients 
(100%) in the 1200 mg cohort. The most frequently reported treatment-related AEs include 
fatigue, nausea, anemia, asthenia, neutropenia, vomiting, leukopenia, increased blood creatinine, 
decreased appetite, diarrhea, hypoalbuminemia, lymphocytopenia, myalgia, thrombocytopenia, 
dizziness, erythema, hyperglycemia, mucosal inflammation and stomatitis. The majority have 
been grades 1 or 2 and reversible. 
The MTD of LEE011 for the 3 weeks on/1 week off schedule is 900 mg. The study continues 
with exploration of alternate dosing schedules and further assessment of safety, tolerability, and 
preliminary anti-tumor activity of LEE011. 
Please refer to the current LEE011 Investigator’s Brochure for additional details. 
1.2.3.2.1 Clinical pharmacokinetics of LEE011 
Preliminary pharmacokinetics data for LEE011 demonstrate that peak plasma concentrations 
were achieved by 1 to 5 hours (range of median Tmax values) following oral dosing. LEE011 
pharmacokinetics data up to 1200 mg exhibit slightly over-proportional increases in exposure 
across the dose range tested. Steady-state is reached by day 8 and effective T1/2 values based on 
accumulation (T1/2, acc) ranged from 24 hours (50 mg QD dose) to 40 hours (600 mg QD dose), 
and 31 hours (900 mg QD dose). The accumulation ratio (Racc) across the studied daily dose of 
50 to 1200 mg ranged from 1.55- to 2.94-fold. 
Please refer to the current LEE011 Investigator’s Brochure for additional details. 
1.2.4 
Overview of combination treatment 
1.2.4.1 
Pre-clinical studies with combinations of RAF and MEK - inhibitors 
Combining inhibitors of sequential steps in the MAPK signal transduction pathway have the 
potential to provide several advantages when compared to single agent treatments. These 
advantages could include reduction or elimination of the emergence of resistance that might 
arise in the single agent setting, greater overall efficacy via more complete pathway suppression, 
and provision of the ability to dose-reduce one or more of the drugs to avoid or minimize 
toxicities. To assess whether either of these latter two benefits might be the case, the effect of 
combining LGX818 and MEK162 on the in vitro proliferation of cell line models that harbor 
BRAFV600E alterations was examined. These studies were carried out in both melanoma and 
colorectal cancer-derived cell lines with standard measures of synergy used to determine 
whether the combination was, dose-shifting, able to boost the overall effects of the single agents, 
or both (Lehar 2009). These studies indicated a statistically significant synergy (p = <0.0001, 
one-tailed T-Test) for the combination when compared to the single agents (Caponigro 2011, 
Novartis, data on file). In cell lines where significant synergy was measured (5/6 CRC and 6/12 
melanoma) both dose-shifting and effect boosts were observed. In addition, in cases where 
synergy was not observed, combining the two inhibitors resulted in dose-additivity. 


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In vivo, the combination of LGX818 and MEK162 has been evaluated in a mouse primary 
xenograft model of human melanoma that expresses BRAFV600E. While there was increase in 
the degree of tumor regression observed in the combination groups compared to single-agent 
MEK162 (3 mg/kg or 10 mg/kg bid) or LGX818 (3 mg/kg bid) respectively, the most dramatic 
effect was on the duration of response. Over the course of 116 days of treatment, the vast 
majority of tumors developed resistance to single-agent MEK162 (8/8 at low dose and 7/8 at 
high dose) or LGX818 (6 out of 7). In contrast, treatment with LGX818 and low dose MEK162 
combination, resulted in only one out of eight tumors developing clear resistance and no tumors 
developed resistance to combination treatment of LGX818 and high dose MEK162. These data 
support the hypothesis that combining RAF and MEK inhibitors will result in a more sustained 
tumor response. 
Collectively these in vitro and in vivo results strongly suggest that combining these inhibitors 
in the clinic in the BRAFV600E setting is likely to result in an increase of anti-tumor activity 
compared to either single agent. 
1.2.4.2 
Clinical studies with combinations of selective RAF and MEK - 
inhibitors 
The concept of dual, vertical inhibition of the ERK/MAPK- pathway is currently being explored 
within a Phase I/II clinical trial. [Study NCT01072175] investigates the safety, PKs, PDs and 
clinical activity of the combination of the BRAF-inhibitor GSK2118436 (GlaxoSmithKline) 
and the selective MEK1/2- inhibitor GSK1120212 in patients with advanced BRAF- mutation 
positive tumor types. One hundred nine patients have been enrolled in the study and preliminary 
results were presented at ASCO 2011 (Infante 2011). Both investigational drugs could be 
administered at full dose in combination, GSK2118436 150 mg BID and GSK1120212 2mg 
QD, showing a significant tumor shrinkage in the majority of the patients with an ORR of 70%. 
The combination was well tolerated and the most common AEs included pyrexia, fatigue, rash, 
diarrhea and nausea. Interestingly, patients experienced less skin toxicities compared to 
monotherapy. 
BRAF-inhibitors including PLX4032, XL-281 and GSK2118436 are associated with 
hyperproliferative skin lesions (ie, keratoacanthomas and squamous-cell carcinomas) in up to 
31% of patients (Flaherty 2009; Flaherty 2010; Kefford 2010), indicating that BRAF inhibitors 
can paradoxically activate the RAF/MEK/ERK pathway and promote growth in RAS 
mutant/BRAF wt tumors (Hatzivassiliou 2010; Cichowski 2010). The decreased occurrence of 
SCC in the GSK2118436/GSK1120212 combination trial, suggests that MEK inhibitors by 
acting downstream of RAF in the RAF/MEK/ERK pathway, may potentially block 
inappropriate signal transduction, originating either from the cell surface or due to RAS/RAF 
mutations, further strengthening the rationale for combining MEK inhibitors with BRAF 
inhibitors in the clinic. 
1.2.4.3 
Pre-clinical studies with combinations of RAF, MEK and CDK - 
inhibitors 
Increased CDK4/6 activity and the accompanying loss of G1/S phase cell cycle control is a 
hallmark of melanoma. This increased activity can occur as a result of several non-exclusive 
events. For instance, one consequence of ERK/MAPK pathway activation due to oncogenic 


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lesions in BRAF and NRAS is the elevation of cyclin D1 levels which in turn interact with and 
activate the CDK4/6 kinases. In addition, molecular alterations that directly increase CDK4/6 
activity such as loss of expression of the CDKN2A gene, which encodes p16 a negative 
regulator CDK4/6, and amplification of CCND1, the gene encoding CyclinD1 are collectively 
observed in a majority of melanomas. Further underscoring the importance of CDK4/6 kinases 
in melanoma, combining the CDK4/6 inhibitor LEE011 with either LGX818 or MEK162 in 
BRAF and NRAS-mutant models of melanoma, respectively, leads to both improved efficacy 
and prolonged anti-tumor responses in vivo (RD-2012-50372, RD-2012-50370). 
The effect of simultaneously combining LGX818, MEK162 and LEE011 on the proliferation 
of BRAF-mutant melanoma cell lines in vitro was examined. The cell lines used were the A-375 
and WM-266-4 models, both of which are highly sensitive to LGX818 and MEK162, and 
derivatives of each of these lines engineered to express one of several proteins known to confer 
resistance to RAF inhibitors including NRASQ61K (Nazarian 2010), BRAF p61 (Poulikakos 
2011), MEK1C121S, and MEK1P124L (Emery 2009). When a fixed ratio of MEK162 and 
LGX818 (1:1, 0–2.7uM) was combined with LEE011 (0–10uM), either synergy or dose- 
additivity was observed in all models. Synergy was observed in both the parental A-375 and 
WM-266-4 cell lines as well as in the NRASQ61K-expressing variant of A-375. In all other 
models either weak synergy or dose-additive effects were observed. 
Collectively these results suggest that adding the CDK4/6 inhibitor LEE011 to the 
LGX818/MEK162 combination in the clinic in BRAFV600 mutant patients is likely to further 
increase the anti-tumor activity of the LGX818/MEK162 combination. 
1.2.4.4 
Clinical studies with combinations of selective RAF, MEK and CDK4/6 
inhibitors 
No studies are currently reported and/or ongoing with a selective RAF, MEK and CDK4/6 
inhibitor triple combination. 
1.3 
Anticipated risks and safety considerations of the study drug 
combinations 
1.3.1 
Dual combination LGX818 and MEK162 
While preliminary clinical data available from ongoing studies with LGX818 and MEK162 as 
single agents suggest overlapping toxicities for the proposed combination which may 
potentially be dose-limiting, including effects on the skin (e.g. rash), initial reports with similar 
class of compounds have shown that selective BRAF inhibitor combines safely with MEK 
inhibitor with a decreased occurrence of skin toxicities (rash, SCC). This data suggests that the 
combination of LGX818 with MEK162 may have an improved safety profile compared the 
respective single agent therapies. 
Retinal toxicity (CSR), GI toxicity (i.e. diarrhea; nausea/vomiting), body edema, and elevations 
in CPK are associated specifically with MEK162. HFSR, photosensitivity and hyperesthesia 
were reported with the use of LGX818. MEK162 also caused ectopic soft tissue mineralization 
in pre-clinical toxicology studies, exclusively in rats. However, the plasma exposure margins 
for soft tissue mineralization in rats are 60-fold above those seen in humans at 60 mg bid. To 


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date there have been no reports of a calcium-phosphate imbalance, including ectopic 
calcifications, associated with the clinical use of MEK162. 
Based on the available data, no significant metabolism-based DDI is foreseen with the LGX818 
and MEK162 combination. Although LGX818 is a UGT1A1 inhibitor and MEK162 is a 
UGT1A1 substrate, the average concentration of LGX818 with 50 mg ME QD dose is expected 
to be well below the IC50 (~4 uM). LGX818 is both a substrate as well as an inhibitor/inducer 
of CYP3A.The inhibition and induction effects of LGX818 on CYP3A do not appeared to be 
significant since the human PK profile on Day15 was similar to Day 1 and no accumulation 
was observed. 
LGX818 is a BCRP inhibitor (IC50 at 10-25 uM) and MEK162 is a BCRP substrate. Since the 
concentration of LGX818 in the gut is expected to be ~0.4 mM with a 50 mg dose (assuming 
all drug dissolved in 250 mL volume), there is a potential for increased MEK162 exposure due 
to BCRP-inhibition by LGX818. A rat ADME study showed that 50% MEK162 was absorbed 
after oral dose. If human is similar to rat, the maximum potential increase in MEK162 exposure 
is 100% with the LGX818 and MEK162 combination. 
For the safety of the study patients, the starting dose of the combination will include a 75% 
fraction of the single agent MTD of MEK162. As the MTD of LGX818 is still under 
consideration, the starting dose will be selected based on a well tolerated dose from the ongoing 
[CLGX818X2101] clinical study. Doses of LGX818 and MEK162 will be alternately escalated 
for each compound during dose escalation (see Section 6.2.3 and Section 6.2.4.2 for provisional 
dose levels and details on the dose escalation process). Furthermore, appropriate eligibility 
criteria and specific DLT criteria as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities are provided in Section 6.1.2 and Appendix 3. The PKs of MEK162 and 
LGX818 will also be assessed in the current study to further evaluate the potential for a PK 
drug-drug interaction. 
1.3.2 
Triple combination LGX818 and MEK162 and LEE011 
Based on the most frequent observed adverse events described for the LGX818 and MEK162 
dual combination (see current LGX818 Investigator Brochure or MEK162 Investigator 
Brochure) and for LEE011 (see Section 1.2.3.2 and current LEE011 Investigators Brochure), 
overlapping toxicities can be expected for gastrointestinal events (such as nausea, vomiting, 
diarrhea) as well as fatigue. 
Since (asymptomatic) QTc prolongation has been observed with LEE011 as a single agent, 
additional collection of post-dose ECGs are implemented into this trial for the triple 
combination. ECGs be collected in triplicate (vs. single ECGs) and the entry criteria for the 
triple-combination study exclude patients with congenital long QT syndrome or family history 
of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade ≥ 3, and patients who 
are currently receiving treatment with agents that are known to cause QTc prolongation in 
humans. During study treatment with the triple combination, use of concomitant medication 
known to cause QTc prolongation is prohibited. 
LEE011 inhibited CYP3A4-catalyzed marker substrate reactions in vitro in human liver 
microsomes with Ki values of 35 μM. Time-dependent inhibition of CYP3A4 was observed 


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with a Ki value of 5 μM and a Kinact value of 0.0245 min-1. Since LGX818 is a substrate for 
CYP3A4, LEE011 has a potential to increase PK exposures of LGX818. In vitro studies 
indicated that LEE011 was mainly metabolized by CYP3A4. Since LGX818 is a more potent 
inducer than an inhibitor of CYP3A4, LGX818 may decrease the exposure of LEE011. 
Quantitative assessment of potential drug-drug interaction was performed using a dynamic 
physiologically based PK (PBPK) model in Simcyp and the simulation confirmed the 
qualitative assessment. At LGX818 450 mg QD and LEE011 200 mg QD, the model predicts 
29% and 14% increase in AUC and Cmax of LGX818, respectively, as well as 47% and 30% 
decrease in AUC and Cmax of LEE011, respectively. 
MEK162 is mainly metabolized by glucuronidation and is not a strong CYP3A4 inhibitor. In 
vitro data and some clinical data suggest MEK162 might have CYP3A4 induction potential. 
However, no significant PK exposure changes for LGX818 were observed in the LGX818 and 
MEK162 dual-combination phase up to date. Even if the induction occurs between MEK162 
and LEE011, it will likely decrease LEE011 exposure and therefore will not pose a safety risk. 
Overall the PK drug-drug interaction between MEK162 and LEE011 is expected to be minor 
and not pose significant safety risk. 
In this ongoing [CMEK162X2110] study, the PK profiles of LGX818 and MEK162 when given 
in combination were generally similar to those in their corresponding single agent studies. With 
increasing LGX818 doses (50mg, 100mg, 200mg, 400mg, 450mg and 600mg), the PK exposure 
of MEK162 did not change. These data indicated that no significant PK drug-drug interactions 
between LGX818 and MEK162 were observed. 
For the safety of the study patients to be treated with the triple combination, the starting dose 
of LEE011 in the triple combination will include a 1/9 fraction of the single agent MTD of 
LEE011 (i.e. MTD 900 mg QD 3 week on/1 week off schedule), i.e 100 mg QD. For the starting 
dose of LGX818 and MEK162, the RP2D of 450mg QD and 45mg BID was selected as a well- 
tolerated dose from the ongoing CMEK162X2110 clinical study for the dual combination. 
Doses of LEE011 and possibly of LGX818 will be alternately escalated for each compound 
during dose escalation (see Section 6.2.3 and Section 6.2.4.2 for provisional dose levels and 
details on the dose escalation process). Furthermore, appropriate eligibility criteria and specific 
DLT criteria as well as specific dose modification and stopping rules are included in this 
protocol. Recommended guidelines for prophylactic or supportive treatment for expected 
toxicities are provided in Section 6.1.2 and Appendix 3. Specific safety assessments (i.e. post- 
dose ECGs/ triplicate ECGs) will be performed to monitor cardiac safety during 
triple-combination study treatment. The PKs of MEK162, LGX818 and LEE011 will also be 
assessed in the current study to further evaluate the potential for a PK drug-drug interaction. 
 
2 
Rationale 
[Any language regarding the triple combination of LGX818/MEK162/LEE011 in this 
Section is not applicable to the USA and Singapore] 


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2.1 
Study rationale and purpose 
About half of the patients with melanoma have an activating mutation in BRAF that results in 
the activation of the RAF/MEK/ERK pathway and plays an important role in the development 
of melanoma. BRAF mutations may also be present in up to 15% of patients with colorectal 
cancer and are associated with a poorer clinical outcome. A number of preclinical studies have 
validated BRAF as a therapeutic target in melanoma, and two selective BRAF inhibitors, 
PLX4032 and GSK2118436, have shown clinical activity in patients with BRAF V600E 
mutated melanoma. The selective BRAF inhibitor, vemurafenib/PLX4032 (Zelboraf®), was 
recently approved by the FDA for the treatment of patients with unresectable or metastatic 
melanoma with the BRAF V600E mutation. However, data also indicate that the duration of 
response to BRAF inhibitors is often short lived (median PFS ~ 6 to 7 months), with resistance 
developing quickly. LGX818 is a highly potent and selective BRAF inhibitor, and preclinical 
data suggest that LGX818 could lead to more sustained clinical responses in patients with 
advanced and/or metastatic BRAF V600 mutant melanoma compared to competitor RAF 
inhibitors (Stuart 2011) (see also Section 1.2.1). 
The redundancy within the multiple signaling pathways activated in cancer, along with the 
likelihood of drug resistance, suggests that combination therapy strategies will be required for 
effective disease management (Smalley 2009). There is preclinical evidence of emerging 
resistance to BRAF- and MEK1/2- inhibitors treatment through MEK1-mutations 
(Montagut 2008; Emery 2009). As demonstrated pre-clinically, the combination of a BRAF and 
a MEK1/2- inhibitor may help to prevent the emergence of resistance to single agent small 
molecule inhibitor therapy, targeting the RAF/MEK/ERK pathway by dual node inhibition 
(Emery 2009; Fremin 2010). The concept of a simultaneous, dual, vertical pathway inhibition 
of the RAF/MEK/ERK pathway is currently being explored by the combination treatment of a 
selective MEK1/2- (GSK1120212) and BRAF- inhibitor (GSK2118436) in cancer patients with 
advanced BRAF mutation positive tumor types. Preliminary results presented at ASCO 2011 
(Infante 2011) [Study NCT01072175] shows significant tumor shrinkage in the majority of the 
patients with an ORR of 70%. Furthermore, results from the NCT01072175 study show that 
selective BRAF inhibitor combines safely with MEK inhibitor with a decreased occurrence of 
cutaneous side effect, such as rash and SCC in comparison to single agent therapy, which further 
strengthen the rationale for combining MEK inhibitors with BRAF inhibitor in the clinic. 
Together, this provides a strong rationale for the combination therapy of selective RAF and 
MEK inhibitors in patients with BRAF V600 dependent advanced or metastatic solid tumor. 
The addition of LEE011 to the dual combination of LGX818 and MEK162 in BRAF-mutant 
melanoma in vitro models displays either additivity or modest synergy. Therefore the triple 
combination will be evaluated in order to (1) investigate whether LEE011 can be safely 
combined with LGX818 and MEK162, (2) whether effects observed in vitro are either 
recapitulated or enhanced in patients and to (3) evaluate whether an improved anti-tumor 
activity and prolonged anti-tumor response can be shown with the triple combination over the 
dual combination. 
The population of BRAF mutant melanoma patients who are naïve for prior treatment with a 
selective BRAF inhibitor, was chosen for the Phase II arm A, to allow a preliminary assessment 


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whether the triple combination is at least as active as the dual combination, with a comparable 
safety profile. 
The primary purpose of the proposed dose-finding Phase Ib study is to estimate the MTD(s) 
and/or the recommended Phase II dose(s) (RP2D(s)) of the dual (LGX818 and MEK162) and 
triple (LGX818 and MEK162 and LEE011) combinations in patients with locally advanced or 
metastatic melanoma, mCRC or any other solid tumor upon agreement with the Sponsor, 
positive for either V600E BRAF mutation, or any other BRAF mutation at the V600 codon (e.g. 
V600K/D/R). 
Once the MTD/RP2D has been determined for the dual combination, additional patients will be 
enrolled in three Phase II arms to further assess the clinical anti-tumor efficacy of the 
combination. The Phase II arm 1 will assess the disease control rate (DCR) of the LGX818 and 
MEK162 combination in patients with BRAF V600 mutant metastatic CRC. In the Phase II arm 
2, the study will assess the objective response rate (ORR) of the combination in metastatic 
BRAF mutant melanoma patients who have progressed after prior treatment with a selective 
BRAF inhibitor (e.g. PLX4032, GSK2118436). In the Phase II arm 3, the study will assess the 
objective response rate (ORR) of the combination in metastatic BRAF mutant melanoma 
patients who are naïve to prior treatment with a selective BRAF inhibitor. The DCR (defined 
as patients with CR or PR or SD) rather than the ORR (defined as patients with CR or PR) will 
be used to evaluate clinical benefit in Phase II arm 1, as only a limited number of patients with 
BRAF mutant mCRC have experienced tumor shrinkage in clinical studies with RAF or MEK 
inhibitors (see Section 1.1.3), with more patients achieving stable disease (SD) than response. 
Also an interim analysis for futility will be performed in arm 1 after 50% of the total number of 
patients in this arm have completed four cycles of treatment, to allow stopping early for futility 
when there is no treatment effect. All three Phase II arms will further assess the safety of the 
LGX818 and MEK162 combination. 
For the triple combination, once the MTD/RP2D has been determined additional metastatic 
BRAF mutant melanoma patients who are naïve to prior treatment with a selective BRAF 
inhibitor will be enrolled in arm A to assess the ORR of this triple combination. The safety of 
the triple combination will also be assessed in the Phase II population. 
2.2 
Rationale for the study design 
The design of this Phase Ib/II, open label, dose escalation study was chosen in order to establish 
a dose of the dual (LGX818 and MEK162) and triple (LGX818 and MEK162 and LEE011) 
combinations for which the safety and tolerability is acceptable, in patients with BRAF V600 
dependent advanced solid tumors. The dose escalation will be guided by a Bayesian logistic 
regression model (BLRM). During the Phase II part, depending on the observed DLT rate, the 
BLRM will be re-run to confirm that the current dose combination still satisfies the overdose 
criteria. Refer to Section 10.4.2.2 for further information. In the Phase II part of the study, a 
Bayesian design will be used in order to estimate the true DCR for the dual-combination arm 1 
population and the true ORR for the dual-combination arms 2 and 3, and the triple-combination 
arm A populations. 
The current open-label dose escalation study design using a BLRM is a well-established method 
to estimate the MTD(s) and/or RP2D(s) in cancer patients. The adaptive BLRM will be guided 


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by the escalation with overdose control (EWOC) principle to control the risk of DLT in future 
patients on study. 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 1998; Neuenschwander 2008; Neuenschwander 
2010), and its development and appropriate use is one aspect of the FDA’s Critical Path 
Initiative. 
2.3 
Rationale for dose and regimen selection 
Refer to Section 6.2.2 for detailed information on the rationale for the starting dose and regimen 
selection. 
2.4 
Rationale for choice of combination drugs 
Data from pre-clinical and clinical studies suggest that by simultaneous, dual, vertical pathway 
inhibition of the RAF/MEK/ERK signaling pathways, the LGX818 and MEK162 combination 
could lead to increased clinical efficacy and possibly prevent and/or overcome early resistance 
to either single agent in patients with BRAF V600-dependent advanced solid tumors (see also 
Section 1.2.1.2, Section 1.2.2.2 and Section 1.2.4.1). Data from preclinical studies suggest that 
by simultaneous triple-pathway inhibition of the RAF/MEK/ERK and CDK/cyclin signaling 
pathways, the LGX818 and MEK162 and LEE011 combination could possibly prevent and/or 
overcome resistance to and lead to increased clinical efficacy compared to the LGX818 and 
MEK162 dual combination. 
 
3 
Objectives and endpoints 
[Any language regarding the triple combination of LGX818/MEK162/LEE011 in this 
Section is not applicable to the USA and Singapore] 
Objectives and related endpoints are described in Table 3-1. 
 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
Refer to Section 10.4 


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Objective 
Endpoint 
Analysis 
Phase Ib: To estimate the MTD(s) and/or 
RP2D(s) of oral LGX818 in combination with 
oral MEK162, and of oral LGX818 in 
combination with oral MEK162 and oral 
LEE011 in patients with BRAF V600- 
dependent advanced solid tumors 
 
Phase II: To assess clinical efficacy of the 
LGX818 and MEK162 dual combination and 
LGX818 and MEK162 and LEE011 triple 
combination in the respective Phase II 
populations: 
Arm 1: metastatic BRAF V600 mutant mCRC 
patients (dual combination) 
 
Arm 2: metastatic BRAF V600 mutant 
melanoma patients who have progressed after 
prior selective BRAFi treatment (dual 
combination) 
Phase Ib: Incidence of Dose Limiting 
Toxicities 
 
 
 
 
 
 
 
 
 
 
Phase II arm 1: Disease control rate 
(DCR) as per RECIST v1.1 
 
Phase II arms 2 and 3 / arm A: 
Objective Response Rate (ORR) as 
per RECIST v1.1 
Arm 3/ Arm A: metastatic BRAF V600 mutant 
melanoma patients who are naïve to prior 
selective BRAFi treatment (dual and triple 
combination) 
Secondary 
Refer to Section 10.5 
/ Section 10.5.4 
Phase Ib + II: 
To characterize the safety and tolerability of 
LGX818 and MEK162 in combination, and 
LGX818 and MEK162 and LEE011 in 
combination 
Phase Ib 
To determine the single and multiple dose PK 
profile of the LGX818 and MEK162 
combination, and of the LGX818 and MEK162 
and LEE011 combination 
 
To assess preliminary clinical anti-tumor 
activity of the LGX818 and MEK162 
combination, and of the LGX818 and MEK162 
and LEE011 combination 
Phase II 
To further assess clinical efficacy of the 
LGX818 and MEK162 dual combination and of 
the LGX818 and MEK162 and LEE011 triple 
combination in the Phase II populations 
To characterize baseline molecular status of 
molecules relevant to RAF/MEK/ERK and 
EGFR/PI3K/AKT signaling in tumor tissue 
Phase Ib+II 
Incidence and severity of AE 
 
 
 
Phase Ib 
Time vs. plasma concentration, 
basic PK parameters of LGX818 and 
MEK162 and LEE011 and known 
active metabolite(s) 
 
ORR as per RECIST v1.1 
 
 
 
Phase II 
PFS, time to response (TTR), 
duration of response (DOR) as per 
RECIST v1.1, and Overall Survival 
(OS) 
Baseline molecular status 
(mutation/amplification/expression) 
in tumor tissue of potential predictive 
markers of tumor response or 
resistance (BRAF, HRAS, KRAS, 
NRAS, PTEN, cKIT, PIK3CA, 
MAP2K1, MAP2K2, ARAF, c-MET, 
RAF1, EGFR) 
 


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4 
Study design 
[Any language regarding the triple combination of LGX818/MEK162/LEE011 in this 
Section is not applicable to the USA and Singapore] 
- 
- 


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4.1 
Description of study design 
This is a multi-center, open-label, dose finding, Phase Ib dose escalation study to estimate the 
MTD(s) and/or RP2D(s) for the dual combination of LGX818 and MEK162 and triple 
combination of LGX818 and MEK162 and LEE011, followed each independently by a Phase 
II part to assess the clinical efficacy and to further assess the safety of the combinations in 
selected patient populations. Oral LGX818 and MEK162 will be administered once daily and 
BID, respectively, on a continuous schedule. Oral LGX818 and MEK162 and LEE011 will be 
administered once daily on a continuous schedule (LGX818), BID on a continuous schedule 
(MEK162) and once daily three weeks on, one week off (LEE011), respectively. Patients will 
be treated until progression of disease, unacceptable toxicity develops, or withdrawal of 
informed consent, whichever occurs first. Continued treatment beyond progression of disease 
will be allowed under certain circumstances (see Section 6.1.5) Provisional dose levels are 
given in Table 6-1 and Table 6-2. A cycle is defined as 28 days. 
Figure 4-1 
Study Design 
 
Molecular pre-screening 
Patients whose tumors have a documented mutation of BRAF V600 will be enrolled based on 
available local documentation. For patients for whom the molecular status is not known and 
who have a tumor which is routinely screened for a BRAF mutation at a local laboratory, the 
mutation can be determined on either fresh or archival tumor by local routine procedure without 
the need for signing the Molecular pre-screening Informed Consent. However, patients for 
whom molecular status is not known at the time of consideration for enrollment in this study 
and who have a tumor which is not routinely screened for a BRAF mutation at a local laboratory, 
will sign a Molecular pre-screening Informed Consent allowing for the collection of fresh tumor 
sample or use of archival tumor tissue for local assessment of the mutational status. Only once 
the BRAF V600 mutational status is known or determined, the patient is allowed to sign the 
Study Informed Consent Form and start screening (see also Section 7.1.1). 


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Screening period 
Upon signing the Study Informed Consent Form, patients will be evaluated against study 
inclusion and exclusion criteria. Eligible patients will be enrolled in the study within 14 days of 
the commencement of the screening assessments and evaluations (Table 7-1 and Section 7.1.2). 
Dose escalation (Phase Ib) 
The dose escalation part of the trial will be conducted in adult patients with BRAF V600- 
dependent advanced solid tumors (see also Section 5.1). This part of the trial is expected to 
enroll at least 18 patients for the dual combination (LGX818 and MEK162) and at least 12 
patients for the triple combination (LGX818 and MEK162 and LEE011). 
For the dual combination, dose escalation will start at 50mg QD for LGX818 and 45mg BID 
for MEK162. Provisional dose levels are given in Table 6-1. For the triple combination, dose 
escalation will start at 450mg QD LGX818 and 45mg BID MEK162 and 100mg QD LEE011. 
Provisional dose levels are given in Table 6-2. When enrollment of a cohort is complete, further 
enrollment will only resume after the investigators and the Sponsor have jointly decided on the 
next dose escalation step of the combination. At each decision time point, the adaptive BLRM 
provides the upper boundary for the combinations that meet the EWOC criteria. Safety and 
tolerability data, PK, PD, and efficacy, as well as the recommendations from the Bayesian 
model are used to determine the dose combination for the next cohort(s) at a dose escalation 
teleconference. If deemed appropriate and supported by the available and relevant safety, PK, 
PD and efficacy data (and in agreement between the Sponsor and the Investigators), the dosing 
regimen of LGX818 may be changed to BID and/or every-other-day (QOD) dosing (as long as 
the new initial dosing regimen will not exceed the maximum total daily dose tested in this study). 
Should the new dosing regimen of LGX818 be explored, this will be achieved by enrollment of 
patients into a new cohort. 
Various dose pairs will be explored following the recommendation of an adaptive Bayesian 
logistic regression model (BLRM) for dose escalation with overdose control (EWOC) until the 
MTD is determined and/or until a consensus between the Sponsor and Investigators is reached 
and it is considered that there is no benefit of further increasing the dose. At least 6 patients 
eligible for the dose determining set (DDS) must be treated at the dose(s) declared to be the 
MTD/RP2D. At this time the RP2D, a dose less than or equal to the MTD, will be estimated 
based on a review of the totality of the available study data. Note: more than one combination 
and/or dosing schedule may be defined as MTD/RP2D. In the case that all dose combinations 
are considered to be too toxic by the BLRM after the first cohort, no MTD/RP2D can be defined. 
Phase II 
Following MTD/RP2D declaration, for the dual-combination patients will be enrolled in three 
Phase II arms. Phase II arm 1 will consist of 28 patients with non-resectable advanced BRAF 
V600 mutant metastatic colorectal cancer (mCRC) for whom no further effective standard 
therapy is available. An interim analysis for futility will be performed in arm 1 after 50% of the 
total number of patients in this arm have completed four cycles of treatment, to allow stopping 
early for futility when there is no treatment effect. The Phase II arm 2 will consist of 41 patients 
with locally advanced or metastatic BRAF V600 mutant melanoma who have progressed after 


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previous treatment with a selective BRAF inhibitor. The Phase II arm 3 will consist of 40 
patients with locally advanced or metastatic BRAF V600 mutant melanoma who are naïve to 
previous treatment with a selective BRAF inhibitor. An interim analysis for futility will not be 
performed for arms 2 and 3, as signs of clinical activity have been reported for both MEK162 
and LGX818 as single agent in patients with BRAF mutant melanoma patients (see Section 
1.2.1.2 and Section 1.2.2.2.1). 
For the triple combination following MTD/RP2D declaration, 40 patients with locally advanced 
or metastatic BRAF V600 mutant melanoma who are naïve to previous treatment with a 
selective BRAF inhibitor will be enrolled in the Phase II arm A. 
If more than one dose combination or dosing schedule has been defined as MTD/RP2D, the 
Sponsor may decide to open the Phase II arms for more than one MTD/RP2D and/or start the 
Phase II arms with different dose combinations or schedules. This decision will be driven by 
the data available and will be discussed and agreed on between the Sponsor and the investigators. 
30-day safety follow-up assessments 
After study drug discontinuation, all patients must complete End of Treatment assessments 
within 14 days and the safety follow-up assessments for 30 days after the last dose of the study 
treatment (see also Section 7.1.4 and Section 7.1.5.1). 
Study evaluation completion (SEC) 
Note: As of protocol amendment 10, patients will be considered to have completed the 
study after the 30-day safety evaluation or 30 days after treatment discontinuation, 
whichever is earlier. 
The study evaluation completion (SEC) eCRF page records the end of study for every individual 
patient. For details on the time point of completion of SEC, please refer to Section 7.1.4. 
Disease progression and Survival follow-up assessments (Phase II only) 
Note: As of protocol amendment 10, post-treatment disease progression follow-up (if 
applicable) and/or survival follow-up (including documentation of subsequent 
antineoplastic therapies) will no longer be performed for any patient in the Phase II part 
of the study. 
Patients enrolled in the Phase II part of the study who discontinue study treatment for any reason 
other than disease progression will be followed up for progression of disease as detailed in 
Table 7-1 and Section 7.1.5.2. All patients enrolled in the Phase II part of the study will be 
followed for survival (for details see Section 7.1.5.3). 
4.2 
Timing of interim analyses and design adaptations 
An interim analysis for futility will be performed during the Phase II part of the study in arm 1 
dual combination (BRAF mutant mCRC patients) after 50% of the total number of patients in 
this arm have completed four cycles of treatment, to allow stopping early for futility when there 
is no treatment effect (see also Section 4.1-Phase II and Section 10.7). 


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4.3 
Definition of end of the study 
Note: As of protocol amendment 10, the end of study will be when the last patient on 
treatment completes the 30-day follow-up visit or 30 days after treatment discontinuation. 
End of study (Last Patient Last Visit [LPLV]) will be upon completion of the follow-up period 
for the last patient treated with either the dual (LGX818 and MEK162) or triple (LGX818 and 
MEK162 and LEE011) combination as described in Section 4.1. This will occur once the last 
patient in the Phase II part has died or all patients have completed SEC, or have been lost to 
follow-up or withdrew consent, whichever occurs first. 
4.4 
Early study termination 
The study can be terminated at any time for any reason by the Sponsor. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1.4 for a prematurely 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 IECs of the early termination of the trial. 
 
5 
Population 
[Any language regarding the triple combination of LGX818/MEK162/LEE011 in this 
Section is not applicable to the USA and Singapore] 
5.1 
Patient population 
The dose escalation will be conducted in adult patients with locally advanced or metastatic 
melanoma, metastatic colorectal cancer (mCRC) or any other solid tumor upon agreement with 
the Sponsor (like serous ovarian, biliary tract or pancreatic carcinomas; see also Section 1.1.1 
and Table 1-1) harboring the BRAF V600E mutation, or any other BRAF V600 mutation, 
whose disease has progressed despite previous anti-neoplastic therapy or for whom no further 
effective standard therapy is available. Once MTD/RP2D has been determined with either the 
dual and triple combination, additional patients will be enrolled in the respective Phase II parts 
of the study. Patients with BRAF V600 mutant mCRC for whom no further effective standard 
therapy is available, will be enrolled in arm 1 dual combination of the Phase II part of the study. 
Patients with locally advanced or metastatic BRAF V600 mutant melanoma who have 
progressed after previous treatment with a selective BRAF inhibitor will be enrolled in the 
Phase II arm 2 dual combination. Patients with locally advanced or metastatic BRAF V600 
mutant melanoma who are naïve to previous treatment with a selective BRAF inhibitor will be 
enrolled in the Phase II arm 3 dual combination and in the triple combination Phase II arm A. 
Patients enrolled in this study are not permitted to participate in parallel investigational drug or 
device studies. Additionally, patients who have completed the study must not be re-enrolled for 
a second course of treatment. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered enrollment in the study. 


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5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Age ≥ 18 years. 
2. For the dose escalation (Phase Ib): Histologically confirmed diagnosis of locally 
advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on 
Cancer [AJCC]), or confirmed diagnosis of non-resectable advanced metastatic colorectal 
cancer (mCRC), or any other indication upon agreement with the Sponsor, whose disease 
has progressed despite previous anti-neoplastic therapy or for whom no further effective 
standard therapy is available. 
For Phase II arm 1 dual combination: Confirmed diagnosis of non-resectable advanced 
metastatic colorectal cancer (mCRC) for whom no further effective standard therapy is 
available. 
For Phase II arm 2 dual combination: Histologically confirmed diagnosis of locally 
advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on 
Cancer [AJCC]) in patients who have progressed after previous treatment with a selective 
BRAF inhibitor. 
 
3. For Phase II arm 3 dual combination and Phase II arm A triple combination: 
Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage 
IIIB to IV per American Joint Committee on Cancer [AJCC]) in patients who are naïve to 
previous treatment with a selective BRAF inhibitor. 
4. Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation. 
5. Evidence of measurable disease as determined by RECIST v1.1. 
6. World Health Organization (WHO) Performance Status ≤ 2. 
7. Negative serum pregnancy test within 72 hours prior to the first study dose in all women 
of childbearing potential. 
8. Able to understand and voluntarily sign the informed consent form, and ability to comply 
with the study visit schedule and other protocol requirements. Written informed consent 
must be obtained prior to any screening procedures. 
9. For Phase II: Availability of a fresh tumor biopsy at Screening/Baseline, unless sufficient 
fresh tumor tissue was collected during local molecular pre-screening which can be 
submitted to the Sponsor-designated laboratory at Screening. If a tumor biopsy was 
collected after the last anti-neoplastic treatment within 2 months prior to study enrollment, 
the archival tissue of this tumor biopsy will be acceptable for enrollment instead of the 
fresh tumor biopsy (for further details please see also Section 7.2.4). 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Progressive disease following prior treatment with RAF-inhibitors in combination with 
MEK-inhibitors. 
2. Symptomatic or untreated leptomeningeal disease. 
3. Symptomatic brain metastases. Patients previously treated or untreated for brain 
metastases that are asymptomatic in the absence of corticosteroid therapy are allowed to 


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enroll. Brain metastases must be stable with verification by imaging (e.g. brain MRI 
completed at screening demonstrating no current evidence of progressive brain 
metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs. 
For the triple combination: patients presenting any brain metastases detected by 
CT/MRI of the brain at screening are excluded. 
4. Known acute or chronic pancreatitis. 
5. History or current evidence of retinal disease (e.g. central serous retinopathy (CSR), 
retinal vein occlusion (RVO)) or ophthalmopathy as assessed by ophthalmologic 
examination at baseline that would be considered a risk factor for CSR/RVO (e.g., optic 
disc cupping, visual field defects, IOP > 21 mmHg). 
6. Clinically significant cardiac disease and/or recent cardiac events including any of the 
following: 
• CHF requiring treatment (NYH grade ≥ 2), LVEF < 45% as determined by MUGA 
scan or ECHO (for addition of LEE011 in the triple combination please note: patients 
with LVEF less than institutional lower limit of normal are also excluded from study), 
or uncontrolled hypertension (please refer to WHO-ISH guidelines) 
• History or presence of clinically significant ventricular arrhythmias or atrial 
fibrillation 
• Clinically significant resting bradycardia within 12 months prior to starting study drug 
• Unstable angina pectoris or symptomatic pericarditis within 12 months prior to 
starting study drug. 
• Acute Myocardial Infarction (AMI) within 12 months prior to starting study drug. 
• QTcF > 480 msec for dual combination. For addition of LEE011 in the triple 
combination, mean triplicate QTcF > 450 ms at screening or indeterminate 
(i.e., unreadable or not interpretable) at screening. 
• For addition of LEE011 in the triple combination, any of the following within 
12 months prior to starting study drug: history or presence of ventricular 
tachyarrhythmia, complete left bundle branch block, or right bundle branch block and 
left anterior hemi block (bifascicular block). 
• For addition of LEE011 in the triple combination, congenital long QT syndrome or 
family history of unexpected sudden cardiac death. 
• For addition of LEE011 in the triple combination, any heart disease that requires the 
use of a cardiac pacemaker or implantable cardioverter defibrillator ≤ 3 months prior 
to starting study drug or any other clinically significant heart disease 
(e.g. documented congestive heart failure, documented cardiomyopathy). 
7. Patients with any of the following laboratory values at Screening/baseline: 
• Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L] 
• Platelets < 100,000/mm3 [100 x 109/L] 
• Hemoglobin < 9.0 g/dL 
• Serum creatinine >1.5 x ULN or calculated or directly measured CrCl < 50% LLN 
(lower limit of normal) 
• Serum total bilirubin >1.5 x ULN 


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• AST/SGOT and/or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are 
present 
• For addition of LEE011 in the triple combination, serum magnesium, potassium, 
sodium, inorganic phosphate and calcium (corrected for serum albumin) < LLN or not 
correctable with supplement to within normal limits prior to study treatment start, and 
PT/INR >1.5 x ULN or aPTT >1.5 x ULN 
8. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of oral LGX818, MEK162 or LEE011 (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection). 
9. Previous or concurrent malignancy. Exceptions: adequately treated basal cell or squamous 
cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of 
recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively, 
and without evidence of recurrence for at least 3 years prior to study entry. 
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test (> 5 mIU/mL). 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, are not allowed to participate in this study UNLESS they are using 
highly effective methods of contraception throughout the study and for 3 months after 
study drug discontinuation. Highly effective contraception methods include: 
• Total abstinence or 
• Male or female sterilization 
• Combination of any two of the following (a+b or a+c or b+c) 
a. Use of oral, injected, or implanted hormonal methods of contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
Post-menopausal women are allowed to participate in this study. Women are considered 
post-menopausal and not of child bearing 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 six months of spontaneous amenorrhea with serum 
Follicle-Stimulating Hormone (FSH) levels > 40 mIU/mL or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to 
screening. 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 child bearing potential. 
Sexually active males must use a condom during intercourse while taking the drug and for 
5 T1/2 after stopping treatment and should not father a child in this period. A condom is 
required to be used also by vasectomized men in order to prevent delivery of the drug via 
seminal fluid. 
11. History of thromboembolic or cerebrovascular events within the last 6 months, including 
transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary 
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12. Patients who have received radiation therapy (that includes > 30% of the bone marrow 
reserve), chemotherapy, biological therapy (e.g., antibodies) within ≤ 4 weeks (6 weeks 
for nitrosourea, mitomycin-C), or who have been treated with continuous or intermittent 
small molecule therapeutics or investigational agents within 5-half-lives of the agent (or ≤ 
4 weeks when half-life is unknown) prior to starting study drug or who have not recovered 
from the side effects of such therapy (except alopecia). 
13. Patients who have undergone any major surgery within the last 2 weeks prior to starting 
study drug or who would not have fully recovered from previous surgery. 
14. Known Human Immunodeficiency Virus (HIV) infection. 
15. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or study drug 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. 
16. For addition of LEE011 in the triple combination, patients who are currently receiving 
treatment with agents that are known to cause QTc prolongation or induce torsades de 
pointes in humans and cannot be discontinued 7 days prior to Cycle 1 Day 1. 
17. For addition of LEE011 in the triple combination, patients who are currently receiving 
treatment with drugs or herbal medications that are strong inducers of CYP3A4 enzyme or 
substrates of CYP3A4 with a narrow therapeutic index (NTI) and cannot be discontinued 
7 days prior to Cycle 1 Day 1. See Appendix 4, Table 14-9, and Table 14-10 for a partial 
list of CYP3A4 substrates or inducers. 
18. Patients who are currently receiving strong systemic inhibitors of CYP3A4 (refer to Table 
14-10 in Appendix 4 for a partial list of CYP3A4 inhibitors). 
 
6 
Treatment 
[Any language regarding the triple combination of LGX818/MEK162/LEE011 in this 
Section is not applicable to the USA and Singapore] 
6.1 
Investigational treatment, other study treatment, supportive 
treatment 
6.1.1 
Dosing regimen 
The investigator or responsible site personnel should instruct the patient to take the study drugs 
as per protocol (promote compliance). All dosages planned and dispensed to the patient and all 
dose changes and all missed doses during the study must be recorded on the Dosage 
Administration Record eCRF. Drug accountability must be performed on a regular basis. 
Patients will be instructed to return unused study drugs to the site at the end of each cycle. The 
site personnel will ensure that the appropriate dose of each study drug is administered at each 
visit and will provide the patient with the correct amount of drugs for subsequent dosing. 
On days when blood collection is scheduled at the clinic, patients will take the study drugs 
(either in the dual or triple combination) in the clinic under the supervision of the investigator 
or designee. On all other days patients will take the study drugs at home. 


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Patients should be instructed to swallow the capsules and tablets whole and not to chew, crush 
or open them. 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before 
the next scheduled dose. The occurrence and frequency of any vomiting and/or diarrhea (or 
increase stool frequency) during treatment must be noted in the adverse events section of the 
eCRF. In addition, on the days of full pharmacokinetic sampling, the exact time of any episodes 
of vomiting and diarrhea (or increase stool frequency) within the first 4 hours post-dosing on 
that day must be noted in a separate section of the eCRF. 
Any doses that are missed should be skipped and should not be replaced or made up during the 
evening dosing or on a subsequent day, whichever applies. 
Patients must avoid consumption of grapefruit, grapefruit hybrids, pummelos, starfruit, or 
Seville (sour) oranges during the entire study and preferably 7 days before the first dose of study 
medications, due to potential CYP3A4 interaction with the study medications. Orange juice is 
allowed. 
6.1.1.1 
Administration of dual combination (LGX818 and MEK162) 
LGX818 capsules will be co-administered orally initially once daily with MEK162 tablets twice 
daily. The study drugs will be administered as a flat-fixed dose, and not by body weight or body 
surface area. 
• Patients must be instructed to take the study drug combination of one or more tablets of 
MEK162 and one or more capsules of LGX818 together with a large glass of water 
(~250 ml) daily in the morning at approximately the same time every day. On all dose 
administration days patients can take MEK162 and LGX818 with or without food. 
• The second daily dose of MEK162 should be taken together with a glass of water 
irrespective of food. In case the dosing regimen of LGX818 is changed to BID (see 
Section 4.1), the evening dose of MEK162 should be taken together with 2nd (i.e. evening) 
daily dose of LGX818. 
• The prescribed BID doses for MEK162 (and LGX818 in case the dosing schedule would 
be changed to BID) should be taken 12 ± 2 hours apart. 
• In case the dosing regimen of LGX818 is changed to an once-a-day every-other-day 
(QOD) dosing schedule (see Section 4.1), the patients must be instructed to take the first 
dose of the study drug combination on Day 1 of Cycle 1 and afterwards on alternating 
days (D3, D5, D7 etc.). On the non-dosing days of LGX818 (i.e. D2, D4, D6 etc), 
MEK162 should be taken at approximately the same time every morning, with a glass of 
water irrespective of food. There should be at least one day and not more than 2 days 
without LGX818 dosing between cycles. 
6.1.1.2 
Administration of triple combination (LGX818 and MEK162 and 
LEE011) 
LGX818 and LEE011 capsules will be co-administered orally once daily with MEK162 tablets 
twice daily. The study drugs will be administered as a flat-fixed dose, and not by body weight 
or body surface area. 


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• Patients must be instructed to take the study drug combination of one or more tablets of 
MEK162 and one or more capsules of LGX818 and LEE011 together with a large glass of 
water (~250 ml) daily in the morning at approximately the same time every day. On all dose 
administration days patients can take MEK162 and LGX818 and LEE011 with or without 
food. 
• The second daily dose of MEK162 should be taken together with a glass of water 
irrespective of food. 
• The prescribed BID doses for MEK162 should be taken 12 ± 2 hours apart. 
• LEE011 will be taken for 21 consecutive days followed by a 7-day planned break (3 weeks 
on, 1 week off schedule). LGX818 and MEK162 are taken on a continuous schedule. 
6.1.2 
Supportive treatment/precautions 
Because the LGX818 and MEK162 or LGX818 and MEK162 and LEE011 combination could 
trigger photosensitizing reactions, it is recommended that patients should be instructed to avoid 
exposure of skin and eye to direct sunlight as much as possible and to apply sun protection (e.g. 
sunscreen, sunglasses and protective clothing), for the duration of the trial and for at least 1 
week after discontinuation of trial treatment. Any symptoms of photosensitivity must be 
reported on the Adverse Event eCRFs and institutional standard-of-care treatment should be 
initiated promptly. 
For skin toxicity or nausea/vomiting prophylactic treatment may be initiated in all patients at 
the dose level where these toxicities have been observed and in all further patients if at least 1 
patient has experienced skin toxicity or nausea/ vomiting ≥ CTCAE Grade 3 or if at least 2 
patients experienced skin toxicity or nausea/ vomiting ≥ CTCAE Grade 2. However anti- 
emetics may be applied for treatment if the patient has experienced nausea/vomiting CTCAE 
Grade ≥ 1, at the discretion of the physician. 
For rash-like events, institutional standard-of-care treatment should be initiated promptly upon 
occurrence of such events. Treatment of rash may include, but is not limited to, topical or oral 
antibiotics, topical or oral anti-inflammatories, topical or oral corticosteroids and oral anti- 
histamines. The use of emollients and sunscreens has not been evaluated with LGX818/ 
MEK162 or LGX818 /MEK162 /LEE011 but may be used prophylactically or as treatment for 
rash (see also Appendix 3, Section 14.3.1 for guidelines for the treatment of study drug 
combination induced skin toxicity). 
Because hand foot skin reaction (HFSR) has been reported in some patients during LGX818 
single agent treatment, it is recommended that patients are educated prior to starting study 
treatment which activities to avoid like activities that cause friction on hands and feet, and on 
supportive measures for prevention and/or management of HFSR. As guidance for 
recommendations on supportive measures for prevention and/or management, the publication 
with recommendations of an international panel of experts of (van Moos R et al 2008) can be 
used (see also Section 14.3.2). A visit at a podiatrist may also be recommended at the discretion 
of the investigator. Any symptoms of HFSR must be reported on the Adverse Event eCRFs and 
should be treated further according to institutional standard-of-care. 


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Optimal therapy for vomiting or diarrhea will be based on institutional standard-of-care with 
consideration of the medications to be used with caution listed in this protocol (see Section 6.4.2 
and Appendix 4). 
Patients with edema may be treated with diuretic medications if indicated. 
For stomatitis/mucositis-like events, institutional standard-of-care treatment should be initiated 
promptly upon occurrence of such events. 
6.1.3 
Ancillary treatments 
Not applicable. 
6.1.4 
Guidelines for continuation of treatment 
Not applicable. 
6.1.5 
Treatment duration 
Patients may continue treatment with LGX818 and MEK162 or LGX818 and MEK162 and 
LEE011 combination until disease progression, unacceptable toxicity occurs that precludes any 
further treatment and/or treatment is discontinued at the discretion of the investigator or by 
patient refusal (withdrawal of consent). Continued treatment beyond progression of disease will 
be allowed only under special circumstances. For example when according to the assessment 
of the investigator, a patient with progression of disease may benefit from continuation of 
LGX818 and MEK162 or LGX818 and MEK162 and LEE011 treatment, treatment beyond 
progression can be considered. Therefore, if it is judged by the investigator in agreement with 
the Sponsor to be in the best interest of the patient, that patient may remain on study treatment 
as long as the patient continues to benefit from the study drug treatment per investigator 
assessment. Special circumstances can be defined by, for example, cystic lesions, mixed 
responses, and new brain metastasis which is treatable with stereotactic radiotherapy or surgery, 
but not requiring whole brain radiotherapy. 
Dosing beyond progression is not allowed in the following cases: 
• Patients with rapid progression of disease at critical anatomical sites (e.g. cord 
compression) requiring urgent alternative medical intervention. 
• Patients who have clinically relevant worsening of laboratory values. 
• Patients who have a clinically significant decline in performance status at time of 
progression. 
• Patients in the triple combination of LGX818 and MEK162 and LEE011 that appear with 
new brain metastases. 
6.2 
Dose escalation guidelines 
6.2.1 
Definition of treatment cycle 
A complete treatment cycle is defined as 28 days of daily continuous treatment of LGX818 and 
MEK162 and of 21 consecutive days of LEE011 treatment followed by a 7-day planned break 
in combination with daily continuous treatment of LGX818 and MEK162. The first dose of 


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LGX818 plus MEK162 or LGX818 plus MEK162 plus LEE011 defines Day 1 of Cycle 1. All 
treatment cycles have duration of 28 days. There will be no delays between cycles, i.e. study 
day 29 represents Cycle 2 Day 1. 
6.2.2 
Starting dose rationale 
LGX818 and MEK162 dual combination 
The starting dose for the study drug combination is 50mg QD for LGX818 and 45mg BID for 
MEK162, and is based on available data from the ongoing first in human studies 
([CLGX818X2101]) (Novartis) and (ARRAY-162-111) (Array Biopharma) respectively. The 
MTD of single agent MEK162 was established at 60mg/d twice daily. The MTD of LGX818 is 
still under investigation, and current data indicate that 50mg of LGX818 is a well-tolerated dose 
(the most severe toxicity observed at doses ≤ 100 mg micro-emulsion formulation LGX818 thus 
far was a CTCAE grade 3 HFSR toxicity at 100mg/day (see also Section 1.2.1.2). Taking into 
consideration all information currently available about the dose-DLT relationships of LGX818 
and MEK162 as single agents and the uncertainty about the toxicity of the combination, the 
prior distribution of DLT rates derived from the BLRM presented in Appendix 5 indicates that 
the proposed starting dose combination meets the escalation with overdose control (EWOC) 
criteria. Before the first patient first visit, the prior distribution for LGX818 will be updated 
with the most recent data from the LGX818X2101 trial and the model will be re-run in order to 
confirm the proposed starting dose for LGX818 is still eligible, i.e. fulfills the EWOC criteria. 
LGX818 and MEK162 and LEE011 triple combination 
The starting dose for the triple study drug combination is 450mg QD for LGX818 and 45mg 
BID for MEK162 (both continuous schedule) and 100mg QD for LEE011 (3 weeks on, 1 week 
off schedule), and is based on available RP2D dual-combination data from this ongoing study 
and on the first in human study (CLEE011X2101) (Novartis), respectively. The MTD of single 
agent LEE011 was established at 900mg/d once daily on a three week on, one week off schedule. 
The MTD of single agent LGX818 was established at 450mg/d once daily, and the MTD of 
single agent MEK162 was established at 60mg/d twice daily. The RP2Ds for the LGX818 and 
MEK162 dual combination were determined at 450mg LGX818 QD + 45mg MEK162 BID and 
at 600mg LGX818 QD + 45mg MEK162 BID. 
Quantitative DDI assessment using Simcyp simulation predicts 29% and 14% increase in AUC 
and Cmax of LGX818, respectively, as well as 47% and 30% decrease in AUC and Cmax of 
LEE011, respectively when 450 mg QD LGX818 and 200 mg QD LEE011 are co-administered. 
In clinic, LGX818 has been tested at up to 700 mg QD dose and the observed adverse events 
are reversible and manageable. While the potential DDI between the two molecules may result 
in LGX818 concentrations higher than the currently established RP2D, it is not expected to pose 
a significant risk. In addition, no significant DDI risk is expected between 45 mg BID MEK162 
and 100 mg QD LEE011. Therefore, the starting dose of 450mg QD for LGX818 and 45mg 
BID for MEK162 (both continuous schedule) and 100mg QD (3 weeks on, 1 week off schedule) 
for LEE011 is considered acceptable. 
Escalating doses of LEE011 will be used in combination with the 450mg LGX818 QD + 45mg 
MEK162 BID (i.e. RP2D of LGX818 and MEK162 dual combination). The starting dose of 


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LEE011 is proposed at 100mg (1/9 of single agent MTD). Depending on the PK and toxicities 
observed and in accordance with the recommendations from the BLRM, escalating doses of 
LEE011 might also be evaluated in combination with the 600mg LGX818 QD + 45mg MEK162 
BID (i.e. 2nd RP2D of LGX818 and MEK162 dual combination). 
Taking into consideration all information currently available about the dose-DLT relationships 
of LGX818 and MEK162 and LEE011 as single agents, as well as LGX818/MEK162 dual 
combination and the uncertainty about the toxicity of the triple combination, the prior 
distribution of DLT rates derived from the BLRM presented in Appendix 6 indicates that the 
proposed starting dose combination meets the escalation with overdose control (EWOC) criteria. 
Before the first patient is dosed with the triple combination, the Bayesian model will be updated 
with the most recent data from the ongoing LEE011 single agent trial and CMEK162X2110 
dual (LGX818 and MEK162) combination study, to confirm that the proposed starting dose 
combination is still appropriate (i.e. fulfills the EWOC criteria). If the proposed starting doses 
do not meet the criteria, a lower dose combination that satisfies the EWOC criteria will be used. 
6.2.3 
Provisional dose levels 
Provisional dose levels for the dual and triple combination are listed in Table 6-1 and Table 6-2, 
respectively. With the exception of starting dose level 1, actual dose levels will be determined 
following a discussion with participating investigators during dose escalation teleconferences. 
Dose escalation will continue until MTD(s)/RP2D(s) is/are reached. 
 
Table 6-1 
Provisional dose levels dual combination 
Dose level 
LGX818 mg QD 
MEK162 mg BID 
-1 
30 
45 
-1a 
50 
30 
1 (starting dose) 
50 
45 
2 
100 
45 
3 
100 
60 
3a* 
150 
45 
4 
150 
60 
5 
200 
45 
5a* 
200 
60 
* “#” dose levels and “#a” dose levels may be explored in parallel. 
Table 6-2 
Provisional dose levels triple combination 
 
Dose level 
LGX818 mg QD 
MEK162 mg BID 
LEE011 mg QD 
-1 
300 
30 
50 
0 
450 
45 
100 
1 
450 
45 
200 
2 
450 
45 
300 
3 
450 
45 
400 
4 
450 
45 
800 
5 
450 
45 
900 


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Dose level 
LGX818 mg QD 
MEK162 mg BID 
LEE011 mg QD 
NB. If LGX818 is escalated from 450 mg to 600 mg, the dose of MEK162 and LEE011 with remain fixed during 
that escalation step. Dose levels of 600mg LGX818 in combination with MEK162 and LEE011 might be 
explored in parallel with a dose level of 450mg LGX818 in combination with MEK162 and LEE011. 
 
At all decision time points, the adaptive Bayesian logistic model permits alterations in the dose 
increments based on the observed DLTs. Only one of the 2 or 3 combination partners can be 
escalated (e.g., for provisional dose level 3 dual combination only MEK162 is escalated from 
45 mg to 60 mg, and for provisional dose level 3a only LGX818 is escalated from 100 mg to 
150 mg when compared to dose level 2) and the maximum inter-cohort dose escalation is 
limited to 100%, (i.e. up to 100% and 0% increase for LGX818 and MEK162 respectively or 
0% and up to 100% increase for LGX818 and MEK162 respectively for dual combination. i.e. 
up to 33% and 0% and 0% increase for LGX818 and MEK162 and LEE011 respectively or 0% 
and 0% and up to 100% increase for LGX818 and MEK162 and LEE011 respectively for triple 
combination.) Note, however, that dose levels may be explored in parallel, as illustrated in Table 
6-1 and Table 6-2 above. If a decision is made to explore two dose levels at the same time, the 
next dose escalation decision will be made after patients in all dose cohorts have finished cycle 
1. 
Based on the BLRM rules, it will be possible for intermediate dose levels or doses higher than 
the highest provisional dose given or doses lower than the lowest provisional dose given in 
Table 6-1 and Table 6-2 to be explored. Recommendation to study these dose levels will take 
into account the Bayesian model inference, as well as the consideration of the totality of the 
available study data (safety, PK and PD) (see Section 6.2.4.2). 
Process to establish the MTD/RP2D with new MEK162 tablet variants if needed 
based on results of CMEK162X2108/ CMEK162A2101 relative bioavailability 
studies 
If based on the results of the two relative bioavailability studies, the MTD/RP2D of the LGX818 
and MEK162 combination will need to be established (in case dose escalation is ongoing at that 
time) or re-established (in case MTD/RP2D was already determined with original MEK162 
tablet at that time) with one or both of the two new MEK162 tablet variants, a new cohort of 3 
to 6 patients will be enrolled using either the MEK162 smaller tablet or new MEK162 tablet 
variant in combination with LGX818. 
The patients in this cohort will be treated at the highest dose (or MTD/RP2D as applicable) of 
the LGX818 and MEK162 drug combination, that has been evaluated previously in at least 3 
patients and for which safety data was reviewed and was found to satisfy the overdose control 
criteria of the Bayesian model, and will be followed for at least one cycle. The dose of the 
MEK162 smaller tablet and/or new MEK162 tablet variant will be adjusted to the dose of the 
original MEK162 tablet as established in the healthy volunteer relative bioavailability studies 
([CMEK162X2108] and [CMEK162A2101] respectively). The dose of the original MEK162 
tablet will be multiplied by the established factors (as obtained by the CMEK162X2108 or 
CMEK162A2101 studies) to achieve a comparable exposure with the MEK162 smaller tablet 
and/or new MEK162 tablet variant. The dose will be rounded to the lowest dose considering 
the MEK162 tablet available strength. 


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If at the following dose escalation teleconference meaningful differences in terms of safety, 
tolerability and/or PK are observed between the MEK162 smaller and original tablet and/or the 
new MEK162 tablet variant and the original MEK162 tablet both in combination with LGX818, 
then dose adjustments (escalation or de-escalation) may be made to new cohorts in accordance 
with the recommendations of the BLRM until a dose level fulfilling the overdose control criteria 
and/or achieving appropriate PK is reached. Dose escalation will continue until the MTD/RP2D 
is determined (according to procedures outlined in Section 6.2.4). 
Based upon the above outlined evaluation, the patients ongoing on treatment with the original 
MEK162 tablet may transition to the MEK162 smaller tablet or new MEK162 tablet variant at 
the equivalent dose of MEK162, while continuing the same dose level with LGX818. 
6.2.4 
Criteria for dose escalation and determination of MTD 
6.2.4.1 
Definition and estimation of MTD 
The primary objective of the study is to estimate the maximum tolerated dose(s) (MTD(s)) 
and/or RP2D(s) for the (LGX818 and MEK162) dual and (LGX818 and MEK162 and LEE011) 
triple combination. The MTD is defined as the highest drug dosage not causing in the first cycle 
of treatment medically unacceptable, dose-limiting toxicity (DLT) in more than 35% of the 
treated patients. AEs and laboratory abnormalities considered to be DLTs are defined in Table 
6-2. Since several combinations may correspond to this definition more than one MTD/RP2D 
may be identified with different doses of the combination partners. 
The applied adaptive Bayesian methodology provides an estimate of the dual- and triple-drug 
combinations not exceeding the dual- and triple-combination MTDs. Typically the MTD is a 
tested dose with maximum probability of targeted toxicity (DLT rate between 16%-35%). The 
use of EWOC principle limits the risk that a potential next dose will exceed the MTD 
(Section 10.4.2). 
6.2.4.2 
Dose escalation 
For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled 
patients who will be treated at the specified combination dose levels. The first cohort will be 
treated with the starting combination doses as shown in Table 6-1 and Table 6-2. 
Patients must complete a minimum of 1 cycle of treatment with the minimum safety evaluation 
and drug exposure or to 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. If a patient drops-out for reason other than adverse event prior 
to becoming evaluable for the DDS, a new patient may be recruited to the cohort until the 
required number is reached (see Section 7.1.4.2). If only 2 of the 3 patients in a cohort are 
evaluable and neither patient has experienced a treatment-related toxicity > CTCAE grade 1, 
dose escalation decisions may be considered. 
Dose escalation decisions will be made by Investigators and Sponsor study personnel (see 
Section 6.2.4.2.1). 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 


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recommended combination doses for the next cohort of patients will be guided by the Bayesian 
logistic regression model (BLRM) with EWOC principle (Section 2.2). The adaptive Bayesian 
methodology provides an estimate of all combination dose levels of LGX818 and MEK162 or 
LGX818 and MEK162 and LEE011 that do not exceed the corresponding MTD and 
incorporates all DLT information at all dose levels for this estimation. In general, the next 
combination dose will have the highest chance that the DLT rate will fall in the target interval 
(16-35%) and will always satisfy the EWOC principle. In all cases, the combination dose for 
the next cohort will not exceed a 100% increase from the previous combination dose. Smaller 
increases in doses may be recommended by the Investigators and Sponsor upon consideration 
of all of the available clinical data. Clinically relevant toxicities to be taken into consideration 
for dose recommendations will be those assessed as unrelated to disease, disease progression, 
inter-current illness, or concomitant medications. In addition, for certain toxicities such as 
hematologic toxicity (e.g., lymphopenia), and toxicities not associated with end-organ damage 
(e.g., nausea, pain, headache, fever, alopecia), toxicity ≥ CTCAE G2 must be observed in at 
least two thirds of the patients in the previous cohort, to impact the dose escalation. The 
likelihood of appearance of keratoacanthomas (KA) and/or squamous cell carcinomas (SCC) 
with specific and potent BRAF inhibitors is high (~ 35%) and occurs early during the course of 
treatment (median time of 4-12 weeks), as reported for the selective BRAF inhibitors PLX4032 
and GSK2118436 (Flaherty 2010; Kefford 2010; Robert 2011). No metastatic evolution of RAF 
inhibitor-induced SCCs has been reported so far. Patients will be carefully monitored for the 
occurrence of this anticipated on-target side-effect. However, in the context of this study, these 
benign KA and SCC tumors will not be considered for the dose escalation decisions, unless 
judged to be clinically significant by the investigators. If needed to better define the dose- 
toxicity relationship, additional patients may be enrolled to the current combination dose level, 
to a preceding combination dose level, or to an intermediate combination dose level before 
proceeding with further dose escalation. 
If the first 2 patients in a cohort experience a DLT, further enrollment to that cohort will stop 
and the BLRM will be updated with this new information. Re-evaluation of the available safety, 
PK, and PD data will occur. By incorporating information gained at the preceding dose levels, 
additional patients may be enrolled at this combination dose level or a lower combination dose 
level as agreed by Investigators and Sponsor personnel and if the BLRM predicts that the risk 
that this dose exceeds the MTD remains below 25% (EWOC). 
Dose escalation will continue until identification of the MTD or a suitable lower dose for the 
Phase II part of the study. This will occur when the following conditions are met: 
1. at least 6 patients have been treated at this combination dose 
2. this combination dose satisfies one of the following conditions: 
• the posterior probability of targeted toxicity at this combination dose exceeds 50% 
and is the highest among potential doses, or 
• a minimum of 18 patients have already been treated on the trial for the dual 
combination or a minimum of 12 patients have been treated on the trial for the triple 
combination. 
3. it is the dose recommended for the next cohort of patients (either per the model or by 
review of all clinical data by the Sponsor and Investigators in a dose escalation 
teleconference, see Section 6.2.4.2.1) 


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To better understand the safety, tolerability, efficacy, PD and PK of LGX818 and MEK162 or 
LGX818 and MEK162 and LEE011 study drug combinations, additional cohorts of 1 to 6 
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 BRLM 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. 
6.2.4.2.1 Implementation of dose escalation decisions 
To implement dose escalation decisions, the available toxicity information (including AEs 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 Sponsor 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 the Sponsor indicating that the results of the 
previous dose level were evaluated and that it is permissible to proceed to a higher dose level. 
6.2.4.2.2 Intra-patient dose escalation 
Intra-patient dose escalation is not permitted at any time within the first four Cycles of treatment. 
After the fourth cycle is completed, individual patients may be considered for treatment at a 
dose of LGX818 or MEK162 or LEE011 higher than the dose to which they were initially 
assigned. Only one of the investigational study drugs will be escalated at any one time. In order 
for a patient to be treated at a higher dose of either LGX818 or MEK162 or LEE011, he or she 
must have tolerated the lower dose pair for at least four cycles of therapy, e.g., he or she must 
not have experienced at the lower dose pair originally assigned a toxicity of CTCAE Grade ≥ 2 
for which relationship to study drug cannot be ruled out. Moreover, the new, higher dose pair 
with which the patient is to be treated must be a dose pair that has completed evaluation in a 
dose escalation meeting and that has not exceeded the MTD estimated by the Bayesian model 
given all available data. 
There is no limit to the number of times a patient may have his or her dose of either LGX818 
or MEK162 or LEE011 increased. In any further escalation, again only one study drug will be 
increased at any time. Any further increases after the initial intra-patient dose escalation are 
subject to the same rules as for the initial intra-patient escalation. Consultation with the Sponsor 
must occur prior to any intra-patient dose escalation occurring. These changes must be recorded 
on the Dosage Administration Record eCRF. 
6.2.5 
Definitions of dose limiting toxicities (DLTs) 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as at least possibly related to the study medication, as clinically relevant, as unrelated 
to disease, disease progression, inter-current illness, or concomitant medications, which occurs 
≤ 28 days following the first dose of LGX818 and MEK162 or LGX818 and MEK162 and 
LEE011 (Cycle 1) and meets any of the criteria listed in Table 6-3, as applicable. Toxicity will 


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be assessed using the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 
4.03 unless otherwise specified. 
Whenever a patient experiences toxicity that fulfills the criteria for a DLT, treatment with the 
study drug combination will be interrupted and the toxicity will be followed up as described in 
Section 6.2.6. For the purposes of dose escalation and determination of the MTD, DLTs that 
occur during the first cycle will be necessarily considered and included in the BLRM, including 
those in which the event has started in cycle 1 and the confirmation of the DLT occurs in 
subsequent cycles. 
The investigator must notify the Sponsor immediately of any DLT observed. The investigator 
must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 adverse events or 
laboratory abnormalities. 
The rules for re-initiation and dose modification of LGX818 and MEK162 or LGX818 and 
MEK162 and LEE011 treatment are outlined in Section 6.3. 
Table 6-3 
Criteria for defining dose-limiting toxicities for dual and triple 
combination 
 
Toxicity 
Any of the following criteria: 
Blood and lymphatic system 
disordersa 
Febrile neutropenia (ANC  1.0 x 109/L with fever  38.5°C)b 
Investigations (Blood) 
Absolute Neutrophil count CTCAE Grade 3 for > 7 consecutive days 
Absolute Neutrophil count CTCAE Grade 4 
Platelet count CTCAE Grade 3 for > 7 consecutive days and/or with signs of 
bleeding 
Platelet count CTCAE Grade 4 
Skin and subcutaneous 
tissue disorders: 
Rash, HFSR and/or 
photosensitivity 
Rash, HFSR or photosensitivity CTCAE Grade 3 > 7 consecutive days despite 
skin toxicity treatment (as per local practice) 
Rash, HFSR or photosensitivity CTCAE Grade 4 
Eye disorders-Retinopathy / 
Uveitis 
CSR/ CSR-like events CTCAE Grade 3 for > 21 consecutive days confirmed 
by ophthalmologic examination 
CSR/ CSR-like events CTCAE Grade 4 confirmed by ophthalmologic 
examination 
Eye disorders - RVO 
Any grade 
Eye disorders- any other 
CTCAE Grade 3 for > 14 consecutive days 
CTCAE Grade 4 
Gastrointestinal disorders 
Diarrhea CTCAE Grade ≥ 3 ≥ 48 hrs, despite the use of optimal anti-diarrhea 
therapy 
Nausea or vomiting CTCAE Grade ≥ 3 ≥ 48 hrs, despite the use of optimal 
anti-emetic therapy 
Pancreatitis CTCAE Grade ≥ 3 
Investigations (Renal) 
Serum creatinine CTCAE Grade ≥ 3 
Investigations (Hepatic)c 
Blood bilirubin (total bilirubin) CTCAE Grade ≥ 3 
AST or ALT CTCAE Grade ≥3 in conjunction with blood (total) bilirubin CTCAE 
Grade ≥ 2 of any duration 
AST or ALT CTCAE Grade 3 for > 7 consecutive days 
AST or ALT CTCAE Grade 4. 
Serum alkaline phosphatase CTCAE Grade 4 > 7 consecutive days 


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Toxicity 
Any of the following criteria: 
Investigations (Metabolic) 
Serum lipase and/or serum amylase (asymptomatic) CTCAE Grade 3 > 7 
consecutive days 
Serum lipase and/or serum amylase (asymptomatic) CTCAE Grade 4 
Cardiac disorders 
≥ CTCAE Grade 3 
Investigations (Cardiac) 
Serum CK/CPK CTCAE Grade 3 for > 14 consecutive days if clinically 
significant (symptomatic) 
Serum CK/CPK CTCAE Grade 4 for > 14 consecutive days 
QTcF interval ≥ 501 ms on at least two separate ECGs (only for triple 
combination) 
Vascular disorders 
Persistent hypertension CTCAE Grade ≥ 3 requiring more than one drug or 
more intensive therapy than previously 
General disorders and 
administration site conditions 
Fatigue CTCAE Grade 3 for > 7 consecutive days 
Edema CTCAE grade 3 for > 14 consecutive days 
Other Adverse Eventsd 
Any other CTCAE Grade ≥ 3 toxicity (except SCCe) 
a. ≥ CTCAE grade 3 anemia will not be considered a DLT unless judged to be a hemolytic process secondary 
to study drug. ≥ CTCAE grade 3 lymphopenia will not be considered a DLT unless clinically significant. 
b. Not according to CTCAEv4.03 
c. For any CTCAE grade ≥ 3 hepatic toxicity that does not resolve within 7 days to CTCAE Grade ≤ 1 (or 
CTCAE Grade ≤ 2 if liver infiltration with tumor present), an abdominal CT scan has to be performed to 
assess if it is related to disease progression. 
d. An AE must be clinically significant to be defined as a DLT: study drug-related fever, alkaline phosphatase 
elevation, electrolyte abnormalities (including K, NA, Cl, HCO3, Mg, Ca, PO4) that are CTCAE grade 3 
abnormalities will not be considered a DLT unless clinically significant. 
e. SCC has been reported to be an on-target side-effect that is manageable and will not be considered a DLT. 
6.2.6 
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 up 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 such as an ophthalmologist, dermatologist or cardiologist should 
be consulted as deemed necessary. Further guidelines and recommendations for the 
management of specific study drug combination induced toxicities are provided in Table 6-4. 
6.2.6.1 
Follow-up evaluations for appearance of keratoacanthoma (KA) and/or 
squamous cell carcinoma (SCC) 
The skin of patients treated with the LGX818 and MEK162 or LGX818 and MEK162 and 
LEE011 combination will be examined regularly to monitor for the possible development of 
KA and/or SCC, as these have been reported to occur under selective BRAF inhibitor treatment 
(see Section 1.2.4.2). Dermatologic evaluations for this adverse effect will be performed at 
Screening/baseline, every 2 months thereafter and at End of Treatment. 
In case of occurrence of KA and/or SCC, patients will undergo complete surgical excision of 
the skin lesion following institutional standards. 


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6.2.6.2 
Follow-up evaluations for appearance of central serous retinopathy 
(CSR) 
The patients treated with the LGX818 and MEK162 or LGX818 and MEK162 and LEE011 
combination will be examined regularly to monitor for the possible development of CSR, as the 
appearance of CSR has been associated with MEK162 treatment (see Section 1.3). 
Ophthalmologic examinations to check for this adverse effect will be performed at 
Screening/baseline, at Day 15 of Cycle 1, at Days 1 and 15 of Cycle 2, on Day 1 of every month 
thereafter and at End of Treatment. 
Patients 
who 
have 
been 
on 
LGX818/MEK162 
dual-combination 
and 
or 
LGX818/MEK162/LEE011 triple-combination treatment for ≥ 24 months (Cycle 25 Day 1 
onward) without a retinal AE should be evaluated for visual acuity at each scheduled patient 
visit and at the End of Treatment visit. A full ophthalmic examination is required if clinically 
indicated and at the End of Treatment visit. 
Patients developing a CTCAE grade 1 or 2 CSR can be maintained on the study drug 
combination as is detailed in Table 6-4. For these patients it is recommended to follow up the 
CSR with an ophthalmological exam every two weeks (CTCAE Grade 1) or weekly (CTCAE 
Grade 2) for 8 weeks, and subsequently at approximately a 4-weeks interval. The study drug 
dosages of patients developing CSR > CTCAE grade 2 should be interrupted/modified 
according to Table 6-4 and should be followed as described above (Section 6.2.6). 
6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
Patients will be monitored for adverse events at each visit with the NCI CTCAE version 4.03 
used for all grading. If a patient develops toxicity, the dose may be adjusted as outlined in Table 
6-4, which includes criteria for interruption and re-initiation of LGX818 and/or MEK162 and/or 
LEE011, as applicable. All dose modifications should be based on the worst preceding toxicity 
(CTCAE version 4.03). 
All dosing interruptions and changes must be recorded on the Dosage Administration Record 
eCRF. 
If a patient experiences a DLT, study treatment should be interrupted and the toxicity should be 
followed as described in Section 6.2.6. 
6.3.2 
Treatment interruption and treatment discontinuation 
Each patient is only allowed a maximum of two dose reductions after which the patient will be 
discontinued from the study treatment. In addition, a patient should discontinue treatment with 
the LGX818 and MEK162 dual or LGX818 and MEK162 and LEE011 triple combination if, 
after treatment is resumed at a lower dose, the toxicity recurs with the same or worse severity. 
However, the patient may continue to receive study treatment at the next lower dose level, if 
appropriate, at the discretion of the Investigator and in discussion with the Sponsor. If, after 
interruption of treatment and resolution, treatment is resumed at the same dose following the 
criteria in Table 6-4 and the same toxicity recurs with the same or worse severity, next treatment 
re-initiation must resume at the next lower dose level irrespective of duration. For each patient, 


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once a dose level reduction has occurred, the dose level may not be re-escalated during 
subsequent treatment cycles, except in cases where LGX818 dosing was reduced to 450mg QD 
during MEK162 dosing interruption. 
Dose reduction for LGX818 and/or MEK162 and/or LEE011, as applicable means treatment at 
the next lower dose level of the respective study drug. For LGX818 and LEE011, this is the 
next lower previously tested dose level. For MEK162 this is the next lower dose level (please 
see Table 6-1 and Table 6-2). If a patient requires a dose interruption of >21 days from the 
intended day of the next scheduled dose, then the patient must be discontinued from the study 
treatment unless the patient has experienced objective evidence of clinical benefit. If the patient 
has experienced objective evidence of clinical benefit, and in the opinion of the investigator it 
is in the best interest of the patient to remain on study, then following discussion with the 
sponsor, the patient may continue on study treatment. 


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Table 6-4 
Criteria for interruption and re-initiation of LGX818/MEK162/LEE011 triple-combination treatment 
 
Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
No toxicity 
Maintain dose level 
Blood and lymphatic system disorders 
Anemia (Hemoglobin) 
Grade 1 (≥10.0 – LLN g/dL) 
Grade 2 (≥8.0 – <10.0 g/dL) 
Grade 3 (<8.0 g/dL) 
Grade 4 (life threatening consequences; 
urgent intervention indicated) 
No dose adjustment required 
Interrupt LEE011 dosing until recovery to ≤ Grade 2; then re-initiate LEE011 at same dose level. Maintain dose 
level of LGX818 and MEK162. 
Discontinue patient from study drug treatment. 
Febrile neutropenia 
ANC < 1.0 x 109/L, fever ≥ 38.5°Cb 
Grade 3 (ANC <1.0 x 109/L with a single 
temperature of >38.3 ºC [101 ºF] or a sustained 
temperature of ≥38 ºC [100.4 ºF] for more than 
one hour) 
Grade 4 (life-threatening consequences; urgent 
intervention indicated) 
Interrupt dosing until resolved, then  1 dose level 
Interrupt dosing until improvement to ANC ≥ 1.0 x 109/L with no fever. 
Restart at the next lower dose level. 
If febrile neutropenia recurs, discontinue patient from study drug treatment. 
Discontinue patient from study drug treatment. 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations (Blood) 
Neutropenia (neutrophil count [ANC] decreased) 
Grade 1 (ANC < LLN – 1.5 x 109/L) 
Maintain dose level of LGX818 and MEK162 (and LEE011 if applicable) 
or Grade 2 (ANC < 1.5 – 1.0 x 109/L) 
Grade 3 (ANC < 1.0 – 0.5 x 109/L) 
Interrupt dosing of LGX818 and MEK162 (and LEE011 if applicable) until resolved to ≤ Grade 2, then: 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 (and LEE011 if applicable) 
-  If resolved in > 7 days, then  1 dose level* of LGX818 (and LEE011 if applicable) and maintain dose level 
of MEK162 
Grade 4 (ANC < 0.5 x 109/L) 
Interrupt dosing of LGX818 and MEK162 (and LEE011 if applicable) until resolved to ≤ Grade 2, then  1 dose 
level* of LGX818 and MEK162 (and LEE011 if applicable) 
Thrombocytopenia (platelet count decreased) 
Grade 1 (PLT < LLN – 75 x 109/L) 
Maintain dose level of LGX818 and MEK162 (and LEE011 if applicable) 
Grade 2 (PLT < 75 – 50 x 109/L) 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until 
resolved to ≤ Grade 1 
Grade 3 (PLT < 50 – 25 x 109/L) 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until 
resolved to ≤ Grade 1, then: 
-  If resolved in ≤ 7 days, then maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated 
in triple-combination arm). 
-  If resolved in > 7 days and/or with signs of bleeding, then  1 dose level* of LGX818 and MEK162 
(and LEE011 in patients treated in triple-combination arm) 
Grade 4 (PLT < 25 x 109/L) 
Discontinue patient from study drug treatment. 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Gastrointestinal disorders 
Diarrhea 
Grade 1 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm), 
but initiate anti-diarrhea treatment. 
Grade 2 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until 
resolved to Grade ≤ 1 with proper therapy and monitoring and then maintain dose level of LGX818 and 
MEK162 (and LEE011 in patients treated in triple-combination arm) 
- For 2nd occurrence of diarrhea Grade 2 within 15 days, interrupt dosing of LGX818 and MEK162 (and LEE011 
if applicable) until resolved to Grade ≤ 1, then reduce MEK162 and LGX818 (and LEE011 in patients treated 
in triple-combination arm) by 1 dose level* and maintain dose level of LGX818 (and LEE011 in patients 
treated 
in triple-combination arm) 
Grade 3 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until 
resolved to Grade ≤ 1, then reduce dose of LGX818 and MEK162 (and LEE011 in patients treated in triple- 
combination arm) by 1 dose level*. 
Grade 4 
Discontinue patient from study drug treatment. 
Note: Anti-diarrhea medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea. 
Nausea / Vomiting 
Grade 1 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
Grade 2 
Interrupt dosing until recovery to G1 with proper therapy and monitoring – Re-initiate MEK162 and LGX818 
(and LEE011 in patients treated in triple-combination arm) at same dose level – If recurs at G2, interrupt dosing 
of MEK162 and LGX818 (and LEE011 in patients treated in triple-combination arm) until recovery to G1 
and then re-initiate at next lower dose level 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Nausea / Vomiting (continued) 
Grade 3 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm), until 
resolved to Grade ≤ 1, then  1 dose level* of LGX818 and MEK162 (and LEE011 in patients treated in triple- 
combination arm) 
Grade 4 
Discontinue patient from study drug treatment. 
Note: Interrupt dosing for ≥ grade 3 vomiting or nausea only if the vomiting or nausea cannot be controlled with optimal antiemetics (as per local practice). 
Pancreatitis 
Grade 1 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
Grade 2 
Interrupt dosing until recovery to G1 with proper therapy and monitoring – Re-initiate MEK162 and LGX818 
(and LEE011 in patients treated in triple-combination arm) at same dose level – If recurs at G2, interrupt dosing 
of MEK162 and LGX818 (and LEE011 in patients treated in triple-combination arm) until recovery to G1 and 
then re-initiate at next lower dose level 
Grade ≥3 
Discontinue patient from study drug treatment. 
Investigations (Renal) 
Serum creatinine 
Grade 1 (> ULN – 1.5 x ULN) 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
Grade 2 (> 1.5 – 3.0 x ULN) 
Interrupt dosing until recovery to G1 with proper therapy and monitoring – Re-initiate MEK162 and LGX818 
(and LEE011 in patients treated in triple-combination arm) at same dose level – If recurs at G2, interrupt dosing 
of MEK162 and LGX818 (and LEE011 in patients treated in triple-combination arm) until recovery to G1 and 
then re-initiate at next lower dose level 
Grade ≥3 
Discontinue patient from study treatment. 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations (Hepatic**) 
Bilirubin: total bilirubin without ALT/AST increase above baseline value (confirmed 48-72hr later)c 
 
Grade 1 (> ULN – 1.5 x ULN) 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) with 
LFTs monitored bi-weekly. 
Grade 2 (> 1.5 – 3.0 x ULN) 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until 
resolved to Grade ≤ 1, then: 
- If resolved in ≤ 21 days, then maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated 
in triple-combination arm) 
- If resolved in > 21 days, then  1 dose level* of LGX818 and MEK162 (and LEE011 in patients treated 
in triple-combination arm) 
- If not resolved within 28 days, or if toxicity recurs, discontinue patient from all study drug treatment. 
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after dose resumption. 
Grade 3 (> 3.0 x ULN) 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until 
resolved to Grade ≤ 1, then  1 dose level 
- Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after dose resumption 
- If not resolved within 28 days, or if toxicity recurs, discontinue patient from all study drug treatment. 
Grade 4 (> 10.0 x ULN) 
Discontinue patient from study treatment. 
Note: If Grade 3 or 4 hyperbilirubinemia 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. 
AST or ALT without bilirubin elevation > 2 ULN (confirmed 48-72hr later)c 
 
Grade 1 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
and monitor LFTs biweekly. 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
AST or ALT without bilirubin elevation > 2 ULN (confirmed 48-72hr later)c (continued) 
 
Grade 2 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until 
resolved to Grade ≤ 1 (or Grade ≤ 2 in case of liver metastasis), then: 
- If resolved in ≤ 21 days, maintain dose level of LGX818 and MEK162 (and LEE011 for triple-combination 
arm). 
- If resolved in > 21 days, then  1 dose level* of LGX818 and MEK162 (and LEE011 for triple-combination 
arm). 
- If not resolved within 28 days, discontinue patient from all study drug treatment. 
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after dose resumption. 
Grade 3 (> 3.0 x ULN) 
Omit dose of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until resolved 
to ≤ baseline grade, then  1 dose level of dose level of LGX818 and MEK162 (and LEE011 in patients treated 
in triple-combination arm). If not recovered to ≤ baseline grade within 28 days, discontinue patient from all 
study drug treatment. 
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after dose resumption. If toxicity 
recurs, discontinue patient from all study drug treatment. 
Grade 4 (> 10.0 x ULN) 
Discontinue patient from study drug treatment. 
AST or ALT and Bilirubind 
 
For patients with normal ALT and AST and total 
Discontinue patient from study drug treatment. 
bilirubin at baseline: AST or ALT > 3.0 x ULN 
combined with total bilirubin > 2 x ULN without 
evidence of cholestasise 
For patients with elevated AST or ALT or total 
Discontinue patient from study drug treatment. 
bilirubin at baseline: baseline: (AST or ALT 
> 2 x baseline AND > 3.0 x ULN) OR (AST or ALT 
8.0 x ULN) — whichever is lower — combined 
with (total bilirubin > 2 x baseline AND > 2.0 x 
ULN) 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations (Metabolic) 
Asymptomatic amylase and/or lipase elevation 
Grade 1 (> ULN – 1.5 x ULN) 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
and initiate appropriate medical therapy and monitoring. 
Grade 2 (> 1.5 – 2.0 x ULN) 
Interrupt dosing until recovery to G1 with proper therapy and monitoring – Re-initiate MEK162 and LGX818 
(and LEE011 in patients treated in triple-combination arm) at same dose level – If recurs at G2, interrupt dosing 
of MEK162 and LGX818 (and LEE011 in patients treated in triple-combination arm) until recovery to G1 and 
then re-initiation at next lower dose level. 
Grade 3 (> 2.0 – 5.0 x ULN) 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until 
resolved to Grade ≤ 2, then: 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated 
in triple-combination arm) 
- If resolved in  7 days,  1 dose level* of LGX818 and MEK162 (and LEE011 in patients treated 
in triple-combination arm). 
Grade 4 (> 5.0 x ULN) 
Discontinue patient from study drug treatment. 
Note: 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. In cases of asymptomatic elevations of lipase and/or amylase with imaging study which does not show damage to pancreas, liver, 
and gallbladder, if the patient is asymptomatic Grade 2 elevations of lipase and/or amylase occur again at the reduced dose, patients will be discontinued 
permanently from study treatment. 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Cardiac disorders 
Cardiac general 
Grades 1 or 2 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
Grade 3 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until 
resolved to Grade ≤ 1, then  1 dose level* of LGX818 and MEK162 (and LEE011 for triple-combination arm) 
Grade 4 
Discontinue patient from study drug treatment. 
Investigations (cardiac) 
Creatine phosphokinase (CPK) 
Grade 1 (> ULN – 2.5 x ULN) 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
or Grade 2 (> 2.5 – 5.0 x ULN) 
Grade 3 (> 5.0 – 10.0 x ULN) 
If asymptomatic: Maintain dose level of LGX818 and MEK162 (and LEE011 in triple-combination arm) 
If symptomatic: Interrupt dosing of MEK162 and maintain dose of LGX8181 (and LEE011 in patients treated 
in triple-combination arm) until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 14 days, then  1 dose level* of MEK 162 and maintain dose level of LGX8182 (and LEE011 
in patients treated in triple-combination arm) 
- If unresolved after > 14 days, then discontinue patient from study drug treatment. 
Grade 4 (> 10.0 x ULN) 
Interrupt dosing of MEK162 and maintain dose of LGX8181 (and LEE011 in triple-combination arm) until 
resolved to CTCAE Grade ≤ 1, then: 
- If resolved in ≤ 14 days, then  1 dose level of MEK162 and maintain dose level of LGX8182 (and LEE011 
in patients treated in triple-combination arm) 
- If unresolved after > 14 days, then discontinue patient from study drug treatment. 
1 If the LGX818 dose is > 450mg QD, then the LGX818 dose must be reduced to 450mg QD during the MEK162 dosing interruption. 
2 If the LGX818 dose was reduced to 450mg QD during an MEK162 interruption, it must be re-escalated to the previous dose once MEK162 dosing resumes. 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Left ventricle (LV) systolic dysfunction (not according to CTCAE) 
Asymptomatic decrease of > 10% in left ventricle 
Interrupt dosing of MEK162 until LVEF recovers (defined as ≥ LLN and decrease ≤ 10% compared to baseline). 
ejection fraction (LVEF) compared to baseline 
- If the LVEF recovers ≤ 21 days, then  1 dose level of MEK162, maintain dose of LGX818 and LEE011 
and the ejection fraction is below the institution’s 
in patients treated in triple-combination arm, monitor LVEF 2 weeks after restarting on MEK162, 
lower limit of normal and CTCAE Grade 2 
every 4 weeks for 12 weeks and subsequently as per protocol 
- If the LVEF recovers > 21 days, then discontinue patient from study drug treatment and closely monitor LVEF 
until resolution (or for 16 weeks). 
Grade ≥ 3 
Discontinue patient from study drug treatment. 
Electrocardiogram QTcF interval prolonged 
Grade 1 (QTcF 450-480 ms)f 
Maintain dose level(s). Perform steps 1-4 as directed in “For all grades.” 
Grade 2 (QTcF 481-500 ms)f 
Interrupt dosing of MEK162 and LGX818 (and LEE011 in patients treated in triple-combination arm). Perform 
steps 1-4 as directed in “For all grades.” 
Perform a repeat ECG within 1 hour of the first QTcF of ≥ 481 ms. Repeat ECG as clinically indicated until the 
QTcF returns to < 481 ms, restart MEK162 and LGX818 at the same dose (if triple combination, restart LEE011 
with dose reduced one level. 
If QTcF ≥ 481 ms recurs, MEK162 and LGX818 (and LEE011 in patients treated in triple-combination arm) 
should be reduced by 1 dose level. 
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically indicated) for any patients 
who had therapy interrupted due to QTcF ≥ 481 ms. 
Grade 3 (QTcF ≥ 501 ms on at least 
Interrupt dosing of MEK162 and LGX818 (and LEE011 in triple-combination arm). Perform steps 1-4 as 
two separate ECGs)f 
directed in “For all grades.” 
Transmit ECG immediately and confirm prolongation/abnormalities with central assessment. Perform a repeat 
ECG within one hour 
of the first QTcF of > 501 ms. 
If QTcF remains ≥ 501 ms, consult with a cardiologist (or qualified specialist) and repeat cardiac monitoring as 
clinically indicated until the QTcF returns to < 481 ms. 
• If QTcF returns to < 481 ms, reduce MEK162 and LGX818 (and LEE011 in triple-combination arm) by 1 
dose level. 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
• If QTcF remains ≥ 481 ms after performing steps 1-4 as directed in “For all grades,” discontinue all study 
treatments. 
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically indicated) for any patients who had 
therapy interrupted due to QTcF ≥ 501 ms 
If QTcF of ≥ 501 ms recurs, discontinue patient from study drug treatment. 
Electrocardiogram QTcF interval prolonged (continued) 
Grade 4 g (QTcF ≥ 501 or > 60 ms change 
Discontinue patient from study drug treatment, then: 
from baseline and Torsades de pointes 
- Obtain local cardiologist consultation. 
or polymorphic ventricular tachycardia, 
- Perform a repeat ECG within one hour of the first QTcF of ≥ 501 ms. 
or signs/symptoms of serious arrhythmia) 
- If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but at least once a day until the QTcF 
returns to < 501 ms. 
For all grades: 
• 
Check the quality of the ECG and the QT value and repeat if needed. 
• 
Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If outside of the normal range, interrupt LGX818 and MEK162 and LEE011 administration, correct 
with supplements or appropriate therapy as soon as possible, and repeat electrolytes until documented as normal. 
• 
Review concomitant medication usage for the potential to inhibit CYP3A4 and/or to prolong the QT interval. 
• 
Check compliance with correct dose and administration of LGX818 and MEK162 and LEE011. 
Vascular disorders 
Hypertension 
Grade 1 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
Grade 2 
Interrupt dosing until recovery to G1 with proper therapy and monitoring – Re-initiate study drugs at same dose 
level. 
If recurs at G2, interrupt study drugs until recovery to G1 and then re-initiate at next lower dose level. 
Grade 3 (requiring more than one drug or more 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in triple-combination arm), until resolved to Grade ≤ 1, 
intensive therapy than previously) 
then  1 dose level* of LGX818 and MEK162 (and LEE011 in triple-combination arm) 
Grade 4 (life-threatening) 
Discontinue patient from study drug treatment. 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Eye disorders 
Retinal events 
Grade 1 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
and increase frequency of ophthalmic monitoring to at least every 14 days (see also Section 6.2.6.2). 
Grade 2 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
and increase frequency of ophthalmic monitoring to at least weekly (see also Section 6.2.6.2). Refer 
the patient to a retinal specialist within one week for further evaluation. 
- If resolved to Grade ≤ 1 in ≤ 21 days, then maintain dose level of MEK162 and LGX818 (and LEE011 
in patients treated in triple-combination arm) 
- If not resolved to Grade ≤ 1 in ≤ 21 days, then  1 dose level* of MEK162 and LGX818 (and maintain dose 
of LEE011 in patients treated in triple-combination arm). 
- At any time if symptoms worsen, or persist with the same severity for more than 7 days, reduce 1 dose 
levelf of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm). 
Grade 3 
Interrupt dosing of LGX818 and MEK162, (and LEE011 if applicable) until recovery to Grade 1. Re-initiate 
study drugs at next lower dose level. If recurs at Grade 3, discontinue patient from study. 
- If resolved to Grade ≤ 1 in ≤ 21 days, then  1 dose level* of MEK162 and LGX818 (and maintain dose level 
of LEE011 in patients treated in triple-combination arm) 
- If not resolved to Grade ≤ 1 in ≤ 21 days, then discontinue patient from study drug treatment and refer 
the patient to an ophthalmologist for monitoring. 
Grade 4 (retinopathy) 
Discontinue patient from study drug treatment and refer the patient to an ophthalmologist for monitoring.g 
Note: Results and images of ophthalmic examinations must be made available upon request. This includes scans/images of OCTs 
Retinal vein occlusion (RVO)h 
Any grade 
Discontinue patient from study drug treatment and refer the patient to an ophthalmologist for monitoring. 
Note: Results and images of ophthalmic examinations should be made available upon request. 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Other eye events (i.e. retinal detachment) 
Grades 1 or 2 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
and increase frequency of ophthalmic monitoring to at least every 14 days. 
At any time if symptoms worsen, or persist with the same severity for more than 7 days, reduce 1 dose level 
of LGX818 and MEK162.c 
Grade 3 
Interrupt dosing of LGX818 and MEK162 (and maintain dose level of LEE011 in patients treated in triple- 
combination arm) and refer patient to ophthalmologist monitoring within one week.g 
- If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose levelh of LGX818 and MEK162 
- If not resolved to Grade ≤ 1 in > 21 days, discontinue patient from study drug treatment and refer the patient 
to an ophthalmologist for monitoring.h 
Grade 4 
Discontinue patient from study drug treatment and refer the patient to an ophthalmologist for monitoring.g 
Skin and subcutaneous tissue disorders 
Rash / hand foot skin reaction (HFSR) / photosensitivity / Toxic Epidermal Necrolysis (TEN) 
Grade 1 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm), 
but consider initiating appropriate skin toxicity therapy (See Appendix 3). 
Grade 2 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm), 
but initiate/intensify appropriate skin toxicity therapy. 
Grade 3 despite skin toxicity therapy 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm), 
until resolved to Grade ≤ 1 then: 
- If resolved in ≤ 7 days,  1 dose level* of LGX818 and MEK162 (and LEE011 in triple-combination arm) 
- If not resolved after  7 days, discontinue patient from study drug treatment. 
Grade 4 despite skin toxicity therapy 
Discontinue patient from study drug treatment. 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Respiratory, thoracic and mediastinal disorders 
ILD/Pneumonitis 
Maintain dose level of LGX818; adjust dose of MEK162 (and LEE011 in patients treated in triple-combination 
arm) according to Grade below 
Grade 1 
No dose interruption or adjustment of MEK162 (or LEE011 in patients treated in triple-combination arm) is 
required. Initiate appropriate medical therapy and monitor as clinically indicated 
Grade 2 
Interrupt dosing of MEK162 (and LEE011 in patients treated in triple-combination arm) for ≤ 21 days. 
-If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose levelh of MEK162 (and LEE011 in patients treated 
in triple-combination arm), performing an individualized benefit-risk assessment 
-If not resolved to Grade ≤ 1 in ≤ 21 days, then discontinue patient from study drug treatment. 
If Grade 2 recurs, discontinue patient from study drug treatment 
Grade 3/4 
Discontinue patient from study drug treatment 
General disorders and administration site conditions 
Fatigue 
Grades 1 or 2 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
Grade 3 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 (and LEE011 in triple-combination arm) 
- If not resolved after  7 days, then  1 dose level* of LGX818 and MEK162 (and LEE011 in patients treated 
in triple-combination arm) 
Edema 
Grades 1 or 2 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Grade 3 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 14 days, then  1 dose level* of MEK162 and maintain dose of LGX818 (and LEE011 
in patients treated in triple-combination arm) 
- If not resolved after  14 days, then discontinue patient from study drug treatment. 
Other adverse events 
Grades 1 or 2 
Maintain dose level of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) 
Grade 3 
Interrupt dosing of LGX818 and MEK162 (and LEE011 in patients treated in triple-combination arm) until 
resolved to Grade ≤ 1, then  1 dose level* of LGX818 and MEK162 (and LEE011 in triple-combination arm) 
Grade 4 
Discontinue patient from study drug treatment. 
a All dose modifications should be based on the worst preceding toxicity. 
b Not CTCAE grading 
c Dose reduction below 50 mg QD for LGX818, and below 15 mg BID for MEK162 is not allowed. 
d All patients with ALT or AST >5.0x ULN and total bilirubin > 1.5x ULN in the absence of cholestasis must immediately be withdrawn from study treatment and every 
attempt should be made to carry out the liver event follow-up assessments as described below in Section 6.3.3. 
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 
e “Cholestasis” defined as: ALP elevation (>2.0 x ULN and R value (ALT/ALP in x ULN) ,2.0) in patients without bone metastasis, or elevation of ALP liver function in 
patients with bone metastasis. 
f All values refer to the average of triplicate measurements. 
g Ophthalmic monitoring mandated for retinal event, posterior uveitis, RVO: further evaluation with specialized retinal imaging (e.g. ocular coherence tomography, 
angiography). 
h Except: 1) lymphopenia unless clinically significant, 2) occurrence of KA and/or cutaneous SCC, 3) alkaline phosphatase, 4) AEs not considered clinically significant 
like alopecia study drug-related fever, electrolyte abnormalities (including K, NA, Cl, HCO3, Mg, Ca, PO4). 
*  1 dose level refers to: next lower previously tested dose level of LGX818 and LEE011 and the next lower dose level of MEK162 (please see Table 6-1 and Table 6- 
2). 


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Recommended Dose Modifications for (dual) LGX818 and MEK162 or (triple) LGX818 and MEK162 and LEE011 
combination study treatment 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
** Confounding factors and/or alternative causes for increased transaminases should be excluded before dose interruption/reduction. They include but are not limited 
to: concomitant medications, herbal preparations or dietary supplements, infection, hepato-biliary disorder or obstruction, new or progressive liver metastasis, and 
alcohol intake. 


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6.3.3 
Additional follow-up for hepatic toxicities in patients receiving LEE011 
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin 
(fractionated if total bilirubin > 2 x ULN), alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher) and GGT. For patients with Gilbert Syndrome: total and direct 
bilirubin must be monitored, intensified monitoring applies to changes in direct bilirubin only. 
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring 
dose interruption, which involves: 
• Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of 
re-testing can decrease to once a week or less if abnormalities stabilize or return to normal 
values. 
• Obtaining a more detailed history of current symptoms. 
• Obtaining a more detailed history of prior and/or concurrent diseases, including history of 
any pre-existing liver conditions or risk factors. 
• Obtaining a history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplements), alcohol use, recreational drug use, and special diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections (CMV, 
EBV or HSV); autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; 
and biliary tract disease. 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
• Considering gastroenterology or hepatology consultations. 
• Assessing cardiovascular dysfunction or impaired liver oxygenation, including hypotension 
or right heart failure as possible etiologies for liver dysfunction. 
• Considering a liver biopsy, as clinically indicated to assess pathological change and degree 
of potential liver injury. 
6.4 
Concomitant medications 
6.4.1 
Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug combination. All medications (other than study drugs) and 
significant non-drug therapies (including herbal medicines, physical therapy and blood 
transfusions) administered during the study must be listed on the Concomitant 
medications/Significant non-drug therapies eCRF. 
Patients taking concomitant medication chronically should be maintained on the same dose and 
dose schedule throughout the study period, as medically feasible. The days of full PK blood 
sampling should be representative of the other study days with regard to the use of the 
chronically administered concomitant medications. However, if a concomitant medication is 
used intermittently during the study, this medication should be avoided on the days of full PK 
sampling, if medically feasible. 


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The use of bisphosphonates regardless of indication is allowed for the LGX818 and MEK162 
dual combination (prophylactic treatment is not allowed for bisphosphonates with LEE011) 
provided patients have been on stable doses for at least 2 weeks prior to study entry. Stable 
doses should be maintained during the treatment period. Patients requiring initiation of 
bisphosphonates during the course of the study should be discontinued due to progressive 
disease unless disease progression can be completely ruled out and this is clearly documented 
in the patients’ source documentation. 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to 
induction of CYP3A enzymes, thereby potentially increasing the risk of reducing drug exposure 
for CYP3A substrates to subtherapeutic levels. The following forms of corticosteroid treatment 
are permitted: 
• Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airway diseases), eye drops, 
or local injections (e.g., intra-articular); 
• A short duration (< 5 days) of systemic corticosteroids ≤ to the anti-inflammatory potency 
of 4 mg dexamethasone (e.g., for chronic obstructive pulmonary disease, or as an 
antiemetic). 
Refer to the LGX818 Investigator’s Brochure, MEK162 Investigator’s Brochure and LEE011 
Investigator’s Brochure as applicable for information on possible interactions with other drugs. 
Approved Covid-19 vaccines are permitted, including those under an EUA. The timing of 
COVID-19 vaccine administration is at the investigator’s discretion. The administration of a 
COVID-19 vaccine would be recorded as a concomitant medication and standard AE collection 
and reporting processes would be followed. 
 
 
6.4.2 
Permitted concomitant therapy requiring caution and/or action for 
LGX818 and MEK162 
LGX818 is a reversible inhibitor of CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, CYP3A4, and 
UGT1A1. It is also a time dependent inhibitor of CYP3A4. Permitted medications to be used 
with caution in this study include those that are sensitive substrates of CYP1A2, CYP2B6, 
CYP2C8/9, CYP2D6, CYP3A4, and UGT1A1, or those substrates that have a narrow 
therapeutic index (NTI). 
There is a potential for LGX818 to induce CYP3A4 at concentrations >10-50 uM, which may 
reduce the effectiveness of hormonal contraception methods. Therefore, the use of at least one 
form of non-hormonal contraception will be needed during the participation in this study. Please 
see Section 5.3 exclusion criterion 10 for use of contraception methods required for this study. 
LGX818 has been identified to be primarily metabolized by CYP3A4 in vitro. It is advised that 
LGX818 should be taken with caution when co-administered with moderate inhibitors of 
CYP3A4 or strong inducers of CYP3A4 (NB. strong systemic inhibitors of CYP3A4 are 
prohibited (please see Section 6.4.3). 
In vitro data showed that both LGX818 and MEK162 are substrates of P-gp. Thus, the use of 
drugs that are known to inhibit or induce P-gp should be used with caution. LGX818 is a BCRP 


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and P-gp inhibitor. It is also a potent inhibitor of the renal transporters OAT1, OAT3 and OCT2 
and the hepatic transporters OATP1B1 and OATP1B3. Therefore the co-administration of 
drugs that are known to be sensitive or NTI substrate of BCRP, P-gp, OAT1, OAT3, OCT2, 
OATP1B1, and OATP1B3 should be used with caution. 
MEK162 is a substrate for many CYP isoforms, in particular CYP1A2 and CYP2C19. The risk 
of metabolic interaction caused by an effect on an individual isoform is therefore minimized. 
Nevertheless, caution should be used in patients receiving concomitant treatment with other 
drugs that are either potent inhibitors or inducers of these enzymes. 
Patients receiving such medications above must be carefully monitored for potentiating of 
toxicity due to any individual concomitant medication, and may require dose titration of the 
drug substance. Investigators should use caution when prescribing co-medications, as clinical 
experience with these compounds in patients with cancer is often limited. Investigators should 
contact the Sponsor when they are unsure whether a drug should be prescribed to a patient in 
the clinical study. All concomitant medications and dietary supplements must be documented 
on the eCRFs. Please refer to Appendix 4 for a list of medications to be used with caution as 
mentioned above. 
6.4.2.1 
Additional permitted concomitant therapy requiring caution and/or 
action for addition of LEE011 in the triple combination 
LEE01 is a moderate substrate of P-glycoprotein (P-gp). LEE011 is a weak reversible inhibitor 
of CYP1A2. It is recommended that substrates metabolized predominantly by CYP1A2 with a 
narrow therapeutic index be taken with caution. LEE011 was found to inhibit the mitoxantrone- 
resistant protein (MXR or BCRP), and human bile salt export pump (BSEP). Medications to 
be used with caution during triple-combination treatment with LEE011 in this study are listed 
below (see Appendix 4, as this list is not comprehensive and is only meant to be used as a guide. 
Please contact the medical monitor with any questions). These medications should be excluded 
from patient use if possible. If they must be given based on the investigator’s judgment, then 
use with caution and consider a LEE011 interruption if the concomitant medication is only 
needed for a short time. 
• Moderate inhibitors or inducers of CYP3A4/5 (may increase or decrease LEE011 
exposure, respectively) 
• Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index (LEE011 may 
increase exposure to these medications) 
• Strong inhibitors of BSEP (based on in vitro data co-administration with LEE011 may 
lead to intrahepatic cholestasis) 
• Medications that carry a possible risk for QT prolongation (may precipitate QT 
prolongation and TdP) 
• Sensitive substrates of the renal transporters, MATE1, OCT2 and BCRP (has a potential to 
increase exposure to substrates of these transporters, although no animal or clinical data are 
available to support these statements) 
• Strong inhibitors/inducers of P-gp. 


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6.4.3 
Prohibited concomitant therapy dual and triple combination 
• Other investigational therapies must not be used while the patient is on study treatment. 
• Anticancer therapy (chemotherapy, biologic or radiation therapy, palliative radiotherapy 
covering > 25% of the bone marrow reserve, and surgery) other than the study treatment 
must not be given to patients while the patient is on study treatment. If such agents are 
required for a patient, then the patient must be withdrawn from the study. 
• The concomitant use of strong systemic CYP3A4 inhibitors would likely significantly 
increase the exposure of LGX818 and thus should not be used during this study (please 
refer to Table 14-10 in Appendix 4 for a partial list of CYP3A4 inhibitors). 
6.4.3.1 
Additional prohibited concomitant therapy for addition of LEE011 in 
the triple combination 
• Prophylactic treatment with bisphosphonates is not allowed with LEE011. 
• Strong inhibitors or inducers of CYP3A4/5 (may significantly increase or decrease 
ribociclib exposure, respectively) 
• Substrates of CYP3A4/5 with a narrow therapeutic index (LEE011 may increase exposure 
to these medications resulting in toxicity to these medications) 
• Medications with a known risk for QT prolongation and/or TdP (may precipitate QT 
prolongation and TdP in combination with LEE011). See Table 14-12 and the LEE011 
Investigator’s Brochure for a complete list of agents that are known to cause QTc 
prolongation in humans. 
• Other investigational and antineoplastic therapies 
• Herbal preparations/medications that are strong inhibitors or inducers of CYP3A4/5. 
These include but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and 
ginseng. Patients should stop using all herbal medications and dietary supplements at least 
7 days prior to first dose of study treatment. 
 
See Appendix 4 for a partial list of CYP3A4 substrates or inducers. 
6.5 
Patient numbering, treatment assignment and randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient has signed the Molecular pre-screening Informed Consent Form (if applicable) or 
Study Informed Consent Form 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 the Sponsor to the investigative site) with a sequential patient number 
suffixed to it, so that each subject is numbered uniquely across the entire database. 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 screening for any reason, the reason will be entered into the Screening log 
eCRF. 


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6.5.2 
Treatment assignment and randomization 
The assignment of a patient to a particular cohort will be coordinated by the sponsor. 
No randomization will be performed in this study. 
6.6 
Study drug supply 
6.6.1 
Study drug preparation and dispensation 
The Investigator needs to instruct the patient to take the study drugs as per protocol. The 
investigational drugs to be used in this trial are: 
• LGX818, supplied as capsules for oral use of dosage strengths of 10, 25, 50 and 100 mg. 
• MEK162, supplied as film-coated tablets for oral use of dosage strength 15 mg. 
• LEE011, supplied as capsules for oral use of dosage strength of 50 and 200 mg. 
Other strengths might be made available during development of the study drugs if deemed 
necessary. 
All dosages prescribed to the patient and all dose changes during the study must be recorded on 
the Dosage Administration Record eCRF. 
As of protocol amendment 3, two new MEK162 tablet variants were introduced as described in 
the Amendment 3 rationale and Section 6.2.3: 
• MEK162 smaller tablet 
• new MEK162 tablet variant 
Both new tablet variants are available in a 15 mg dosage strength. 
6.6.2 
Study drug packaging and labeling 
LGX818 capsules, MEK162 tablets and LEE011 capsules are packaged in HDPE bottles with 
child resistant closures. 
Study drug labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug but no information about the patient. 
As of protocol amendment 3, the MEK162 smaller tablet and new MEK162 tablet variant as 
described in this protocol, will be distinguishable by the following naming on the study drug 
labels: 
• MEK162 15mg_NVS FMI (refers to the MEK162 smaller tablet). 
• MEK162 15mg_NVS CSF (refers to the new MEK162 tablet variant). 
6.6.3 
Drug supply and storage 
Study drugs will be centrally supplied by the Sponsor or a Sponsor-designated CRO, and must 
be received by a designated person at the study site, handled and stored safely and properly, and 
kept in a secured location to which only the investigator and designated assistants have access. 
Upon receipt, the study drugs should be stored according to the instructions specified on the 
drug labels. 


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6.6.4 
Study drug compliance and accountability 
6.6.4.1 
Study drug compliance 
At the day of a scheduled visit to the clinic, the patient will take the study drugs under 
supervision of the Investigator or designee. The time of dose administration must be recorded 
in the Dose Administration Record eCRF. For all other study days, the patient will take the 
study drugs at home. 
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. 
Patients will be instructed to write down the date and time of administration in a patient diary 
provided by the sponsor. The investigator or designee must check compliance and note any drug 
interruptions in the Dose Administration record page of the eCRFs. 
6.6.4.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment (including Lot numbers) according to local institutional guidelines for drug 
accountability. 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 to the Sponsor’s monitor or to the Sponsor address provided in the investigator 
folder at each site. 
6.6.5 
Disposal and destruction 
The drug supply can be returned to and destroyed by the clinical supply vendor, as appropriate. 
Study drug destruction at the investigational site will only be permitted if authorized by the 
Sponsor in a prior agreement and if permitted by local regulations. 
 
7 
Visit schedule and assessments 
[Any language regarding the triple combination of LGX818/MEK162/LEE011 in this 
Section is not applicable to the USA and Singapore] 
7.1 
Study flow and visit schedule 
Note: As of protocol amendment 10, all efficacy and safety assessments will be completed 
per local standard-of-care, or otherwise as clinically indicated. See Table 7-2. 
Table 7-1 and Table 7-2 list all of the assessments and indicates with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the patient’s 


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source documentation. The table indicates which assessments produce data to be entered into 
the database (D) or remain in source documents only (S) (“Category” column). 
All screening assessments must be completed within 14 days before the first dose, with the 
exception of pregnancy test, which must be performed within 72 hrs before the first dose. The 
Screening/baseline imaging assessments must be completed within 21 days before first dose of 
study treatment, except whole-body bone scans, if applicable, which can be performed within 
6 weeks of study treatment start. For PK sampling, the samples may be obtained ± 1 day from 
the scheduled date (except for PK sampling on Cycle 1 Day 1) under the LGX818 QD or BID 
dosing schedule. In case QOD dosing would be introduced for LGX818, the PK sampling must 
be performed on the specified day of dosing. For all other on-treatment visits, there is a ± 3-day 
window on assessments to take into account scheduling over public or religious holidays if not 
explicitly specified otherwise. For on-study imaging assessments, a ± 7 day window is allowed, 
except for the tumor assessment on C1D28 which must be performed between week 3 and 4 
after starting the study drug combination (C1D28 tumor assessment not applicable for Phase II 
parts). Patients who have been on the LGX818/MEK162 dual-combination and 
LGX/MEK162/LEE011 triple-combination treatment for ≥ 24 months (Cycle 25 Day 1 
onwards) will be evaluated for all potential sites of tumor lesions every 8-12 weeks (± 7 days) 
until disease progression. Every effort must be made to follow the schedule outlined in Table 
7-1 and Table 7-2. 
Assessments which are indicated to be performed at Screening/baseline and on Cycle 1 Day 1, 
need only to be repeated at Cycle 1 Day 1 if Screening/baseline assessment was more than 3 
days earlier. 


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Table 7-1 
Visit evaluation schedule 
 
Category 
Reference to Section 
Molecular 
Pre-Screening 
Screening /Baseline 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
30-day safety FUm 
Disease progression 
FU (Phase II only) 
SECa 
Survival FU (Phase II 
only) 
Visit Name 
1 
2 
3 
4 
5 
6 
7 
8 
10 
201 
11 
202 
13 
14 
777 
778 
Day of cycle 
-14 
to-1 
1 
2 
8 
15 
16 
22 
28 
1 
8 
15 
22 
28 
1 
15 
28 
≤14d 
from last 
dose 
Molecular pre- 
screening Informed 
Consent, if applicable 
D 
7.1.1 / 
11.3 
X 
Documented BRAF 
mutation 
D 
7.1.1 
X 
Obtain Study 
Informed Consent 
D 
7.1.2 / 
11.3 
X 
Demography 
D 
7.1.2.3 
Xb 
X 
Inclusion / Exclusion 
criteria 
D 
5.2 / 5.3 
X 
Relevant medical 
history/current 
medical conditions 
D 
7.1.2.3 
X 
Diagnosis and extent 
of cancer 
D 
7.1.2.3 
X 
Prior antineoplastic 
therapy 
D 
7.1.2.3 
X 
Prior/concomitant 
medications 
D 
7.1.2.3 
X 
CONTINUOUS 


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Category 
Reference to Section 
Molecular 
Pre-Screening 
Screening /Baseline 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
30-day safety FUm 
Disease progression 
FU (Phase II only) 
SECa 
Survival FU (Phase II 
only) 
Visit Name 
1 
2 
3 
4 
5 
6 
7 
8 
10 
201 
11 
202 
13 
14 
777 
778 
Day of cycle 
-14 
to-1 
1 
2 
8 
15 
16 
22 
28 
1 
8 
15 
22 
28 
1 
15 
28 
≤14d 
from last 
dose 
Physical examination 
S 
7.2.2.1 
X 
X 
Xc 
X 
Xc 
X 
Xc 
X 
C3c,d 
X 
Vital signs 
D 
7.2.2.2 
X 
X 
Xc 
X 
Xc 
X 
Xc 
X 
C3c,d 
X 
Performance status 
(WHO) 
D 
7.2.2.3 
X 
X 
Xc 
X 
X 
Xc 
X 
C3c,d 
X 
Height 
D 
7.2.2.4 
X 
Weight 
D 
7.2.2.4 
X 
X 
X 
X 
X 
Hematology 
D 
7.2.2.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
C3 
X 
Clinical chemistry 
D 
7.2.2.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
C3 
X 
Additional LFT 
D 
7.2.2.5.2 
X 
X 
C4 
Coagulation 
D 
7.2.2.5.3 
X 
X 
X 
X 
X 
Urinalysis (and 24h 
urine collection if 
applicable) 
D 
7.2.2.5.4 
X 
X 
X 
X 
X 
X 
Pregnancy test 
D 
7.2.2.5.5 
X 
X 
X 
X 
Dermatologic 
evaluation 
D 
7.2.2.6 
X 
Day 1 of odd-numbered 
Cycles (C3, C5, etc.) 
X 
Ophthalmologic 
examination 
D 
7.2.2.7 
X 
X 
X 
X 
Xe 
X 
ECG 12-leadf 
D 7.2.2.8.1/ 
7.2.2.8.2 
X 
X 
X 
X 
X 
X 
X 


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Category 
Reference to Section 
Molecular 
Pre-Screening 
Screening /Baseline 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
30-day safety FUm 
Disease progression 
FU (Phase II only) 
SECa 
Survival FU (Phase II 
only) 
Visit Name 
1 
2 
3 
4 
5 
6 
7 
8 
10 
201 
11 
202 
13 
14 
777 
778 
Day of cycle 
-14 
to-1 
1 
2 
8 
15 
16 
22 
28 
1 
8 
15 
22 
28 
1 
15 
28 
≤14d 
from last 
dose 
Cardiac imaging 
D 
7.2.2.8.3 
X 
X 
C5, 
C8 
C11g 
X 
Tumor imaging 
assessments 
(RECIST 1.1) 
D 
7.2.1 
X 
Xc,h 
X 
C4, 
C6 
Xi 
X 
Xj 
Brain MRI/CT 
D 
7.2.1 
Xk 
Phone calls for 
Disease progression 
FU (if applicable) 
S 
7.2.1 
X 
(monthly) 
Adverse events 
D 
8 
X 
(procedure- 
related 
SAEs only) 
CONTINUOUS 


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Category 
Reference to Section 
Molecular 
Pre-Screening 
Screening /Baseline 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
30-day safety FUm 
Disease progression 
FU (Phase II only) 
SECa 
Survival FU (Phase II 
only) 
Visit Name 
1 
2 
3 
4 
5 
6 
7 
8 
10 
201 
11 
202 
13 
14 
777 
778 
Day of cycle 
-14 
to-1 
1 
2 
8 
15 
16 
22 
28 
1 
8 
15 
22 
28 
1 
15 
28 
≤14d 
from last 
dose 
LGX818 
administration 
D 
6.1.1 / 
6.6 
CONTINUOUS 
MEK162 
administration 
D 
6.1.1 / 
6.6 
CONTINUOUS 
LEE011 
administration (only 
for triple combination) 
D 
6.1.1 / 
6.6 
3 weeks on, 1 week off schedule 
(once daily for 21 days followed by a 7-day rest [28-day cycle]). 
Blood for PK (up to 
cycle 10) – not for 
PhII arm 1 unless if 
required 
D 
7.2.3 
X 
X 
X 
X 
X 
X 
Archival tumor 
sample (paraffin 
block/slides) with an 
accompanying 
pathology report 
D 
7.2.4.1 
X 
Fresh tumor sample 
from biopsy/resection 
D 
7.2.4.1 
X (if 
needed) 
Xl 
X 
X 
(at 
relapse) 
X 
(at 
relapse) 


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Category 
Reference to Section 
Molecular 
Pre-Screening 
Screening /Baseline 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
30-day safety FUm 
Disease progression 
FU (Phase II only) 
SECa 
Survival FU (Phase II 
only) 
Visit Name 
1 
2 
3 
4 
5 
6 
7 
8 
10 
201 
11 
202 
13 
14 
777 
778 
Day of cycle 
-14 
to-1 
1 
2 
8 
15 
16 
22 
28 
1 
8 
15 
22 
28 
1 
15 
28 
≤14d 
from last 
dose 
Fresh skin biopsy 
(only applicable for 
those patients from 
whom fresh tumor 
sample is collected) 
D 
7.2.4.2 
X 
X 
X 
(at 
relapse) 
X 
(at 
relapse) 
Blood for genetic 
analysis 
D 
7.2.4.3 
X 
(or any 
other 
visit) 
Phone calls for 
survival follow-up 
(every 3 months) 
S 
7.1.5 
X 
X 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
D 
7.1.5 
X 
X 
X 
X 
End of study 
evaluation 
D 
7.1.5 
Xa 


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Category 
Reference to Section 
Molecular 
Pre-Screening 
Screening /Baseline 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
30-day safety FUm 
Disease progression 
FU (Phase II only) 
SECa 
Survival FU (Phase II 
only) 
Visit Name 
1 
2 
3 
4 
5 
6 
7 
8 
10 
201 
11 
202 
13 
14 
777 
778 
Day of cycle 
-14 
to-1 
1 
2 
8 
15 
16 
22 
28 
1 
8 
15 
22 
28 
1 
15 
28 
≤14d 
from last 
dose 
a. SEC eCRF should be completed once the 30-day safety follow-up period is completed for the Phase Ib patients and for those Phase II patients who have progressed 
during study treatment. For patients enrolled in the Phase II parts who discontinue study treatment for any reason other than disease progression, the SEC eCRF should 
be completed upon progression, the initiation of subsequent anticancer therapies or death. 
b. For only those patients who have signed the molecular pre-screening IC; does not have to be repeated at Screening for these patients. 
c. Not applicable for patients enrolled in the Phase II parts of the study. 
d. C3=only during Cycle 3 
e. Patients who have been on the LGX818/MEK162 dual-combination and LGX818/MEK162/LEE011 triple-combination treatment for ≥ 24 months (Cycle 25 Day 1 onward) 
without a retinal AE should be evaluated for visual acuity at each scheduled patient visit and at the End of Treatment visit. A full ophthalmic examination is required 
if clinically indicated and at the End of Treatment visit. 
f. All ECGs should be performed either before blood sample collection or at least 0.5 hours after blood sample collection. 
g. Day 1 of every third cycle until Cycle 11 (i.e. Day 1 of Cycle 5, 8 and 11) and Day 1 of every fourth Cycle thereafter (i.e. Day 1 of Cycle 15, 19 etc.). 
h. Should be performed between week 3 and 4 of Cycle 1. 
i. Patients who have been on either combination treatment for ≥ 24 months (Cycle 25 Day 1 onward) will have CT/MRI scans every 8-12 weeks (± 7 days). 
j. Patients who have been on either combination treatment for ≥ 24 months (Cycle 25 Day 1 onward) and then discontinue study treatment for any reason other than disease 
progression will have CT/MRI scans every 8-12 weeks (± 7 days). 
k. Applicable only for patients enrolled in the triple-combination part of the study. 
l. Fresh sample should only be collected at Screening/baseline if insufficient fresh tumor tissue was collected during local molecular pre-screening. Fresh tumor samples are 
mandatory for all patients in Phase II of the study at Screening/Baseline, although archival tissue is acceptable in some cases, (refer to Section 7.2.4.1.1). 
m. Following the 30-day follow-up, when clinically appropriate, it is recommended patients be monitored with physical examinations, dermatological examinations, and chest 
CT scans for cutaneous and non-cutaneous secondary malignancies for up to 6 months after the last encorafenib dose or until initiation of another antineoplastic therapy. 


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Table 7-2 
Visit evaluation schedule for patients as of Amendment 10 
 
Procedure or Assessmenta 
As of Amendment 10 
Category 
Protocol Section 
Treatment 
EOT 
30-day safety FU 
Study Evaluation 
Completion 
Per local 
standard-of-care 
(Recommended 
every 4 weeks) 
Recommended 
every 
8-12 weeks 
Physical examinationb 
S 
7.2.2.1 
X 
X 
Vital signs / weight 
D 
7.2.2.2 
X 
X 
Performance Status (WHO) 
D 
7.2.2.3 
X 
X 
Single ECG 12-lead 
D 
7.2.2.8.1/ 
7.2.2.8.2 
X 
X 
Hematology 
D 
7.2.2.5.1 
X 
X 
Clinical chemistry 
D 
7.2.2.5.2 
X 
X 
Coagulation 
D 
7.2.2.5.3 
X 
X 
Dipstick Urinalysisc 
D 
7.2.2.5.4 
Xc 
X 
Pregnancy testd 
D 
7.2.2.5.5 
X 
X 
Cardiac imaginge 
D 
7.2.2.8.3 
as clinically 
indicated 
X 
Visual acuityf 
D 
7.2.2.7 
X 
X 
Ophthalmologic examinationf 
D 
7.2.2.7 
as clinically 
indicated 
X 
Dermatologic examinationb 
D 
7.2.2.6 
X 
LGX818/MEK162 (Dual combination patients)- 
Dispense and/or assess compliance 
D 
6.1.1 / 6.6 
X 
LGX818/MEK162/LEE011 (Triple combination 
patients) - Dispense and/or assess compliance 
D 
6.1.1 / 6.6 
X 
Adverse events 
D 
8 
X 
X 
X 
Concomitant medications 
D 
7.1.2.3 
X 
X 
X 
Tumor imaging assessments (RECIST 1.1) 
D 
7.2.1 
Per institutional standar-of-care 
End of study evaluationg 
D 
7.1.5 
X 


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Procedure or Assessmenta 
As of Amendment 10 
Category 
Protocol Section 
Treatment 
EOT 
30-day safety FU 
Study Evaluation 
Completion 
Per local 
standard-of-care 
(Recommended 
every 4 weeks) 
Recommended 
every 
8-12 weeks 
a. The minimally required procedures/assessments are indicated; these or any additional procedures/assessments can be repeated more frequently per 
standard-of-care or if clinically indicated. 
b. Following the 30-day Safety Follow-up, when clinically appropriate, it is recommended patients be monitored with physical examinations, dermatological 
examinations, and chest CT scans for cutaneous and non-cutaneous secondary malignancies for up to 6 months after the last LGX818 dose or until initiation of 
another antineoplastic therapy. 
c. To be conducted if clinically indicated. 
d. Local urine test for women of childbearing potential only. 
e. Assessed by ECHO or MUGA. The same method should be used throughout the study. Patients who develop signs/symptoms of CHF at any point during the study 
are required to have an evaluation by ECHO or MUGA. 
f. Patients who have been on the LGX818/MEK162 dual combination and LGX818/MEK162/LEE011 triple combination treatment for ≥ 24 months (Cycle 25 Day 1 
onward) without a retinal AE should be evaluated for visual acuity per local standard-of-care (recommended every 4 weeks) and at the End of Treatment visit. A full 
ophthalmic examination is required if clinically indicated and at the End of Treatment visit. 
g. SEC eCRF should be completed once the 30-day safety follow-up period is completed or 30 days after treatment discontinuation. 


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7.1.1 
Molecular Pre-screening assessments 
Potential eligible patients must have documentation on the BRAF V600 mutational status of 
their disease. For patients considered for enrollment in this study, whose BRAF mutational 
status is unknown, archival or fresh tumor tissue should be provided to a local laboratory to 
identify the presence of a BRAF V600 mutation (a V600E mutation, or any other BRAF V600 
mutation) prior to start of screening. 
Patients who have a tumor which is not routinely screened for a BRAF mutation at a local 
laboratory, will be asked to sign and date an IRB/IEC approved Molecular pre-screening 
Informed Consent Form before the collection of the fresh tumor tissue or use of archival tumor 
tissue. A copy must be given to the patient or to the person signing the form. 
If confirmed that the patient’s tumor harbors a BRAF V600 mutation the patient will be allowed 
to sign the Study Informed Consent Form and start screening. 
7.1.2 
Screening 
The Study IRB/IEC approved Informed Consent Form (ICF) must be signed and dated before 
any screening procedures are performed (procedures which are part of the clinical routine 
during the initial diagnostic work-up of the patient may be performed before obtaining the ICF). 
A copy of the ICF must be given to the patient or to the person signing the form. The 
Investigator or designee must record the date when the study informed consent was signed in 
the medical records of the patient. 
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments. 
For details of assessments, refer to Table 7-1. All Screening/baseline imaging scans must be 
completed within 21 days prior to the first dose of study treatment. All other screening 
assessments must be completed within 14 days prior to the first dose. 
7.1.2.1 
Eligibility screening 
When the patient is considered eligible for study treatment, the Investigator should complete 
the Patient Registration Form and send it to the Sponsor. The allocation of patients to treatment 
cohorts will be handled by the Sponsor. 
7.1.2.2 
Information to be collected on molecular pre- screening and screening 
failures 
Patients who sign an ICF but fail to be started on study treatment for any reason will be 
considered a screen failure. Both patients who sign a Molecular pre-screening ICF and are 
considered ineligible after molecular pre-screening, as well as patients who are found not 
eligible after signing the Study ICF, will be considered as screening failures and data will be 
handled in the same manner. 
For all screening failures, the only information collected on the eCRF will be the Screening Log 
and the Demography pages. 


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7.1.2.3 
Patient demographics and other baseline characteristics 
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, prior concomitant medications, diagnosis and extent of tumor, 
baseline tumor mutation status and details of prior anti-neoplastic treatments. 
7.1.3 
Treatment period 
Note: As of protocol amendment 10, all efficacy and safety assessments will be completed 
per local standard-of-care practice, or otherwise as clinically indicated. See Table 7-2. 
During the treatment period, the patient must follow the Investigators instructions with regards 
to contraception, concomitant medications, and dosing regimen (see Section 6.1.1 for dosing 
regimen guidelines). There is no fixed treatment duration; patients may continue treatment with 
the LGX818 and MEK162 dual combination or LGX818 and MEK162 and LEE011 triple 
combination until disease progression, unacceptable toxicity occurs that precludes any further 
treatment and/or treatment is discontinued at the discretion of the investigator or by patient 
refusal (withdrawal of consent). 
If a patient remains on study although the patient required a dose interruption of > 21 days, 
because the patient had experienced objective evidence of clinical benefit and in the opinion of 
the investigator it is in the best interest of the patient to remain on study (see also Section 6.3.2), 
then this decision and report of a discussion with the sponsor, must be reported in the source 
documentation and in a comment in the eCRF. 
If a patient remains on study although the patient’s disease progressed (see also Section 6.1.5), 
then this decision and documentation of a discussion with the sponsor, must be reported in the 
source documentation and as an investigator comment in the eCRF. 
For details of the frequency of the visits and assessments during the treatment period, refer to 
Table 7-1 and Table 7-2. 
7.1.4 
End of treatment visit, including premature withdrawal and study 
completion visit 
Note: As of protocol amendment 10, patients will be considered to have completed the 
study after the 30-day safety evaluation or 30 days after treatment discontinuation, 
whichever is earlier. Post-treatment disease progression follow-up (if applicable) and/or 
survival follow-up (including documentation of subsequent antineoplastic therapies) will 
no longer be performed for any patient in the Phase II part of the study; see Table 7-2. 
Patients who discontinue study treatment should be scheduled for an End of Treatment (EOT) 
visit as soon as possible and within 14 days after the last study drug dose, at which time all of 
the assessments listed for the EOT visit will be performed. For patients who had to interrupt 
study treatment for more than 14 days and then permanently discontinue study treatment 
without restarting, the EOT visit should be scheduled as soon as possible after the decision of 
discontinuation. An EOT eCRF page should be completed, giving the date and primary reason 
for stopping the study treatment. At a minimum, all patients who discontinue study treatment, 
including those who refuse to return for a final visit, will be contacted for safety evaluations 
during the 30 days following the last dose of study treatment. 


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Patients who discontinue study treatment should also return for 30-day safety FU (see 
Section 7.1.5.1), Disease progression FU (if applicable, see Section 7.1.5.2) and survival FU 
(only for Phase II patients, see Section 7.1.5.3) assessments at the visits according to Table 
7-1 and Table 7-2 and should not be considered withdrawn from the study. If patients refuse 
to return for these visits or are unable to do so, every effort should be made to contact them or 
a knowledgeable informant by telephone to obtain the FU information. 
If a patient discontinues study treatment, but continues study assessments in the FU period, the 
patient remains on study until such time as he/she completes protocol criteria for ending study 
assessments. At that time, the reason for study completion should be recorded on the Study 
Evaluation Completion (SEC) eCRF page. 
The SEC eCRF page records the end of study for every individual patient and should be 
completed for all patients enrolled in the Phase Ib part and those patients enrolled in the Phase 
II part who have progressed during study treatment, once the 30-day safety follow-up period is 
completed. For patients enrolled in the Phase II part who discontinue study treatment for any 
reason other than disease progression, the SEC eCRF should be completed upon progression or 
the initiation of subsequent anticancer therapies or death. Note: the survival FU assessments do 
continue beyond the SEC for all patients enrolled in the Phase II part. 
7.1.4.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients may be withdrawn from the study if any of the following occur: 
• Unacceptable AE(s), or failure to tolerate study treatment 
• Delay in dosing > 21 consecutive days 
• Pregnancy of the patient 
• Patient withdrew consent 
• Lost to follow-up 
• Disease progression 
• Initiation of new cancer therapy 
7.1.4.2 
Replacement policy 
Dose Escalation (Phase Ib) 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 (3) or at most the maximum 
number (6) of evaluable patients is achieved within the cohort (Section 10.8). Minimum and 
maximum numbers of evaluable patients per cohort are defined in Section 6.2.4.2. 
Phase II part: During the Phase II part no replacement will be needed. 


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7.1.5 
Follow-up period 
Patients lost to follow-up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator 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. 
7.1.5.1 
30-day safety follow-up period 
All patients must have safety evaluations for 30 days after the last dose of study treatment. 
Information related to AEs (including concomitant medication taken for ongoing AEs) and 
ongoing anti-neoplastic treatments will be collected for 30 days after the last dose of study drug. 
All AEs suspected to be related to study treatment should be followed up weekly, or as clinically 
indicated, until resolution or stabilization. 
7.1.5.2 
Disease progression follow-up period 
Note: As of protocol amendment 10, no post-treatment disease progression follow-up will 
be performed. 
Patients enrolled in the Phase II part of the study who discontinue study treatment for any reason 
other than disease progression will be followed up monthly via a phone call and will have 
CT/MRI scans every 8 weeks (± 7 days) as detailed in Table 7-1 and Section 7.2.1, until disease 
progression or the initiation of subsequent anticancer therapies, or death, or until all patients 
have completed SEC, or have been lost to follow-up or withdrew consent, whichever occurs 
first. 
Patients 
who 
have 
been 
on 
the 
LGX818/MEK162 
dual-combination 
or 
LGX818/MEK162/LEE011 triple-combination treatment for ≥ 24 months (Cycle 25 Day 1 
onward) and then discontinue study treatment for any reason other than disease progression will 
be followed up by CT/MRI scans every 8-12 weeks (± 7 days) as detailed in Table 7-1 and 
Section 7.2.1, until disease progression, death, removal of consent to follow, the initiation of 
subsequent anticancer therapies or until End of Study (see Section 4.3), whichever occurs first. 
7.1.5.3 
Survival follow-up period 
Note: As of protocol amendment 10, no survival or subsequent antineoplastic therapy 
information will be collected. 
All patients enrolled in the Phase II part of the study will be followed for survival every 3 
months per phone call until death, or until all patients have completed SEC, or have been lost 
to follow-up or withdrew consent, whichever occurs first. Possible newly started antineoplastic 
therapies during this FU period must be recorded on the Antineoplastic therapy since 
discontinuation eCRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor response will be evaluated locally by the investigator according to the guideline based 
on RECIST version 1.1 (see Appendix 1). Each subject will be evaluated for all potential sites 
of tumor lesions at Screening/baseline, at the end of Cycle 1 (not applicable for patients enrolled 


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in the Phase II part of the study) and Cycle 2 and then every 8 weeks (2 cycles) thereafter during 
the study treatment until disease progression. Screening/baseline imaging assessments may be 
performed within 21 days of treatment start, except whole-body bone scans, if applicable, which 
can be performed within 6 weeks of treatment start. On-study tumor assessments have a ± 7 day 
window, except for the tumor assessment on C1D28 which must be performed between week 
3 and 4 after starting the study drug combination. Patients who have been on the 
LGX818/MEK162 dual- or triple-combination treatment for ≥ 24 months (Cycle 25 Day 1 
onward) will be evaluated for all potential sites of tumor lesions every 8-12 weeks (± 7 days) 
until disease progression. 
There will be a tumor assessment at End of Treatment (± 3 days) if the patient discontinues for 
any reason other than disease progression and the last tumor assessment has been performed > 
21 days prior to this day. Subjects included in the Phase II part of the study, who discontinue 
study treatment due to another reason than disease progression, should be followed up monthly 
via a phone call and undergo tumor assessments every 8 weeks (± 7 days) until disease 
progression or initiation of subsequent anti-neoplastic therapy, or death, whichever occurs first 
(Section 7.1.5.2). Patients who have been on either dual- or triple-combination treatment for ≥ 
24 months (Cycle 25 Day 1 onward) and then discontinue study treatment for any reason other 
than disease progression will have CT/MRI scans every 8-12 weeks (± 7 days). 
At Screening/baseline the following should be performed: 
• A CT scan with intravenous (i.v.) contrast of chest, abdomen and pelvis is required for all 
patients. 
• In subjects with a history of asymptomatic brain metastases, a brain MRI or CT scan must 
be performed. 
• In subjects participating in the triple-combination part of the study a brain MRI or CT with 
intravenous (i.v.) contrast scan to assess CNS disease must be performed. Contrast 
enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then brain 
MRI without contrast or brain CT with/without contrast is acceptable. 
• If clinically indicated, a whole-body bone scan (i.e., if bone metastases are suspected or 
known at baseline) should be performed. Sites may use a whole-body bone imaging 
method per their local standard-of-care (e.g., Tc99m bone scan, NaF PET scan, or whole- 
body bone MRI). Skeletal lesions identified on a whole-body bone scan at baseline, which 
are not visible on the chest, abdomen and pelvis CT (or MRI) scan should be imaged at 
baseline using localized CT, MRI or x-ray. 
• Color photography if skin lesions are present (it is recommended to include a ruler to 
estimate the size of the lesion). 
Every effort must be made to assess each lesion that is measured at Screening/baseline by the 
same method throughout the study so that the comparison is consistent. 
At all post-Screening/baseline assessments the following should be performed: 
• All patients are required to undergo chest, abdomen and pelvis CT or MRI scans. 
• Brain MRI or CT scan, if metastases were documented at baseline. 
• Skeletal lesions identified at baseline should continue to be imaged at subsequent 
scheduled visits using localized CT, MRI or x-ray if not visible on the chest, abdomen and 


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pelvis CT or MRI scan. After baseline, whole-body bone scans need not be repeated, 
unless clinically indicated. 
• Color photography of any skin lesions documented at baseline (it is recommended to 
include a ruler to estimate the size of the lesion). 
• Additional tumor assessments (e.g. MRI or CT of the brain) may be performed if there is 
symptomatic evidence suggesting the possibility of disease progression based on clinical 
symptoms or physical exam at any time. 
Criteria required for determining partial or complete response should be present for at least 
4 weeks. All complete and partial responses must be confirmed by a second assessment at least 
4 weeks later. Note: sites must make sure for patients enrolled in the Phase Ib part of the study 
that at least 4 weeks are scheduled between the tumor assessments on C1D28 and C2D28 to 
allow confirmation of response. 
CT scans should be acquired with i.v. contrast. If a patient is known to have a medical 
contraindication to CT i.v. contrast agent or develops a contraindication during the study, a CT 
scan without i.v. contrast of the chest and MRI with i.v. contrast, if possible, of the abdomen 
and pelvis may be performed. A CT scan of the brain, preferably with i.v. contrast, may be 
performed if MRI is contra-indicated. 
Chest x-ray or ultrasound should not be used for tumor response assessments in this study. 
Any lesions that have been subjected to loco-regional therapies (e.g., radiotherapy, ablation, 
etc.) should not be considered measurable, unless they have clearly progressed since the therapy. 
Previously treated lesions that have not progressed should be considered non-measurable and 
therefore, assessed as non-target lesions. 
While FDG-PET scans are not required for this study, sites may perform combined PET/CT 
scans per their local standard-of-care, provided the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of oral and intravenous contrast media. If 
acquired according to local standard-of-care, FDG-PET may be relied upon to document 
progressive disease in accordance with RECIST v1.1 (Appendix 1). 
Each center should have a designated radiologist responsible for the interpretation of scans and 
response evaluations for study subjects. Preferably, a single radiologist should perform all 
evaluations for an individual subject. 
7.2.2 
Safety and tolerability assessments 
Note: As of protocol amendment 10, safety assessments will be performed as indicated in 
Table 7-2. 
Safety will be monitored by assessing the procedures listed below as well as collecting of the 
adverse events at every visit. For details on AE collection and reporting, refer to Section 8. All 
safety assessments should be performed pre-dose unless specified otherwise. 


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7.2.2.1 
Physical examination 
Note: As of protocol amendment 10, physical examinations will be performed as outlined 
in Table 7-2. 
A complete physical examination will be performed at Screening/baseline and will include the 
examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, peripheral vascular system and neurologic 
system. If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, 
and pelvic exams will be performed. 
A short physical exam (examination of general appearance) will be at all visits during treatment 
unless the investigator considers a complete physical examination is necessary. 
Physical examinations will take place at the following visits irrespective of the time of dosing: 
• Screening/Baseline 
• Cycle 1 Days 1, 8, 15 and 22 (for Phase II: Cycle 1 Days 1 and 15) 
• Cycles 2 and 3: at Day 1 and Day 15 (for Phase II: Cycles 2 and 3 at Day 1) 
• Cycle 4 and Onwards: Day 1 
• EOT 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical examination 
findings that are identified during the active collection period and meet the definition of an AE 
or SAE (Appendix 7Appendix 7Appendix 7Appendix 7Appendix 7) must be reported according 
to the processes in Section 8.1.1 and Appendix 7. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s eCRF. 
7.2.2.2 
Vital signs 
Note: As of protocol amendment 10, vital signs will be performed as outlined 
in Table 7-2. 
Vital signs include blood pressure, temperature and pulse measurements. After the patient has 
been sitting for five minutes, with back supported and both feet placed on the floor, systolic and 
diastolic blood pressure will be measured three times using an automated validated device (e.g. 
OMRON), with an appropriately sized cuff. The repeat sitting measurements will be made at 1- 
to 2-minute intervals and the mean of the three measurements will be used. In case the cuff sizes 
available are not large enough for the patient's arm circumference, a sphygmomanometer with 
an appropriately sized cuff may be used. 
Vital signs will take place pre-dose at: 
• Screening/Baseline 
• Cycle 1 Days 1, 8, 15 and 22 (for Phase II: Cycle 1 Days 1 and 15) 
• Cycles 2 and 3: at Day 1 and Day 15 (for Phase II: Cycle 3 at Day 1) 
• Cycle 4 and onwards: Day 1 
• EOT 


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7.2.2.3 
Performance status 
Note: As of protocol amendment 10, WHO Performance Status will be performed as 
outlined in Table 7-2. 
Assessment of WHO Performance Status (Table 7-3) will be performed at screening and 
regularly throughout the whole study period irrespective of the time of dosing: 
• Screening/Baseline 
• Cycle 1 Days 1, 8 and 15 (for Phase II: Cycle 1 Days 1 and 15) 
• Cycles 2 and 3: Day 1 and Day 15 (for Phase II: Cycles 2 and 3 at Day 1) 
• Cycle 4 and onwards: Day 1 
• EOT 
Performance status should be obtained on the scheduled day, even if study medication is being 
held. 
Table 7-3 
WHO performance status scale 
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 housework, 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. 
7.2.2.4 
Height and weight 
Note: As of protocol amendment 10, weight information will be collected as outlined 
in Table 7-2. 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured. 
Height information will be collected only at Screening/baseline. Weight information will be 
collected at Screening/baseline, Day 1 of each cycle and at EOT irrespective of dosing time. 
7.2.2.5 
Laboratory evaluations 
Note: As of protocol amendment 10, laboratory evaluations will be performed as 
outlined in Table 7-2. 
Sites will use their local laboratories for the analysis of all safety lab samples collected at the 
time points indicated in the Visit Schedule (Table 7-1 and Table 7-2). More frequent 
assessments may be performed if clinically indicated, or at the investigator’s discretion, and 
these should be recorded on the Unscheduled Visit eCRFs. 
Abnormal laboratory values that are clinically relevant (e.g., require an interruption or delay to 
study treatment, lead to clinical symptoms, or require therapeutic intervention) must be 
documented in the Adverse Event eCRF. If any abnormal laboratory value constitutes an AE, 
then these must be recorded on the Adverse Event eCRF. 


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The Sponsor will be provided with a copy of the site’s local laboratory certification and 
tabulation of the normal ranges for each parameter required at study start and should be kept up 
to date on an ongoing basis. In addition, if at any time a patient has laboratory parameters 
obtained from a different outside laboratory, the Sponsor must be provided with a copy of the 
certification and a tabulation of the normal ranges for that laboratory. 
7.2.2.5.1 Hematology 
The following will be assessed: 
WBC count plus differential (total neutrophil including bands, lymphocyte, monocyte, 
eosinophil, basophil and other counts), RBC count, hemoglobin, hematocrit and platelet count. 
Hematology assessments will be performed pre-dose at: 
• Screening/baseline 
• Cycle 1 Days 1, 8, 15 and 22. (For Cycle 1 Day 1, before first dose unless screening 
samples were collected <72 hrs prior). 
• Cycles 2 and 3: Day 1 and Day 15 
• Cycles 4 and onwards: Day 1 
• EOT 
7.2.2.5.2 Clinical chemistry 
The following will be assessed: 
Sodium, potassium, chloride, bicarbonate, total calcium, inorganic phosphate, magnesium, urea 
or blood urea nitrogen (BUN), creatinine, uric acid, bilirubin (total, indirect and direct), AST, 
ALT, creatine phosphokinase (CPK) (if total CPK is elevated ≥ CTCAE Grade 2, then weekly 
measure isoenzymes in blood, and myoglobin in blood and urine until resolved to ≤ CTCAE 
Grade 1), albumin, total protein, alkaline phosphatase, lactate dehydrogenase (LDH), glucose, 
amylase, lipase. 
The following do not need to be collected during Phase II: chloride, urea (BUN), and uric acid. 
These parameters will be measured pre-dose at: 
• Screening/baseline 
• Cycle 1 Days 1, 8, 15 and 22. (For Cycle 1 Day 1, before first dose unless screening 
samples were collected <72 hrs prior). 
• Cycles 2 and 3: Day 1 and Day 15 
• Cycles 4 and onwards: Day 1 
• EOT 
Additional liver function test (LFT = AST, ALT, alkaline phosphatase and bilirubin (total, 
indirect and direct)) will be assessed at the following times: 
• Cycle 2: Day 8 and Day 22 
• Cycle 4: Day 15 
Total cholesterol, triglycerides, HDL, and LDL (to be collected for Phase Ib only): 


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• Cycle 1 Day 1 
• Cycle 2 Day 1 and Day 1 of every other subsequent cycle (C4D1, C6D1 etc.) 
• EOT 
TSH (free T4, and free T3 should also be measured only if clinically indicated) will be assessed 
at the following times (to be collected for the Phase Ib part of the protocol only): 
• Cycle 1 Day 1 
• Day 1 of every 3 months (Cycle 4, 7 etc) 
• EOT 
7.2.2.5.3 Coagulation 
Coagulation profiles will include a prothrombin time (PT) or international normalized ratio 
(INR), activated partial thromboplastin time (aPTT), and fibrinogen 
Coagulation profiles will be performed at: 
• Screening/baseline 
• Cycle 1 Day 1 before first dose, unless screening samples were collected <72 hrs prior 
• Day 1 of all subsequent cycles 
• EOT 
7.2.2.5.4 Urinalysis 
Urine color and appearance should be evaluated. A macroscopic urinalysis (dipstick or other 
equivalent method according to local practice), including bilirubin, ketones, leukocytes, protein, 
glucose, blood, and specific gravity should be performed. 
Abnormal findings will be followed up with a microscopic evaluation and/or additional 
assessments as clinically indicated. A microscopic evaluation (WBC/HPF, RBC/HPF, and any 
other evaluations depending on macroscopic findings) need only be performed if the urinalysis 
result is abnormal (except for institutions where microscopic urinalysis is not available). 
Urinalysis will be performed at: 
• Screening/baseline 
• Cycle 1 Days 1 and 15 (Day 1 before first dose, unless screening samples were collected 
<72 hrs prior) 
• Day 1 of all subsequent cycles 
• EOT 
Note: If at Screening/baseline there is documentation of [+2] result or higher for protein from 
urinalysis, a 24-hour urine collection for total protein and measured creatinine clearance (CrCl) 
must be obtained. Whenever a 24-hour urine collection is performed, the total volume of urine 
must be recorded on the appropriate eCRF. 


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7.2.2.5.5 Pregnancy and assessments of fertility 
All females of childbearing potential will have a serum pregnancy test ≤72 hrs before first dose 
of study drug and a urine or serum during study treatment (Day 1 of Cycle 2 and onwards) and 
at the End of Treatment visit. 
A positive urine pregnancy test requires immediate interruption of study treatment until serum 
β-HCG is performed and found to be negative. If positive, the patient must be discontinued 
from the study. 
7.2.2.6 
Dermatologic evaluations 
Note: As of protocol amendment 10, dermatologic evaluations will be performed as 
outlined in Table 7-2. 
Skin evaluations will be performed by dermatologists at Screening/baseline, every 8 weeks 
thereafter (±1 week; Day 1 of Cycle 3, 5 etc.) and at the End of Treatment visit to look for the 
appearance of squamous cell carcinoma or keratoacanthomas. This assessment can be done pre- 
or post-dose. 
In the occurrence of these lesions, the lesions should be removed and the patient must be treated 
as per institutional practice. 
7.2.2.7 
Ophthalmologic examination 
Note: As of protocol amendment 10, ophthalmological evaluations will be performed as 
outlined in Table 7-2. Patients who have been on dual or triple combination treatment 
for ≥ 24 months (Cycle 25 Day 1 onward) without a retinal AE should be evaluated for 
visual acuity per local standard-of-care (recommended every 4 weeks) and at the EOT 
visit. A full ophthalmological examination is required if clinically indicated and at the 
EOT visit. 
Full ophthalmological examination including slit lamp examination, visual acuity testing, visual 
field testing, tonometry (IOP), OCT and indirect fundoscopy (with dilation) with attention to 
retinal abnormalities (especially CSR and RVO), should be performed by an ophthalmologist 
at the following time points and as clinically indicated: 
• Screening/baseline 
• Cycle 1 Day 15 
• Cycle 2 Days 1 and 15 
• Day 1 of all subsequent Cycles* 
• EOT 
*Patients who have been on dual- or triple-combination treatment for ≥ 24 months (Cycle 25 
Day 1 onward) without a retinal AE should be evaluated for visual acuity at each 
scheduled patient visit and at the End of Treatment visit. A full ophthalmic examination 
is required if clinically indicated and at the End of Treatment visit. 
For patients with clinical suspicion of retinal changes additional assessments of fluorescein 
angiography and/or focal ERG (where feasible) are recommended and should be performed 


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upon the discretion of the treating physician. Any observed abnormalities and/or changes to 
Screening/baseline must be documented in the Adverse Event eCRF. 
7.2.2.8 
Cardiac assessments 
Note: As of protocol amendment 10, cardiac assessments will be performed as outlined 
in Table 7-2. 
 
7.2.2.8.1 Electrocardiogram (ECG) schedule for the dual combination 
At Screening/baseline a standard 12 lead ECG (local assessment) will be performed to assess 
eligibility. Subsequent 12-lead ECGs are to be conducted at the following time points: 
• Cycle 1 Days 1 and 15 predose 
• Cycle 2 Days 1 and 15 predose 
• Day 1 of all subsequent cycles predose 
• EOT 
For all patients, prior to the first administration of the LGX818 and MEK162 combination on 
Cycle 1 Day 1, three sequential 12 lead ECGs, separated by at least 5-10 minutes, must be 
performed. The average of the triplicate ECG measurements will serve as the patient’s baseline 
value for post-dose comparisons. Single ECGs will be performed for the other pre-dose ECGs 
during the study at the indicated time points, at EOT and if clinically indicated. 
7.2.2.8.2 Electrocardiogram (ECG) schedule for the triple combination 
At Screening/baseline a standard 12 lead ECG (local assessment) will be performed to assess 
eligibility. Subsequent triplicate 12-lead ECGs are to be conducted at the following time points: 
• Cycle 1 Days 1 and 15: pre-dose, 1.5 hrs (± 0.5 hr) and 4 hr (± 0.5 hr) post-dose 
• Cycle 2 Day 1: pre-dose, 1.5 hrs (± 0.5 hr) and 4 hr (± 0.5 hr) post-dose 
• Cycle 2 Day 15: pre-dose 
• Day 1 of subsequent cycles: pre-dose 
• EOT 
All ECGs for patients treated with the triple study drug combination should be taken before a 
blood sample or at least 0.5 hours after a blood sample to avoid potential effects of blood-draw 
on ECG readout. 
For any patients who had therapy interrupted due to QTcF ≥ 481 ms, ECGs should be repeated 
7 days and 14 days after dose resumption (then as clinically indicated). For all patients 
experiencing a grade 3 QTcF interval prolongation, hypokalemia, hypomagnesaemia and 
oxygenation status should be monitored. 
All ECGs (except the screening ECG) for patients treated with either the dual or triple study 
drug combination will be independently reviewed by a central laboratory. Instructions for the 
collection and transmission of ECGs to the independent reviewer will be provided in the ECG 
Manual. Interpretation of the tracing must be made by a qualified physician and documented 
on the ECG eCRF page. Each ECG tracing print-out should be labeled with the study number, 
patient initials (where regulations permit), patient number, date, and kept in the source 


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fu addition to LGX818 MEK162/AR00426032 and LEE0l1/LE  803 anal ses 
documents at the study site. Clinically significant abnoimalities present when the patient signed 
infonned consent should be reported on the relevant medical histoiy/cmTent medical conditions 
eCRF page. Clinically significant findings must be discussed with the Sponsor's Medical 
Monitor prior to enrolling the patient in the study. New or worsened clinically significant 
findings occmTing after infoimed consent must be recorded on the AE eCRF page. 
7.2.2.8.3 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram 
• 
The left ventricular heait function will be evaluated by ECHO or MUGA at 
Screening/baseline, during the study on Day 1 of Cycle 2, Day 1 of eveiy third cycle until 
Cycle 11 (i.e. Day 1 of Cycle 5, 8 and 11) and Day 1 of every fomth Cycle thereafter (i.e. 
Day 1 of Cycle 15, 19 etc.), at the End of Treatment visit and if clinically indicated 
iiTespective of the time of dosing. The same procedure should be used throughout the 
study. 
7.2.3 
Pharmacokinetics 
The blood sampling regiinens for deteimining the phaimacokineticsof MEK162 and its priinaiy 
active metabolite AR00426032, LGX818, and LEE0ll and its metabolite LEQ803 after oral 
administration of the dual or triple combination as applicable, ai·e given in Table 7-3 (dose 
escalation) and Table 7-4 (dual-combination Phase II aims 2 and 3, and aim 1 ifrequii·ed as per 
instruction from Sponsor/ triple-combination Phase II aim A). Blood samples for LGX818, 
MEK162/AR00426032 and LEE011/LEQ803 (as applicable) plasma concentr·ation 
measurements will be collected and evaluated on all patients enrolled in the dose escalation and 
on a selected number of patients in the dual-combination Phase II anns 2 and 3 (and aim 1 if 
requii·ed as per instruction from the Sponsor for assessment of the potential iinpact of 
demographic differences (e.g. Japanese vs Caucasian) and triple- combination Phase II aim A, 
paits of the study. 
 
Plasma samples remaining from the analysis may be retained by the Sponsor for additional 
investigations (e.g. long teim stability, reproducibility). 
A detailed description of the planned phaimacokinetic analyses is given in Section 10.5.3. 
7.2.3.1 
Pharmacokinetic blood sample collection and handling 
7.2.3.1.1 Blood collection plan 
Dose Escalation: From all patients tr·eated in the dose escalation part, blood for full 
phaimacokinetic profiling of LGX818 and MEKl62, and LEE011 if applicable will be collected 
on Cycle 1 Days 1 and 15 (including a 24 hr post dose sample on the following day; see Table 
7-4). Additionally, pre-dose samples will be collected on Day 1 of Cycle 2 through Cycle 10. 


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Dual combination Phase II arm 1: No PK sampling will be performed for patients enrolled in 
this arm. The exception to this is for newly enrolled patients in which an assessment of the 
potential impact of demographic differences on the PK of the LGX818 and MEK162 
combination may be made, if required as per instruction from the Sponsor. 
Dual combination Phase II arms 2 and 3: From the first 10 patients in each arm, and if 
required as per instruction from the Sponsor, from additional patients in which an assessment 
of the potential impact of demographic differences on the PK of the LGX818 and MEK162 
combination may be made. Blood for pharmacokinetic profiling of LGX818 and MEK162 will 
be collected on Cycle 1 Days 1 and 15 (including a 24 hr post dose sample on the following 
day; see Table 7-4) to study the CCI     of the study drug dual combination. The 4- and 
6-hour post-dose samples collected during dose escalation are replaced with a 5-hour post-dose 
sample for these patients to collect less blood from the patients but still cover the PK profile of 
the study drugs. Additionally, pre-dose samples will be collected on Day 1 of Cycle 2 through 
Cycle 10 for those patients. 
PK blood sample collection time points will remain the same if the dosing schedule of LGX818 
would change to a BID and/or QOD dosing schedule. 
Triple-combination Phase II arm A: From the first 10 patients, blood for pharmacokinetic 
profiling of LGX818 and MEK162 and LEE011 will be collected on Cycle 1 Days 1 and 15 
(including a 24 hr post dose sample on the following day; see Table 7-4) to study the CCI  
of the study drug triple combination. Additionally, pre-dose samples will be collected on 
Day 1 of Cycle 2 through Cycle 10 for those patients. 
For all patients from whom PK samples are collected (either treated with the dual or triple 
combination), exact dates and clock times of drug administration and actual PK blood draw will 
be recorded on the appropriate eCRF. Any sampling problems (e.g. patient took study drug 
before draw took place) must be noted in the comments section of the eCRF and on appropriate 
source documentation. The time of the last meal should be recorded on PK sampling days Cycle 
1 Days 1 and 15 on the appropriate eCRF. 
If vomiting or diarrhea occurs within 4 hrs following study drugs administration on the days of 
full PK blood sampling, the exact time (using the 24-h clock) of any vomiting or diarrhea 
episode should be recorded in a separate section of the eCRF in addition to recording this on 
the AE eCRF. 
Complete instructions for sample collection, processing, handling and shipment will be 
provided in the [CMEK162X2110 Laboratory Manual]. 
Table 7-4 
Schedule of blood sample collections for PK in dose escalation 
Cycle 
Day 
PK 
collection 
No. 
LGX818 
PK 
Sample 
No 
LGX818 
PK 
collection 
No. 
MEK162 
PK 
sample 
No. 
MEK162 
PK 
collection 
No. 
LEE011a 
PK 
sample 
No. 
LEE011a 
Scheduled time 
relative to dosing 
1 
1 
101 
101 
201 
201 
501 
501 
Pre-dose* 
1 
1 
101 
102 
201 
202 
501 
502 
0.5 hr post dose 
1 
1 
101 
103 
201 
203 
501 
503 
1.5 hr post dose 
1 
1 
101 
104 
201 
204 
501 
504 
2.5 hr post dose 
1 
1 
101 
105 
201 
205 
501 
505 
4 hr post dose 


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Cycle 
Day 
PK 
collection 
No. 
LGX818 
PK 
Sample 
No 
LGX818 
PK 
collection 
No. 
MEK162 
PK 
sample 
No. 
MEK162 
PK 
collection 
No. 
LEE011a 
PK 
sample 
No. 
LEE011a 
Scheduled time 
relative to dosing 
1 
1 
101 
106 
201 
206 
501 
506 
6 hr post dose 
1 
1 
101 
107 
201 
207 
501 
507 
8 hr post dose 
1 
2 
102 
108 
202 
208 
502 
508 
24 hr post dose 
immediately prior to 
dosing on C1D2 
1 
15 
103 
109 
203 
209 
503 
509 
Pre-dose* 
1 
15 
103 
110 
203 
210 
503 
510 
0.5 hr post dose 
1 
15 
103 
111 
203 
211 
503 
511 
1.5 hr post dose 
1 
15 
103 
112 
203 
212 
503 
512 
2.5 hr post dose 
1 
15 
103 
113 
203 
213 
503 
513 
4 hr post dose 
1 
15 
103 
114 
203 
214 
503 
514 
6 hr post dose 
1 
15 
103 
115 
203 
215 
503 
515 
8 hr post dose 
1 
16 
104 
116 
204 
216 
504 
516 
24 hr post dose 
immediately prior to 
dosing on C1D16** 
2 
1 
105 
117 
205 
217 
505 
517 
Pre-dose* 
3 
1 
106 
118 
206 
218 
506 
518 
Pre-dose* 
4 
1 
107 
119 
207 
219 
507 
519 
Pre-dose* 
5 
1 
108 
120 
208 
220 
508 
520 
Pre-dose* 
6 
1 
109 
121 
209 
221 
509 
521 
Pre-dose* 
7 
1 
110 
122 
210 
222 
510 
522 
Pre-dose* 
8 
1 
111 
123 
211 
223 
511 
523 
Pre-dose* 
9 
1 
112 
124 
212 
224 
512 
524 
Pre-dose* 
10*** 
1 
113 
125 
213 
225 
513 
525 
Pre-dose* 
NA 
NA 
NA 
1001+ 
NA 
2001+ 
NA 
5001+ 
Unscheduled**** 
*Collect PK sample immediately prior to the start of oral study drug combination (LGX818 and MEK162 or 
LGX818 and MEK162 and LEE011) administration. 
**Schedule PK collection together with collection fresh tumor and skin biopsy (if applicable). If it is not possible 
to collect the tumor and skin biopsy on C1D16, then an additional unscheduled pre-dose PK sample should be 
collected on the day fresh tumor biopsy and skin biopsy is collected. For patients for who a fresh skin/tumor 
biopsy is not collected, the C1D16 PK sample should be collected on the scheduled time point and day. The 
PK sample at this time point should be collected prior to the collection of the blood for genetic analysis sample. 
*** Pre-dose PK samples will be collected up to Cycle 10 only. 
****Applies only to samples collected before effective date of Protocol Amendment Version 09. Unscheduled 
PK samples will be uniquely, sequentially numbered 1001, 1002 etc. for LGX818 and 2001, 2002 etc for 
MEK162 and 5001, 5002 etc for LEE011. 
a only for patients treated with the triple study drug combination. 
Table 7-5 
Schedule of blood sample collections for PK in dual-combination 
Phase II arms 2 and 3, (and arm 1 if requireda) / triple-combination 
Phase II arm A 
Cycle 
Day 
PK 
collection 
No. 
LGX818 
PK 
Sample 
No 
LGX818 
PK 
collection 
No. 
MEK162 
PK 
sample 
No. 
MEK162 
PK 
collection 
No. 
LEE011b 
PK 
sample 
No. 
LEE011b 
Scheduled time 
relative to dosing 
1 
1 
301 
301 
401 
401 
601 
601 
Pre-dose* 
1 
1 
301 
302 
401 
402 
601 
602 
0.5 hr post-dose 


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Cycle 
Day 
PK 
collection 
No. 
LGX818 
PK 
Sample 
No 
LGX818 
PK 
collection 
No. 
MEK162 
PK 
sample 
No. 
MEK162 
PK 
collection 
No. 
LEE011b 
PK 
sample 
No. 
LEE011b 
Scheduled time 
relative to dosing 
1 
1 
301 
303 
401 
403 
601 
603 
1.5 hr post dose 
1 
1 
301 
304 
401 
404 
601 
604 
2.5 hr post dose 
1 
1 
301 
305 
401 
405 
601 
605 
5 hr post dose 
1 
1 
301 
306 
401 
406 
601 
606 
8 hr post dose 
1 
2 
302 
307 
402 
407 
602 
607 
24 hr post dose 
immediately prior to 
dosing on C1D2 
1 
15 
303 
308 
403 
408 
603 
608 
Pre-dose* 
1 
15 
303 
309 
403 
409 
603 
609 
0.5 hr post-dose 
1 
15 
303 
310 
403 
410 
603 
610 
1.5 hr post dose 
1 
15 
303 
311 
403 
411 
603 
611 
2.5 hr post dose 
1 
15 
303 
312 
403 
412 
603 
612 
5 hr post dose 
1 
15 
303 
313 
403 
413 
603 
613 
8 hr post dose 
1 
16 
304 
314 
404 
414 
604 
614 
24 hr post dose 
immediately prior to 
dosing on C1D16** 
2 
1 
305 
315 
405 
415 
605 
615 
Pre-dose* 
3 
1 
306 
316 
406 
416 
606 
616 
Pre-dose* 
4 
1 
307 
317 
407 
417 
607 
617 
Pre-dose* 
5 
1 
308 
318 
408 
418 
608 
618 
Pre-dose* 
6 
1 
309 
319 
409 
419 
609 
619 
Pre-dose* 
7 
1 
310 
320 
410 
420 
610 
620 
Pre-dose* 
8 
1 
311 
321 
411 
421 
611 
621 
Pre-dose* 
9 
1 
312 
322 
412 
422 
612 
622 
Pre-dose* 
10*** 
1 
313 
323 
413 
423 
613 
623 
Pre-dose* 
NA 
NA 
NA 
3001+ 
NA 
4001+ 
NA 
6001+ 
Unscheduled**** 
a Only for newly enrolled patients in which an assessment of the potential impact of demographic differences 
on the PK of the LGX818 and MEK162 combination may be made, if this assessment is required. 
b Only for patients treated with the triple study drug combination. 
*Collect PK sample immediately prior to the start of oral study drug combination (LGX818 and MEK162 or 
LGX818 and MEK162 and LEE011) administration. 
**Schedule PK collection together with collection fresh tumor and skin biopsy. If it is not possible to collect the 
tumor and skin biopsy on C1D16, then an additional unscheduled pre-dose PK sample should be collected on 
the day fresh tumor biopsy and skin biopsy is collected. The PK sample at this time point should be collected 
prior to the collection of the blood for genetic analysis sample. 
*** Pre-dose PK samples will be collected up to Cycle 10 only. 
**** Applies only to samples collected before effective date of Protocol Amendment Version 09. Unscheduled 
PK samples will be uniquely, sequentially numbered 3001, 3002 etc. for LGX818 and 4001, 4002 etc for 
MEK162 and 6001, 6002 etc for LEE011. 
 
 
7.2.3.2 
Analytical method 
For all samples collected, one tube will be shipped to each analytical lab for analysis. Refer to 
the [CMEK162X2110 Laboratory Manual] for detailed instructions for the collection, handling, 
and shipping of samples. 


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Plasma LGX818 concentrations will be measured at the Sponsor or designated CRO using a 
validated liquid chromatography-tandem mass spectrometiy (LC/MS/MS) assay. The lower 
limit of quantitation (LLOQ) is cmTently 1.0 ng/mL. 
Plasma concenti·ations of MEK162 and its metabolite, AR00426032, will be measured by the 
Sponsor (or designated CRO using a validated LC/MS/MS assay with an LLOQ of 5.0 ng/mL. 
Plasma concentl'ations of LEE0ll and its metabolite, LEQ803 will be measured (only 
applicable for ti·iple combination) at the Sponsor or at a designated CRO using a validated liquid 
chromatography-tandem mass specti·ometiy assay (LC/MS/MS). The lower limit of 
quantitation (LLOQ) is cmTently 1.0 ng/mL. 
7.2.4 
Biomarkers 
Note: As of protocol amendment 10, biomarker samples at time of relapse will no longer 
be collected. 
As outlined in Table 7-6, tumor, 
samples will be collected before and/or during 
ti·eatmentwith the LGX818 andMEK162 orLGX818 andMEK162 andLEE0l 1 dual and ti·iple 
combination res ectivel to investi ate the effect of the dm at the molecular andcellular level 


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Table 7-6 
Biomarker sample collection schedule 
Visit 
Details 
Tumor Biopsy Samples 
Screening/baseline 
Phase lb: A fresh tumor biopsy at Screening/baseline is highly recommended if 
accessible, and required from at least one patient of each dose level". 
Phase II: A fresh tumor biopsy at Screening/baseline is mandatory for all 
patients, however archival tissue is acceptable in some cases, please see 
Section 7.2.4.1.1. 
Cycle 1 Day 16 ( + 5 days.. ) 
A fresh on-treatment tumor biopsy is highly recommended, if accessible and if a 
fresh tumor biopsy was collected at Screening/baseline, at C1D16 (+ 5 days.. ) 
before the patients receive their morning dose on that day. This biopsy is 
required from at least one patient of each dose level during the dose escalation, 
and from at least 15 metastatic melanoma patients each enrolled in Phase II 
arm 2 and 3 dual combination and in Phase II arm A triple combination, and at 
least 6 metastatic CRC patients • enrolled in Phase II arm1 dual combination. 
.. For scheduling purposes the biopsy can be taken 5 days after the specified 
time point or earlier during Cycle 1 at the discretion of the investigator on Day 8 
(always pre-morning dose on the scheduled day and always paired with a pre- 
dose PK sample (except for Phase II arm 1 dual combination if no PK is 
collected)). 
At time of relapse 
If feasible according to the investigator, collection of a fresh tumor biopsy is 
strongly encouraged upon patient relapse (irrespective of whether a fresh tumor 
biopsy was collected at Screening/Baseline or on-treatment). This sample will 
be used to investigate changes in pathway signaling and potential mechanisms 
of resistance. The sample should be collected while the patient is still on study 
treatment or as soon as possible after study treatment discontinuation. For 
Phase II patients who are followed for disease progression after study 
treatment discontinuation, a fresh tumor biopsy should only be collected if the 
patient relapses within 2 months of study drugs discontinuation. 
Archival tumor sample with 
Requested from all patients and required for those in the Phase lb and II parts 
an accompanying pathology 
 not providing a fresh tumor biopsy sample. Sample should be a paraffin 
report, at 
 embedded block (preferred) or a representative number of slides as described 
Screening/baseline 
in the (CMEK162X2110 Laboratory Manual]. 
• evaluable paired tumor biopsies (pre and on-treatment (i.e. Screening/baseline and C1D16 + 5 days, or 
C1D8)) 


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7.2.4.1 
Biomarker assessments in tumor 
7.2.4.1.1 Screening/baseline tumor sample 
Representative tumor tissue (archival and/or fresh tumor sample) will be required from all 
patients at Screening/baseline. For patients enrolled in the Phase II paii of the study, a fresh 
tumor biopsy at Screening/baseline is mandato1y for all patients, unless sufficient fresh tumor 
tissue was collected dming local moleculai· pre-screening which can be submitted to the 
Sponsor-designated laborato1y at Screening (please refer to [CMEK162X2110 Laborato1y 
Manual] for details on collection, handling and shipment). If a tumor biopsy was collected after 
the last anti-neoplastic treatment within 2 months prior to study enrollment, the archival tissue 
of this tumor biopsy will be acceptable for enrollment instead of the fresh tumor biopsy. This 
sample will be used to investigate the 
of molecules in addition to BRAF that 
ai·e relevant to RAF/MEK./ERK and PI3K/AKT signaling pathways, (e.g. NRAS, PTEN, c-Kit, 
PIK3CA, etc.), to investigate the PTEN protein expression (IHC) and to potentially identify 
other predictive markers of efficacy. In addition, these samples are planned to be used for 
assessment of other genetic abnonnalities in the RAF/MEK./ERK and EGFR/PI3K/AKT 
signaling pathways, other pathways that may interact with the RAF/MEK./ERK and 
EGFR/PI3K/AKT signaling pathways, or ai·e thought to be important in cancer. 
 
 


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7.2.4.1.4 Collection of tumor biopsies 
Two biopsy passes must be obtained for all fresh tumor biopsies. The processing is described 
in Table 7-7. Detailed instructions for the collection, handling, and shipment of samples are 
outlined in the [CMEK162X2110 Laborato1y Manual]. 
Table 7-7 
Processing requirements for fresh tumor biopsy samples 
Tumor fragment 
number 
Processing requirements 
1 
Formalin-fixed paraffin- embedded (FFPE) 
To be processed/embedded 
together 
2 
Formalin-fixed paraffin- embedded (FFPE) 
 


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7.2.5 
Other assessments 
No additional tests will be perfo1med on patients entered into this study. 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events and Serious Adverse Events 
The definitions of an AE and an SAE can be found in Section 14.7, Appendix 7. 
AEs will be repo1ied by the patient (or, when appropriate, by a caregiver, Slmogate, or the 
patient's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, doclllllenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate infonnation both to detennine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the patient to discontinue the 
study treatment. 
Each patient will be questioned about the occmTence of AEs in a nonleading manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
info1mation in an expedited fashion. 
8.1.1 
Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs ("active collection period") 
for each patient begins from the time the patient provides informed consent, which is obtained 
before the patient's paiiicipation in the study (ie, before undergoing anystudy related procedure 
and/or receiving study treatment), through and including a minimlllll of 30 calendar days, except 
as indicated below, after the last administration of the study treatment. 
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator 
and Pfizer concurs with that assessment. 
For patients who are screen failures, the active collection period ends when screen failure status 
is dete1mined. 
If the patient withdraws from the study and also withdraws consent for the collection of future 
info1mation, the active collection period ends when consent is withdrawn. 
If a patient definitively discontinues or temporarily discontinues study treatment because of an 
AE or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the CT 
SAE Repo1i Fo1m. 
Investigators ai·e not obligated to actively seek AEs or SAEs after the patient has concluded 
study pa1iicipation. However, if the investigator learns of any SAE, including a death, at any 
time after a patient has completed the study, and he/she considers the event to be reasonably 


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related to the study treatment, the investigator must promptly report the SAE to Pfizer using the 
CT SAE Report Form. 
Patients who sign the molecular pre-screening ICF 
For patients who sign the molecular pre-screening ICF (see Section 4.1 and Section 7.1.1), AEs 
which occur after signature of this consent will only be captured if they meet the definition of 
serious as outlined in Section 14.7.2 and are associated with study related procedures (e.g. an 
invasive procedure such as biopsy). Once the study ICF is signed, all AEs per the descriptions 
below will be captured in the AE eCRF. 
Patients who sign the study ICF 
For patients whose BRAF mutational status is known and sign the study ICF, AEs that begin or 
worsen after informed consent should be recorded in the AE eCRF. Conditions that were 
already present at the time of informed consent should be recorded in the Medical History eCRF. 
Adverse event monitoring should be continued for at least 30 days 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 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 to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected though 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 
(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 Grade 1-4) 
2. Its duration (start and end dates) 
3. Its relationship to the study treatment (reasonable possibility that AE is related: No, Yes) 
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 taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
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) 


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of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
8.1.1.1 
Reporting SAEs to Pfizer Safety 
All SAEs occurring in a patient during the active collection period as described in Section 8.1.1. 
are reported to Pfizer Safety on the CT SAE Report Form immediately upon awareness and 
under no circumstance should this exceed 24 hours, as indicated in Section 14.7, Appendix 7. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
If a patient begins a new anticancer therapy, SAEs occurring during the above indicated active 
collection period must still be reported to Pfizer Safety irrespective of any intervening treatment. 
Note that a switch to a commercially available version of the study treatment is considered as a 
new anticancer therapy for the purposes of SAE reporting. 
8.1.1.2 
Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a patient during the active collection period, which 
begins after obtaining informed consent as described in Section 11.3, will be recorded on the 
AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the patient. 
If a patient begins a new anticancer therapy, the recording period for nonserious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the CRF 
during the above indicated active collection period. Note that a switch to a commercially 
available version of the study treatment is considered as a new anticancer therapy for the 
purposes of SAE reporting. 
8.1.2 
Methods of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 14.7, Appendix 
7. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the patient is the preferred method to inquire about AE 
occurrences. 
8.1.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
at subsequent visits/contacts. For each event, the investigator must pursue and obtain adequate 
information until resolution, stabilization, the event is otherwise explained, or the patient is lost 
to follow-up. 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of possible 
causality. Any information relevant to the event, such as concomitant medications and illnesses, 


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must be provided. In the case of a patient death, a summary of available autopsy findings must 
be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Section 14.7, Appendix 7. 
8.1.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
treatment under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRBs/ECs, and investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives SUSARs or other specific safety information (e.g., summary or 
listing of SAEs) from the sponsor will review and then file it along with the Investigator’s 
Brochure for the study and will notify the IRB/EC, if appropriate according to local 
requirements. 
8.1.5 
Exposure During Pregnancy or Breastfeeding and Occupational 
Exposure 
Exposure to the study treatment under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness. 
8.1.5.1 
Exposure During Pregnancy 
An EDP occurs if: 
• A female patient is found to be pregnant while receiving or after discontinuing study 
treatment. 
• A male patient who is receiving or has discontinued study treatment exposes a female 
partner prior to or around the time of conception. 
• A female is found to be pregnant while being exposed or having been exposed to study 
treatment due to environmental exposure. Below are examples of environmental 
exposure during pregnancy: 
• A female family member or healthcare provider reports that she is pregnant 
after having been exposed to the study treatment by ingestion. 
• A male family member or healthcare provider who has been exposed to the 
study treatment by ingestion then exposes his female partner prior to or 
around the time of conception. 


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The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to termination 
of pregnancy). 
• If EDP occurs in a patient or a patient’s partner, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP Supplemental 
Form, regardless of whether an SAE has occurred. Details of the pregnancy will be 
collected after the start of study treatment and until 30 days after last dose. 
• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the patient enrolled in the 
study, the information is not recorded on a CRF; however, a copy of the completed CT 
SAE Report Form is maintained in the investigator site file. 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for all 
EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural integrity 
of the terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, 
neonatal death, or congenital anomaly [in a live born baby, a terminated fetus, an intrauterine 
fetal demise, or a neonatal death]), the investigator should follow the procedures for reporting 
SAEs. Additional information about pregnancy outcomes that are reported to Pfizer Safety as 
SAEs follows: 
• Spontaneous abortion including miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study treatment. 
Additional information regarding the EDP may be requested by the sponsor. Further follow-up 
of birth outcomes will be handled on a case by case basis (e.g., follow-up on preterm infants to 
identify developmental delays). In the case of paternal exposure, the investigator will provide 
the patient with the Pregnant Partner Release of Information Form to deliver to his partner. The 
investigator must document in the source documents that the patient was given the Pregnant 
Partner Release of Information Form to provide to his partner. 
8.1.5.2 
Exposure During Breastfeeding 
An exposure during breastfeeding occurs if: 


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• A female patient is found to be breastfeeding while receiving or after discontinuing 
study treatment. 
• A female is found to be breastfeeding while being exposed or having been exposed to 
study treatment (ie, environmental exposure). An example of environmental exposure 
during breastfeeding is a female family member or healthcare provider who reports that 
she is breastfeeding after having been exposed to the study treatment by inhalation or 
skin contact. 
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours of 
the investigator’s awareness, irrespective of whether an SAE has occurred. The information 
must be reported using the CT SAE Report Form. When exposure during breastfeeding occurs 
in the setting of environmental exposure, the exposure information does not pertain to the 
patient enrolled in the study, so the information is not recorded on a CRF. However, a copy of 
the completed CT SAE Report Form is maintained in the investigator site file. 
An exposure during breastfeeding report is not created when a Pfizer drug specifically approved 
for use in breastfeeding women (e.g., vitamins) is administered in accord with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the exposure during breastfeeding. 
8.1.5.3 
Occupational Exposure 
An occupational exposure occurs when a person receives unplanned direct contact with the 
study treatment, which may or may not lead to the occurrence of an AE. Such persons may 
include healthcare providers, family members, and other roles that are involved in the trial 
patient’s care. 
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE. The information 
must be reported using the CT SAE Report Form. Since the information does not pertain to a 
patient enrolled in the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file. 
8.1.6 
Cardiovascular and Death Events 
Cardiovascular events are to be managed per the dose modification guidelines in Section 6.3. 
Additionally, cardiovascular events will be reported per AE and SAE reporting guidelines and 
ECG criteria, as detailed in Section 8.1 and Section 14.7, Appendix 7 and Section 7.2.2.8, 
respectively. AEs and SAEs that result in death are to be reported per the reporting guidelines 
as outlined in Section 8.1 and Section 14.7, Appendix 7. 
8.1.7 
Disease-Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs 
Not applicable. 
8.1.8 
Adverse Events of Special Interest 
Not applicable. 


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8.1.8.1 
Lack of Efficacy 
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE. 
8.1.9 
Medical Device Deficiencies 
Not applicable. 
8.1.10 
Medication Errors 
Medication errors may result from the administration or consumption of the study treatment by 
the wrong patient, or at the wrong time, or at the wrong dosage strength. 
Exposures to the study treatment under study may occur in clinical trial settings, such as 
medication errors. 
 
Safety Event 
Recorded on the AE CRF 
Reported on the CT SAE Report Form 
to Pfizer Safety Within 24 Hours of 
Awareness 
Medication errors 
Only if associated with an 
AE or SAE 
Only if associated with an SAE 
 
Medication errors include: 
• Medication errors involving patient exposure to the study treatment; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study patient. 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
If applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of 
the CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
8.2 
Treatment Overdose 
There is no known antidote for an overdose of either LGX818, MEK162 or LEE011. Supportive 
measures should be instituted. 
In the event of an overdose, the investigator/treating physician should: 
1. Contact the medical monitor within 24 hours. 
2. Closely monitor the patient for any AEs/SAEs and laboratory abnormalities for at least 
5 half-lives or 28 calendar days after the overdose of study treatment (whichever is 
longer). Closely monitor the patient for any AEs/SAEs. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
4. Overdose is reportable to Safety only when associated with an SAE. 


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Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor Medical Monitor based on the clinical evaluation of the patient. 
8.3 
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. 
8.4 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will not be in place for this trial. Instead, the Sponsor 
will convene a joint teleconference with the participating Investigators of the dose escalation at 
the end of each treatment cohort. At the dose escalation teleconference the clinical course 
(available safety information including both DLTs and all ≥ CTCAE Grade 2 toxicity data 
during Cycle 1, PK and PD data as appropriate) 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 BLRM (with EWOC) recommendation, and a medical review of available 
relevant clinical, PK, PD and laboratory data. The parties i.e. study Investigators and the 
Sponsor, must reach a consensus on whether to declare MTD, escalate the dose any further, or 
whether to de-escalate and/or expand recruitment into particular cohorts. The Sponsor will 
prepare minutes from these meetings and circulate them to all concerned (Section 6.2.4.2.1). 
 
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. 
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 at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 


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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. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Sponsor personnel 
(or designated CRO) will review the protocol and eCRFs 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 eCRFs, 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 eCRFs 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 eCRF entries. The Sponsor’s 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 eCRFs 
are performed according to the study-specific monitoring plan. 
9.3 
Data collection 
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. 
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. 
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 Sponsor-assigned laboratory or 
contracted central labs. ECG data (except the screening/baseline ECG) collected during the 
study will be reviewed and processed centrally by a specialist CRO. Designated investigational 
site staff will enter the information required by the protocol into the appropriate eCRF (and/or 
designated laboratory requisition forms that are printed on 2 or 3-part, non-carbon-required 
paper). Field monitors will review the eCRFs and laboratory paper requisition forms for 
accuracy and completeness and instruct site personnel to make any required corrections or 


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additions. One copy of the requisition form will be forwarded to each analytical laboratory with 
the respective sample(s) by the field monitor or by the designated investigational site staff; and 
one copy will be retained at the investigational site. 
9.4 
Database management and quality control 
Sponsor personnel (or designated CRO) 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 investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments 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. 
Biomarker and PK samples and ECG (except screening/baseline) will be processed centrally, 
and the results for these will be sent electronically to the Sponsor (or a designated CRO). 
After database lock, the investigator will receive a CD-ROM or paper copies of the patient data 
for archiving at the investigational site. 
 
10 
Statistical methods and data analysis 
[Any language regarding the triple combination of LGX818/MEK162/LEE011 in this 
Section is not applicable to the USA and Singapore] 
Data will be analyzed by the Sponsor and/or designated CRO. Any data analysis carried out 
independently by the investigator must be submitted to the Sponsor before publication or 
presentation. 
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. Data will be summarized with 
respect to demographic and baseline characteristics, efficacy and safety observations and 
measurements and all relevant PK and PD measurements. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
An initial clinical study report (CSR) will be presented based on the Ph Ib/II patients’ data from 
the dual study drug combination. The cut-off for reporting will be either LPFV + 18 months or 
when 80% of the patients treated with the dual study drug combination can be assessed for PFS, 
whichever occurs first. 
Additional data for any patients continuing to receive the LGX818 and MEK162 dual 
combination past the cut off point for the initial reporting, as allowed by the protocol, and the 
Phase Ib/II patients’ data from the LGX818 and MEK162 and LEE011 triple combination will 
be summarized in a final CSR that will be prepared when all patients have completed or 
discontinued from the study. 


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The following rules will be followed for reporting results unless stated otherwise: 
• Phase Ib dose escalation data: Cohorts of patients treated with the same dose 
combination and regimen during the dose escalation part will be pooled into a common 
treatment group. All summaries, listings, figures and analyses will be displayed / 
performed by treatment group unless otherwise specified. 
• Phase II data: Data will be summarized and listed by study arm. 
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected, Section 7.1.2.2, will not 
be included in any analysis, but will be reported in the CSR as separate listings. 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The FAS includes all patients who received at least one dose of LGX818 or MEK162 or 
LEE011. Patients will be classified according to the planned treatment regimen (dose, schedule, 
tablet variant). 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 
Safety Set 
The safety set includes all patients who received at least one dose of LGX818 or MEK162 or 
LEE011, and have at least one valid post-baseline safety assessment. The statement that a 
patient had no AEs (on the AE eCRF) constitutes a valid safety assessment. 
Patients will be classified according to treatment received, where treatment received is defined 
as: 
• The treatment assigned if it was received at least once, or 
• The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received. 
10.1.3 
Dose-Determining Set 
The dose-determining set (DDS) includes all patients from the safety set who either completed 
a minimum exposure requirement and have sufficient safety evaluations or discontinued 
prematurely due to a dose limiting toxicity (DLT). 
A patient is considered to have met the minimum exposure requirement if having received at 
least 75% of the planned combination doses (i.e. 21 out of 28 planned daily doses for QD or 
BID, 11 out of 14 planned doses for an every other day dosing schedule, and 16 days out of 21 
days for 3 week on, 1 week off dosing schedule) of study treatment within the first Cycle of 
dosing. The length of a cycle is 28 days. 
Patients who do not experience DLT during the first cycle will be 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 
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10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for all patients in the FAS. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
10.3.1 
Study treatment 
The actual dose and duration in days of LGX818 and MEK162 and LEE011 treatment as well 
as the dose intensity (computed as the ratio of actual dose received and actual duration) and the 
relative dose intensity (computed as the ratio of dose intensity and planned dose 
received/planned duration), will be listed and summarized by means of descriptive statistics. 
The summary data will be presented for each treatment cycle individually, as well as for all 
study days as a single category. The daily doses of LGX818, MEK162, and LEE011 for each 
patient will be summarized using descriptive statistics (e.g. mean, median, and modal doses). 
The FAS will be used. For patients who switch to the new MEK162 tablet variants, dose 
intensity will be calculated based on the bioavailability ratio between the original and new 
MEK162 tablet variants if the new and old variants are not similar. Details will be provided in 
report analysis plan (RAP). 
10.3.2 
Concomitant therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug treatment will be listed by patient and summarized by ATC (Anatomical therapeutic 
chemical classification system) term by means of contingency tables. 
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. 
10.4 
Primary objective 
Phase Ib 
The primary purpose of the Phase Ib part of the study is to estimate the MTD(s) and/or RP2D(s) 
of the LGX818 and MEK162 dual combination and MTD(s) and/or RP2D(s) of LGX818 and 
MEK162 and LEE011 triple combination in patients with solid tumors harboring a BRAF V600 
mutation (see Section 3). The corresponding method of analysis is an adaptive Bayesian logistic 
regression model (BLRM) guided by the escalation with overdose control (EWOC) principle 
(Babb 1998). 
Phase II 
The primary purpose of the Phase II part of the study is to assess the efficacy of the RP2D(s) of 
the dual combination of LGX818 and MEK162 combination in patients with metastatic BRAF 


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V600 mutant mCRC (arm 1), in patients with metastatic BRAF V600 mutant melanoma who 
have progressed after prior treatment with selective BRAF inhibitor (arm 2) and in patients with 
metastatic BRAF V600 mutant melanoma who are naïve to prior treatment with selective BRAF 
inhibitor (arm 3). The primary purpose of the Phase II part of triple combination of LGX818 
and MEK162 and LEE011 is to assess the efficacy of the RP2D(s) in patients with metastatic 
BRAF V600 mutant melanoma who are naïve to prior treatment with selective BRAF inhibitor 
(arm A). 
10.4.1 
Variable 
Phase Ib 
Estimation of the MTD of the combination treatment will be based upon the estimation of the 
probability of DLT in Cycle 1 for patients in the dose-determining set. This probability is 
estimated by the model in Section 10.4.2. Note that more than one dose-combination of dual 
combination (LGX818 and MEK162) or triple combination (LGX818 and MEK162 and 
LEE011) may be identified as a MTD, and more than one RP2D may be established for further 
evaluation in the phase II part of the study. 
The dose determining set (DDS) will be used for all dose determining analyses. 
Phase II 
 
Dual combination (LGX818 and MEK162) 
For arm 1, the primary variable is the Disease Control Rate (DCR) at week 16. DCR is defined 
as the proportion of patients with a best overall response of complete response (CR), partial 
response (PR) or stable disease (SD). Estimation of the true DCR in this part of the study will 
be based upon observed DCR for patients in the FAS. The true DCR is estimated using a 
Bayesian design. The primary analysis of the DCR will be based on the local review of overall 
lesion responses. 
For arms 2 and 3, the primary variable is the Objective Response Rate (ORR), defined as the 
proportion of patients with a best overall response of complete response (CR) or partial response 
(PR). Estimation of the true ORR in this part of the study will be based upon observed ORR for 
patients in the FAS. The true ORR is estimated using a Bayesian design. The Primary analysis 
of the ORR will be based on the local review of overall lesion responses. 
Triple combination (LGX818 and MEK162 and LEE011) 
For arm A, the primary variable is the Objective Response Rate (ORR), defined as the 
proportion of patients with a best overall response of complete response (CR) or partial response 
(PR). Estimation of the true ORR in this part of the study will be based upon observed ORR for 
patients in the FAS. The true ORR is estimated using a Bayesian design. The Primary analysis 
of the ORR will be based on the local review of overall lesion responses. 


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10.4.2 
Statistical hypothesis, model, and method of analysis 
10.4.2.1 Phase Ib 
An adaptive BLRM guided by the EWOC principle will guide the dose escalation of the 
combination treatment to its MTD(s)/RP2D(s). A 5-parameter BLRM for combination 
treatment will be fitted on the dose-limiting toxicity data (i.e. absence or presence of DLT) 
accumulated throughout the dose escalation, for modeling the dose-DLT relationship of 
LGX818 (capsule formulation) and MEK162 when given in combination. While developing 
dual combination (LGX818 and MEK162) all information available about the dose-DLT 
relationship of the single agents LGX818 (i.e., from [LGX818X2101] study on both the capsule 
and micro-emulsion formulations) and MEK162 [ARRAY-162-111 study] will be summarized 
in prior distributions, based on a meta-analytical predictive approach to properly down-weight 
the information. The 5 parameter BLRM will be extended to a 10-parameter BLRM to model 
the dose-DLT relationship of LGX818 (capsule formulation) and MEK162 and LEE011 when 
given in combination. Three week on 1 week off DLT data from [CLEE011X2101] will be 
summarized in prior distributions based on a meta-analytical predictive approach to properly 
down-weight the information. 
The 5-parameter BLRM for MEK162 original tablet 
The 5-parameter BLRM is formulated in the following way: Let π1(d1) be the probability of a 
DLT if LGX818 is given as a single agent at dose d1, and π2(d2) the probability of a DLT if 
MEK162 is given as a single agent at dose d2. The dose-response relationship is then modeled 
as: 
LGX818: logit(π1(d1)) = log(α1) + β1log(d1/d1*) 
MEK162 original tablet: logit(π2(d2)) = log(α2) + β2log(d2/d2*) 
Odds(π12(d1,d2))) = π12(d1,d2)/(1- π12(d1,d2)) 
= exp(η12(d1/d1*)(d2/d2*))(π1(d1)+ π2(d2) - π1(d1)π2(d2))/((1- π1(d1))(1- π2(d2))), 
where 
• logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], π(d) is the probability of a DLT at dose d, 
• π12(d1,d2) is the probability of a DLT given the combination doses 
• d1*= 100mg and d2*= 60mg are the reference doses of LGX818 and MEK162 original 
tablet respectively, 
• α1, α2, β1, β2 > 0 and -∞ < η12 < ∞ is a scalar. With η12 the interaction term between 
LGX818 and MEK162 original tablet. 
For further details on the statistical model including the prior specification for the model 
parameters refer to Appendix 5. 
The 5-parameter BLRM for MEK162 smaller tablet/ new tablet variant 
The 5-parameter BLRM is formulated in the following way: Let π1(d1) be the probability of a 
DLT if LGX818 is given as a single agent at dose d1, and π3(d3) the probability of a DLT if 


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MEK162 is given as a single agent at dose d3. The dose-response relationship is then modeled 
as: 
LGX818: logit(π1(d1)) = log(α1) + β1log(d1/d1*) 
MEK162 smaller tablet/ new tablet variant: logit(π3(d3)) = log(α3) + β3log(d3/d3*) 
Odds(π13(d1,d3))) = π13(d1,d3)/(1- π13(d1,d3)) 
= exp(η13(d1/d1*)(d3/d3*)))(π1(d1)+ π3(d3) - π1(d1)π3(d3))/((1- π1(d1))(1- π3(d3))), 
where 
• logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], π(d) is the probability of a DLT at dose d, 
• π13(d1,d3) is the probability of a DLT given the combination doses 
• d1*= 100mg and d3* are the reference doses of LGX818 and MEK162 respectively. The 
value of d3* will be determined prior to first DETC for the MEK162 smaller tablet/ new 
tablet variant. 
• α1, α3, β1, β3 > 0 and -∞ < η13 < ∞ is a scalar. With η13 the interaction term between 
LGX818 and MEK162 smaller tablet/new tablet variant. 
For further details on the statistical model including the prior specification for the model 
parameters refer to Appendix 5. 
The 10-parameter BLRM 
The 10-parameter BLRM is formulated in the following way: Let λ1(d1) be the probability of 
DLT if LGX818 is given as a single agent at QD dose d1, λ2(d2) the probability of DLT if 
MEK162 is given as a single agent at BID dose d2, and λ3(d3) the probability of DLT if LEE011 
is given as a single agent at 3 week on 1 week off dose of d3. 
The single agent dose-DLT relationships are then modeled as: 
LGX818: logit(π1(d1)) = log(α1) + β1log(d1/d1*) 
MEK162: logit(π2(d2)) = log(α2) + β2log(d2/d2*) 
LEE011: logit(π4(d4)) = log(α4) + β3log(d4/d4*) 
The 
dose-DLT 
relationships 
of 
the 
dual 
combinations 
of 
LGX818+MEK162, 
LGX818+LEE011 and MEK162+LEE011 are modeled as: 
Odds(π12(d1,d2))) = π12(d1,d2)/(1- π12(d1,d2)) 
= exp(η12(d1/d1*)(d2/d2*))(π1(d1)+ π2(d2) - π1(d1)π2(d2))/((1- π1(d1))(1- π2(d2))), 
Odds(π14(d1,d4))) = π14(d1,d4)/(1- π14(d1,d4)) 
= exp(η14(d1/d1*)(d4/d4*)))(π1(d1)+ π4(d4) - π1(d1)π4(d4))/((1- π1(d1))(1- π4(d4))), 
Odds(π24(d2,d4))) = π24(d2,d4)/(1- π24(d2,d4)) 
= exp(η24(d4/d4*)(d2/d2*)))(π2(d2)+ π4(d4) – π2(d2)π4(d4))/((1- π2(d2))(1- π4(d4))), 
The dose-DLT relationship of the triple combination is subsequently modeled as: 
Odds(π124(d1, d2,d4))) = π124 (d1, d2,d4)/(1- π124(d1,d2,d4)) 


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= 
exp(η124(d1/d1*)(d2/d2*)(d4/d4*)+ 
η12(d1/d1*)(d2/d2*)+ 
η14(d1/d1*)(d4/d4*)+ 
η24(d2/d2*)(d4/d4*))( π1(d1)+ π2(d2)+ π4(d4) – π1(d1)π2(d2)-π1(d1)π4(d4)-π2(d2)π4(d4)+ 
π1(d1)π2(d2) π4(d4))/((1- π1(d1))(1- π2(d2))(1- π4(d4))), 
where logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], d1* = 100mg (QD), d2* = 60mg (BID) and d4* = 
400mg (3 week on 1 week off) are the reference doses of LGX818, MEK162 and LEE011 
respectively, α1, α2, α4, β1, β2 , β4> 0 and -∞ < ζ12, ζ13, ζ23, ζ124 < ∞ are constants. 
For further details on the statistical model including the prior specification for the model 
parameters refer to Appendix 6. 
Dose recommendation 
Dose recommendation will be based on posterior summaries including the mean, median, 
standard deviation, 95%- credible interval, and the probability that the true DLT rate for each 
dose combination lies in one of the following categories: 
• [0%, 16%) under-dosing 
• [16%, 35%) targeted toxicity 
• [35%, 100%] excessive toxicity 
Following the principle of EWOC, after each cohort of patients the dose combination 
recommended by the BLRM is the one with the highest posterior probability of DLT in the 
target interval [16%, 35%) among the doses fulfilling the overdose criterion that there is less 
than 25% chance of excessive toxicity. 
In addition, the maximum inter-cohort combined dose escalation across the 2 combination 
partners is limited to 100%, where 100% refers to the sum of the relative escalation for each of 
the combination partners, e.g. 100% and 0% increase for LGX818 and MEK162 respectively, 
0% and 100% increase for LGX818 and MEK162 respectively, etc. 
Summaries of the posterior distribution of model parameters and posterior distribution of DLT 
rates based on the DLT data from all patients enrolled in the study and included in the DDS will 
be produced. 
10.4.2.2 Phase II 
Efficacy will be assessed using the local CT/MRI assessments evaluated under RECIST version 
1.1, Appendix 1. The Best Overall Response (BOR) for each patient and individual lesion 
measurements will be listed. The (BOR) is the best response recorded from the start of the 
treatment until disease progression. Based on patients’ BOR during study, the Objective 
Response Rate (ORR) and the Disease control Rate (DCR) are then calculated. 
The ORR is defined as the proportion of patients with a best overall response of Complete 
Response (CR) or Partial Response (PR). The DCR is defined as CR or PR or Stable Disease 
(SD). 
Patients who withdrew prematurely due to progression of disease without having any post-dose 
tumor assessment will be classified as treatment failures. Similarly, patients who died due to 
their disease without having any post-dose tumor assessment will be classified as treatment 
failures. 


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Arm 1 dual combination: patients with metastatic BRAF V600 mutant mCRC 
A Bayesian design will be used in order to estimate the true DCR. Inferential statements will 
be based on the uncertainty of this quantity. For a Bayesian design it is required to specify a 
prior distribution for the parameter of interest, in this case DCR. 
For the current study, the prior clinical assumption for a MEK inhibitor in BRAF V600 mutant 
mCRC at pre-specified dose-levels will be used in order to derive a minimally informative 
unimodal Beta prior distribution that reflects the level of uncertainty around the DCR before 
starting the current trial. At completion of the study, this prior distribution will be updated with 
all the data available in this part of the study. 
Once updated, the distribution summarizes the probability that the true DCR at the dose of the 
LGX818 and MEK162 combination used in the Phase II lies in the following categories: 
• [0, 20%) unacceptable efficacy 
• [20%, 30%) limited efficacy 
• [30%, 40%) moderate efficacy 
• [40%, 100%] clinically relevant efficacy 
If the observed DCR is equal or greater than 30% (i.e. 9 or more patients with BOR of SD, PR 
or CR), then this will be considered as evidence of clinically relevant anti-tumor efficacy of the 
LGX818 and MEK162 combination in BRAF V600 mutant mCRC. Note that for a sample size 
of 28, if at least 9 patients with DCR are observed, then the true DCR has posterior risk of being 
in the unacceptable efficacy category of less than 10% (Section 10.8). If the observed DCR is 
less than 20% then inactivity will be declared. 
A minimally informative Beta prior distribution of the true DCR is derived as follows: a priori 
it is assumed that the true mean of the DCR equals 30%. A true DCR of 30% is the midpoint 
between limited and moderate efficacy and serves as a compromise between a skeptical view 
assuming the treatment has only limited efficacy and an optimistic view assuming the treatment 
has moderate efficacy. 
The parameters of the minimally informative Beta prior distribution of the DCR are then derived 
noting that b = 1 and 
a (a + b ) = 0 . 30 
i.e.  a = 0 . 428 
and 
b = 1 
Arm 2 dual combination: patients with metastatic BRAF V600 mutant melanoma 
who have progressed after prior treatment with selective BRAF inhibitor 
A Bayesian design will be used in order to estimate the true ORR. Inferential statements will 
be based on the uncertainty of this quantity. For a Bayesian design it is required to specify a 
prior distribution for the parameter of interest, in this case ORR: 
For the current study, the prior clinical assumption for a MEK inhibitor in BRAF V600 mutant 
melanoma at pre-specified dose-levels will be used in order to derive a minimally informative 
unimodal Beta prior distribution that reflects the level of uncertainty around the ORR before 
starting the current trial. At completion of the study, this prior distribution will be updated with 
all the data available in this part of the study. 


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Once updated, the distribution summarizes the probability that the true ORR at the dose of the 
LGX818 and MEK162 combination used in the Phase II lies in the following categories: 
• [0, 10%) unacceptable efficacy 
• [10%,15%) limited efficacy 
• [15%, 20%) moderate efficacy 
• [20%, 100%] clinically relevant efficacy 
If the observed ORR is equal or greater than 15% (i.e. 7 or more patients with BOR of PR or 
CR), then this will be considered as evidence of clinically relevant anti-tumor efficacy of the 
LGX818 and MEK162 combination in BRAF V600 mutant melanoma. Note that for a sample 
size of 41, if at least 7 responses (CR or PR) are observed, then the true ORR has posterior risk 
of being in the unacceptable efficacy category of less than 10% (Section 10.8). If the observed 
ORR is less than 10% then inactivity will be declared. 
A minimally informative Beta prior distribution of the true ORR is derived as follows: a priori 
it is assumed that the true mean of the ORR equals 15%. A true ORR of 15% is the midpoint 
between limited and moderate efficacy and serves as a compromise between a skeptical view 
assuming the treatment has only limited efficacy and an optimistic view assuming the treatment 
has moderate efficacy. 
The parameters of the minimally informative Beta prior distribution of the ORR are then derived 
noting that b = 1 and 
a (a + b ) = 0 . 15 
i.e. 
a = 0 . 176 
and 
b = 1 
Arm 3 dual combination / Arm A triple combination: patients with metastatic 
BRAF V600 mutant melanoma who are naïve to prior treatment with selective 
BRAF inhibitor 
A Bayesian design will also be used in order to estimate the true ORR in these populations. 
Inferential statements will be based on the uncertainty of this quantity. For a Bayesian design it 
is required to specify a prior distribution for the parameter of interest, in this case ORR: 
For the current study, a minimally informative unimodal Beta prior distribution 
(Neuenschwander et al 2008) is developed for ORR. The prior distribution reflects the level of 
uncertainty around the ORR before starting the current trial. At completion of the study, this 
prior distribution will be updated with all the data available in this part of the study. 
Once updated, the distribution summarizes the probability that the true ORR at the dose of the 
dual combination (LGX818 and MEK162) and triple combination (LGX818 and MEK162 and 
LEE011) used in the Phase II lies in the following categories: 
• [0, 30%) unacceptable efficacy 
• [30%, 40%) limited efficacy 
• [40%, 50%) moderate efficacy 
• [50%, 100%] clinically significant efficacy 
If the observed ORR is equal to or greater than 40% (i.e. 16 or more patients with BOR of PR 
or CR for a sample size of 40), then this will be considered as evidence of clinically relevant 
anti-tumor efficacy of the dual combination (LGX818 and MEK162) or triple combination 
(LGX818 and MEK162 and LEE011) in BRAF V600 mutant melanoma patients who have not 


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been previously treated with selective BRAF inhibitor. Note that for a sample size of 40, if at 
least 16 responses (CR or PR) are observed, then the hue ORR has posterior risk of being in the 
unacceptable efficacy catego1y of less than 10% (Section 10.8). If the observed ORR is less 
than 30% then inactivity will be declared. A minimally infonnative Beta prior dish·ibution of 
the h11e ORR is derived as follows: a priori it is assumed that the h11e mean of the ORR equals 
40%. A hue ORR of 40% is the midpoint between limited and moderate efficacy and serves as 
a compromise between a skeptical view assuming the h·eatment has only limited efficacy and 
an optimistic view assuming the h·eatinent has moderate efficacy. 
The parameters of the minimally infonnative Beta prior dish·ibution of the ORR are then derived 
noting that b=l and a/(a+b)=0.4 i.e. a=0.67 and b=l. 
Re-assessment of the MTD/RP2D 
A re-assessment of the dual-combination MTD/RP2D will be perfonned (using dual- 
combination data only) after at least 10 patients in the Phase II paii (aim 1 + aim 2 + aim 3) of 
the study have been h'eated for at least one cycle. A re-assessment of the h'iple-combination 
MTD/RP2D will be perfo1med after at least 10 patients in the Phase II paii of the study have 
been h·eated with the h·iple combination for at least one cycle. The BLRM will be re-nm to 
confnm that the cmTent dose combination still satisfies the overdose criteria for the model. If 
this combination fails to satisfy the criteria, a change to the doses lmder study will be made 
subject to the BLRM recommendation. If different RP2Ds ai·e used for ann 1, aim 2 and aim 3, 
respectively, then the above re-assessment will be done by RP2D rather than combining the 
aims. 
Emollment in the Phase II anns will not be inte1n1pted due to this re-assessment of the 
MTD/RP2D. 
10.4.3 
Handling of missing values/censoring/discontinuations 
Patients who are ineligible for the DDS may be replaced as described in Section 7.1.4.2. 
Continuing events (e.g. AEs, concomitant medication, etc) will be summarized using the data 
cut-off date as the date of completion, with an indication within listings that the event is 
continuing. For patients who discontinue the study with ongoing events, the discontinuation 
date will be used as the completion date of the event with the appropriate censoring as described 
in the above pai·agraph. 
Patients for whom no best overall response can be assessed at the time of the primaiy analysis 
will be h·eated as h·eatinent failmes. 
The reason for discontinuation from study will be smnmai·ized and listed, along with dates of 
first and last study dmg h'eatinent, dmation of exposme to study dmg h'eatment and date of 
discontinuation for each patient. 
Other missing data will simply be noted as missing on appropriate tables/listings. 
10.4.4 
Supportive analyses 
 


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If deemed necessary, a sensitivity analysis will be performed using central imaging assessments 
according to RECIST v1.1 (see Appendix 1, Section 14.1). The same method of analysis as for 
the primary analysis will be used, using the FAS. 
10.5 
Secondary objectives 
10.5.1 
Efficacy 
Phase Ib. A secondary objective of the Phase Ib is to assess preliminary clinical anti-tumor 
activity of the combination in patients with BRAF V600-dependent advanced solid tumors. For 
all efficacy analyses the FAS will be used. 
Anti-tumor activity will be assessed using the Investigator imaging assessments under RECIST 
version 1.1, Appendix 1. The Best Overall Response (BOR) for each patient and individual 
lesion measurements will be listed. The (BOR) is the best response recorded from the start of 
the treatment until disease progression. ORR will be estimated for this patient population. TTR 
and DOR will be assessed if at least one responder is observed. 
Phase II. Local imaging assessments will be used for all Phase II efficacy assessments of tumor 
activity. The FAS will be used. 
Overall survival (OS) is defined as the time from 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 contact. 
Kaplan-Meier estimates with confidence intervals for median survival and survival probabilities 
for specific time points will be presented. 
The secondary endpoint progression-free survival (PFS) will be analyzed using Kaplan-Meier 
estimates (including plots) with 95% confidence interval for median survival. If a patient has 
not had an event, he/she will be censored at the date of last adequate response assessment. PFS 
is defined as the number of days from the first day of treatment to the date of the first 
documented progression of disease or date of death, whichever occurs first. PFS will be 
summarized by arm. 
Kaplan-Meier estimates based on all responders with 95% confidence intervals will be 
presented for the secondary endpoint duration of overall response (DOR). This analysis based 
on responders will be used as a descriptive analysis. DOR is the time between the date of first 
documented response (CR or PR) and the date of documented progression or censoring. 
Censoring will occur at the last adequate tumor assessment date at which continued response is 
documented. 
The secondary endpoint time to response (TTR) is the time between the date of first treatment 
administration and the first documented response (CR or PR). Patients who did not achieve a 
confirmed PR or CR will be censored at the last adequate tumor assessment date when they did 
not progress, or at maximum follow-up (i.e. FPFV to LPLV used for analysis) when they had 
an event for PFS. 
If deemed necessary, analyses of TTR and DOR as described above, will be performed using 
central imaging assessments (RECIST v1.1). FAS will be applied. 


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10.5.2 
Safety 
For all safety analyses, the safety set will be used, unless otherwise specified. The assessment 
of safety will be based mainly on the frequency of adverse events and on the number of 
laboratory values that fall outside of pre-determined ranges. All individual safety data reported 
in the clinical data base will be listed by patient and dose level. 
The overall observation period will be divided into three mutually exclusive segments: 
• pre-treatment period: from day of patient’s informed consent signature to the day before 
first dose of study treatment. 
• on-treatment period: from day of first dose of study treatment to 30 days after last dose of 
study medication. 
• post-treatment period: starting at day 31 after last dose of study treatment. 
10.5.2.1 Adverse events 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by primary system organ class, severity based on the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, type of adverse 
event, and relationship to the study drug by dose level on the pool of patients recruited during 
the dose escalation part of the study as well as on the complete pool of patients (including dose 
escalation and Phase II parts). Deaths reportable as SAEs and non-fatal serious adverse events 
will be listed by patient and tabulated by primary system organ class, type of adverse event, and 
dose level. 
DLTs will be listed and their incidence summarized by primary system organ class, worst grade 
based on the CTCAE version 4.03, type of adverse event, and by dose level in the dose 
escalation part. The dose-determining set will be used for these summaries. 
Details of analysis to be performed are given in the Reporting and Analysis Plan (RAP). 
10.5.2.2 Laboratory abnormalities 
All laboratory values will be converted into SI units and the severity grade calculated using 
CTCAE, version 4.03. Parameters for which a grading does not exist will be classified into 
low/normal/high group by means of laboratory normal ranges. 
For each laboratory test (e.g. hematology, biochemistry etc) a listing of laboratory values will 
be provided by laboratory parameter, patient, and dose level. The frequency of notable 
laboratory abnormalities (i.e., newly occurring CTC grade 3 or 4 laboratory toxicities) will be 
displayed by parameter, cycle and dose level. Similarly, the frequency of all laboratory 
abnormalities will be displayed by parameter, worst CTCAE grade experienced and dose level. 
A separate listing will display notable laboratory abnormalities. 
Laboratory data will be summarized by presenting grade shift tables for those parameters for 
which CTCAE allows classification. All remaining data will be summarized by presenting shift 
tables based on normal ranges. 
Laboratory data will be also be displayed by presenting summary statistics of raw data and 
change from baseline values (means, medians, standard deviations, ranges). 


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10.5.2.3 Other Safety data 
Any other safety information collected will be listed and notable values will be flagged. Any 
statistical tests performed to explore the data will be used only to highlight any interesting 
comparisons that may warrant further consideration. Additionally, the following outputs will 
be produced: 
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 
• shift table baseline to worst on-treatment result 
• table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
Ocular 
• Listing of ocular assessment for all patients with at least one abnormality will be 
presented. 
10.5.2.4 Tolerability 
Tolerability of study drug treatment will be assessed by summarizing the number of treatment 
dose interruptions and dose reductions. Reasons for dose interruption and dose reductions will 
be listed by patient and summarized. Cumulative dose, dose intensity and relative dose intensity 
of MEK162, LGX818 and LEE011 will be listed by patient and summarized. Categories for 
relative dose intensity of the combination MEK162, LGX818 and LEE011 will be specified as 
< 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The number and proportion of 
patients within each category will be presented. 
10.5.3 
Pharmacokinetics 
A secondary objective of this study is to determine the single and multiple dose pharmacokinetic 
profile of the dual combination (MEK162 and LGX818), and the triple combination (LGX818 
and MEK162 and LEE011). 
For plasma LGX818, the LLOQ is 1.0 ng/mL, for MEK162 is 5.0 ng/mL and LEE011 is 
1.0 ng/mL. All concentrations below the LLOQ 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. The parameters displayed on Table 10-1 will be estimated and reported. 
Descriptive graphical plots of individual and mean plasma concentration (per treatment) along 
with its time course will be generated. Further graphical exploratory analyses will be carried 
out if deemed appropriate. Pharmacokinetic parameters for each dose cohort will be analyzed 
by descriptive statistics, including the mean, SD, CV% or median (range). Since tmax is generally 
evaluated by a non-parametric method, median values and ranges will be given for this 
parameter. 


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Assessment of dose-proportionality, inter- and intra-individual variability and steady-state 
attainment will be conducted. If appropriate, an analysis of variance (ANOVA) will be 
performed on log-transformed AUCs and Cmax using a linear mixed effect model to assess day 
effect. 
Details of PK analysis presented will be given in the Reporting and Analysis Plan. Any other 
exploratory analysis will be conducted if necessary. 
Table 10-1    PK parameters 
Variable Definition 
Cmax 
Maximum observed plasma concentration after drug administration [mass x volume-1] 
Cmax,ss 
Maximum observed plasma concentration during a dosing interval at steady state [mass x volume-1] 
Ctrough 
Measured concentration at the end of a dosing interval at steady state (taken directly before next 
administration) [mass x volume-1] 
tmax 
Time to reach Cmax [time] 
tmax,ss 
Time to reach Cmax at steady state [time] 
AUCtau 
Area under the concentration-time curve during a dosing interval [mass x time x volume-1] 
AUCinf 
Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal 
phase [mass x time x volume-1] 
AUCtau,ss Area under the concentration-time curve during a dosing interval at steady state [mass x time x 
volume-1] 
t1/2 
Elimination half-life associated with the terminal slope (z) of a semi logarithmic concentration-time 
curve [time] 
CL/F 
Apparent total plasma clearance of drug after oral administration [volume x time-1] 
V/F 
Apparent volume of distribution [volume] 
RA 
Accumulation ratio calculated as AUCtau,ss/AUCtau,dose1 
In addition, in case drug accumulation is observed upon multiple dosing, additional PK 
parameters describing drug accumulation will be added to the analysis (i.e. effective half-life). 
10.5.3.1 Data handling principles 
10.5.3.1.1 
Analysis sets 
Only PK blood samples with date and time and for which the last prior dose dates and times are 
adequately recorded will be included in the PK analyses. Samples taken from patients who 
vomited within 4 hrs of dosing will be excluded from the analysis. The FAS will be used. 
10.5.3.1.2 
Basic tables, figures and listings 
Descriptive statistics (mean, standard deviation, CV% or median (range)) will be presented for 
all parameters for each dose cohort. When a geometric mean is presented, it will be stated as 
such. CL/F will be assessed for MEK162, LGX818 and LEE011, as applicable, and only median 
values and ranges will be given for tmax. 
Descriptive graphical plots of individual plasma concentration by time will be generated, as 
will mean concentration time profiles for MEK162, LGX818 and LEE011, as applicable. 
Further graphical exploratory analyses will be carried out if deemed appropriate. 


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10.5.3.1.3 
Advanced data analysis methods 
 
10.5.4 
Biomarkers 
10.5.4.1 Outline of the data analysis 
As a project standard, only patient pre-selection and PD markers collected in the clinical 
database will be analyzed by the Sponsor. Since this clinical trial was not designed to address 
specific hypotheses related to patient pre-selection or PD markers, the analysis of this data 
should be viewed as explorato1y and hypotheses generating. Analytical results from such 
analyses may be used to generate additional hypotheses that must then be verified with data 
derived from subsequent clinical trials. No adjustment for multiple comparisons is planned. 
If the number of samples is inadequate to perfonn a rigorous data analysis, then the available 
data will only be listed. Additional analyses that may be perfo1med after the completion of the 
end-of-study clinical study repo1t will be documented in separate repo1ts. These analyses may 
include but are not limited to the meta-analysis of data from this study combined with data from 
other studies or the analysis of patient pre-selection or PD markers generated from samples 
collected during the study but analyzed after the database lock and completion of the clinical 
study repo1t. The data analysis will be described in an addendum of the RAP or in a stand-alone 
analysis plan document, as appropriate. 
10.5.4.2 Data handling principles 
All measurements below their respective LLOQs or missing data will be labeled as such in the 
concentration data listings. Measurements below the LLOQ will be treated as zero in summaiy 
statistics. Change from baseline analyses will only be perfonned on patients with measurable 
sainples and pre- and post-treatment time points. 
10.5.4.3 Data analysis principles 
10.5.4.3.1 
Analysis sets 
The FAS will be used for all analyses. The number of patients with measureable samples will 
be identified in the summaries and relevant propo1tions will be calculated against this number 
of patients. 


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10.5.4.3.2 
Basic tables, figures and listings 
To characterize baseline molecular status of molecules relevant to RAF/MEKIMAPK and 
EGFR/PI3K./AKT signaling in tumor tissue in the Phase II parts of the study, baseline molecular 
status (mutation/amplification/expression) in tumor tissue of potential predictive markers 
(BRAF, HRAS, KRAS, NRAS, PTEN, cKIT, PIK3CA, MAP2Kl, MAP2K2, ARAF, c-MET, 
RAFI, EGFR) will be summarized by patient group. All biomarker assessments obtained from 
the full complement of fresh pre- and post-treatment paired tumor/skin biopsies collected in the 
trial will be listed by patient and time point and summarized using descriptive statistics by time 
point. 
All biomarker assessments only collected at baseline will be listed by patient and summarized 
using descriptive statistics. 
All biomarker assessments obtained from tumor samples from patients with disease progression 
will be listed by biomarker and by patient. 
10.5.4.3.3 
Advanced analysis methods 
 
10.5.5 
Resource utilization 
Not applicable. 
10.5.6 
Patient-reported outcomes 
Not applicable. 
 
10.7 
Interim analysis 
An interim analysis for futility will be perfo1med in the phase II BRAF V600 mutant mCRC 
aim (dual-combination ann 1), when 14 patients (50% of the total sample size) have completed 
4 cycles of treatment. As mentioned in Section 10.8, study results ai·e successful if  9 responses 
ai·e observed at the end of the trial. At the interim analysis, if the predictive probability of 
success is < 13%, i.e. if less than 3 responses (DCR at week 16) are observed, this study ai·m 
will be stopped for futility. 
10.8 
Sample size calculation 
Phase lb 
Dose escalation: Cohorts of 3 to 6 evaluable patients will be emolled in the dose escalation 
pait including at least six patients at the MTD/RP2D level, as described in Section 6.2.4. 


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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 PK parameters as required. At least 18 patients are expected to be 
treated in the dual-combination dose-escalation part of the study, for the model to have 
reasonable operating characteristics relating to its MTD recommendation (see Appendix 5 for 
details). At least 12 patients are expected to be treated in the triple-combination dose- escalation 
part of the study. 
Phase II 
Arm 1 dual combination: Based on the prior distribution and decision rules described in 
Section 10.4, it was explored how likely it is to wrongly declare activity given the true DCR = 
20%, and how likely it is to correctly declare activity given the true DCR = 40%, when 28 
patients are evaluated. 
• If the true DCR = 20%, the probability to wrongly declare activity (i.e. seeing at least 9 
patients with SD or better) is 9.0%. 
• If the true DCR = 40%, the probability to correctly declare activity (i.e. seeing at least 9 
patients with SD or better) is 85.2%. 
If 9 out of 28 patients have at least SD or better, then the posterior risk of the true DCR being 
in the unacceptable category is 7.0%. 
Note: if the interim analysis is performed, the probability to correctly declare activity if the true 
DCR = 40% is 82.3%. 
Arm 2 dual combination: Based on the prior distribution and decision rules described in 
Section 10.4, it was explored how likely it is to wrongly declare activity given the true ORR = 
10%, and how likely it is to correctly declare activity given the true ORR = 20%, when 41 
patients are evaluated: 
• If the true ORR = 10%, the probability to wrongly declare activity (i.e. seeing at least 7 
responses) is 11.0%. 
• If the true ORR = 20%, the probability to correctly declare activity (i.e. seeing at least 7 
responses) is 73.9%. 
If 7 out of 41 patients have PR or CR, then the posterior risk of the true ORR being in the 
unacceptable category is 9.8%. 
Arm 3 dual combination / Arm A triple combination: Based on the prior distribution and 
decision rules described in Section 10.4, it was explored how likely it is to wrongly declare 
activity given the true ORR = 30%, and how likely it is to correctly declare activity given the 
true ORR = 50%, when 40 patients are evaluated: 
• If the true ORR=30%, the probability of wrongly declaring at least moderate efficacy (i.e. 
at least 16 responses) is 11.5%. 
• If the true ORR=50%, the probability of correctly declaring at least moderate efficacy (i.e. 
seeing at least 16 responses) is 92.3%. 
If 16 out of 40 patients have PR or CR, then the posterior risk of the true ORR being in the 
unacceptable category is 9.0%. 


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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. A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC/REB must be given to the Sponsor 
before study initiation. 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 the Sponsor’s monitors, auditors, Sponsor Clinical Quality 
Assurance representatives, designated agents of the Sponsor, 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 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 eCRFs. 
The Sponsor will provide investigators in a separate document with 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 the Sponsor before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Sponsor’s monitor after IRB/IEC/REB approval. 
Women of child bearing 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. 
For this study, the following ICFs apply: 


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• Molecular pre-screening consent form (if applicable) 
• Study consent form; one for dual study treatment combination and one for triple study 
treatment combination [the ICF for triple study treatment combination (LGX818 / 
MEK162 / LEE011) is not applicable for the USA and Singapore]. 
11.4 
Discontinuation of the study 
The Sponsor 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 
The Sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 
Data Sharing 
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes of 
“bonafide scientific research” that contributes to the scientific understanding of the disease, 
target, or compound class. Pfizer will make available data from these trials 24 months after 
study completion. Patient-level data will be anonymized in accordance with applicable privacy 
laws and regulations. CSRs will have personally identifiable information redacted. 
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not be 
provided to applicants with significant conflicts of interest, including individuals requesting 
access for commercial/competitive or legal purposes. 
11.7 
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 an Array BioPharma- 
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 


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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 
11.8 
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 the Sponsor. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
11.9 
Audits and inspections 
Source data/documents must be available to inspections by the Sponsor or designee or Health 
Authorities. 
11.10 
Financial disclosures 
Financial disclosures should be provided by study personnel who is 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 the Sponsor 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 the 
Sponsor and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 


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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 the Sponsor, 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, 
the Sponsor should be notified of this action and the IRB/IEC/REB at the study site should be 
informed within 10 working days. 


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13 
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14 
Appendices 
14.1 
Appendix 1 - Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) Harmonization of Efficacy Analysis of Solid Tumor 
Studies 
This document is based on Novartis implementation guidelines version 3. 
Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FPFV 
First patient first visit 
GBM 
Glioblastoma multiforme 
LPLV 
Last patient last visit 
MRI 
Magnetic resonance imaging 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Report Analysis Preparation 
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 
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 2000) and the revised RECIST 
guidelines (version 1.1) (Eisenhauer 2009). 
This document will not address the use of RECIST 1.1 for glioblastoma multiforme (GBM). 
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 14.1.28 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the analysis plan(s) to provide further details needed for programming. 


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14.1.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria for tumor responses (Therasse 2000) 
and the revised RECIST guidelines (version 1.1) (Eisenhauer 2009). 
The assessment schedule for tumor assessments is described in Section 7.2.1 of the protocol. 
Frequency of tumor re-evaluation while on treatment should be adapted to the type and schedule 
of treatment, and the type of tumor treated. 
It is assumed that all information which is considered for assessment of the tumor is captured 
in the RECIST eCRF, i.e. not merged from several sources. 
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 14.1.26. 
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. 
• 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 10mm and <15mm 
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. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (longest diameter <10 mm with CT scan or pathological lymph nodes with  10 to 
< 15 mm short axis), e.g., blastic bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, 
abdominal masses that are not confirmed and followed by imaging techniques, and cystic 
lesions. 
If any lesion should be handled differently, this must be clearly stated and justified in the 
protocol, e.g. tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable, and the conditions under which such lesions should be considered 
must be defined in the protocol when appropriate. 


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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 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 14.1.26. 
14.1.6 
Methods of tumor measurement - general guidelines 
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. 
• If different window for baseline assessments is allowed in the protocol this must be 
justified in the protocol. 
• 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 5mm 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 be allergic to CT contrast or develops allergy 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 change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However another 
response assessment than the 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. 
If head and neck tumors and those of extremities are evaluated in the study, please specify the 
methods in detail in the protocol. 
• 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: 


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• 
If the positive FDG-PET at follow-up coITesponds to a new site of disease confinned by 
CT, this is PD. 
• 
 If the positive FDG-PET at follow-up is not confnmed as a new site of disease on CT, 
additional follow-up CT are needed to dete1mine if there is tiuly progression occuITing at 
that Site (if so, the date of PD will be the date of the initial abnonnal CT scan). 
• 
If the positive FDG-PET at follow-up coITesponds 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 smTounded by aerated lung. However, CT is preferable. 
• 
Ultrasound: When the prirna1y endpoint of the study is objective response evaluation, 
ulti·asound should not be used to measure tmnor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. Ulti·asound might also be useful to confinn 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 expe1iise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tmnor 
response should be resti·icted to validation pmposes in specialized centers. However, such 
techniques can be useful in confnming complete pathological response when biopsies are 
obtained. 
If tmnor markers are used in the study for the response assessment, the criteria must be clearly 
stated in the protocol and the presence of abno1mality in tmnor markers be entered in the eCRF 
page for RECIST evaluations (see also Section 14.1.8). 
• 
 Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after ti·eatment to differentiate between residual benign lesions 
and residual malignant lesions in tmnor types such as ge1m cell tmnors). Cytologic 
confnmation of neoplastic nature of any effusion that appears or worsens during h'eatment 
is required when the measurable tmnor has met the criteria for response or stable disease. 
Under such circUlllStances, the cytologic examination of the fluid collected will pennit 
differentiation between response and stable disease (an effusion may be a side effect of the 
ti·eatment) or progressive disease (if the neoplastic origin of the fluid is confnmed). 
When pathological response is being used, the protocol must clearly state details on how 
pathological responses are documented. 


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• 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. 
If the protocol is considering specific symptoms as objective signs of clinical progression, e.g. 
bone pain or GI bleeding, then the criteria for clear worsening of these non-measurable ‘lesions’ 
indicative of PD should be clearly specified in the protocol. In that case, the protocol should 
clearly specify that additional criteria are used to complement RECIST criteria. 
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) should be at least 10mm 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 metastasis). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
If the protocol is considering specific symptoms for assessment of the tumor, e.g. bone pain or 
GI bleeding, then these symptoms are to be entered as non-target lesions with either presence 
or absence or as a new lesion (based on protocol specified criteria). In that case, the protocol 
should clearly specify that additional criteria are used to complement RECIST criteria. 


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For cancers which are known to metastasize in bone, the protocol should specify if and how 
bone lesions should be handled, e.g. if they are not identified only at baseline and end of study 
by scintigram but also followed throughout the study by bone X-ray or CT scan. 
14.1.8 
Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameter 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 
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. 
If tumor markers are used as non-target lesions to evaluate response, please specify criteria for 
CR, SD and PD in the protocol, e.g. CR=’Normalization of tumor marker level’, PD=’Elevation 
of tumor markers to certain level’, SD=’Not qualifying for CR or PD’. These criteria are 
indication and study specific. In that case, the protocol should clearly specify that additional 
criteria are used to complement RECIST criteria. 
14.1.9 
Follow-up & 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. 
When a tumor does not disappear completely and shrinks to less than the slice thickness a 
default value should be assigned depending on the slice thickness. With 5 mm contiguous slice 
thickness, the default value will be 5 mm. Similarly, for a 7 mm slice thickness, the default 
value will be 7 mm. Actual measurement should be given for all lesions larger than the default 
value. 
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. 


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If a nodal lesion shrinks to less than the slice thickness a default value should be assigned 
depending on the slice thickness. With 5 mm contiguous slice thickness, the default value will 
be 5 mm. Similarly, for a 7 mm slice thickness, the default value will be 7 mm. Actual 
measurement should be given for all lesions larger than the default value. 
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. 
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 <10mm in size. In this case, the target lesion response is CR 
3. 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 three 
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). Proper documentation should be available to support this decision. 


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• 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 
100mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140mm (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 10mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10mm are considered normal a CR for target lesion response 
should be assigned when nodal target lesions shrink to less than 10mm 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 the absolute sum of the remaining 
nodal target lesions increases by at least 5mm and at least one of those remaining 
lesions are at least 10mm in size. i.e. if the short axis of a remaining nodal target 
lesion increases from 5 mm to 10 mm or from 7 mm to 12.5 mm this is called PD, but 
if it increases from 7 mm to 10 mm it does not qualify for PD. 


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When both nodal and non-nodal lesions are still present there may be rare occasions when a PD 
for target lesion response is primarily due to increases in size of nodal lesions but where the 
target lymph nodes are still all less than 10mm in size. This kind of rare anomaly is acceptable 
since otherwise the rules for determining target lesion response would become too complex. 
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 
Incomplete Response/ 
Stable Disease (SD): 
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 baseline. 
1. Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, the opinion of 
the treating physician does prevail and the progression status should be confirmed later on by the review panel 
(or study chair). 
 
Notes on non-target lesion response 
• 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. < 10mm). 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 ‘Incomplete 
response/Stable disease’ unless any of the lesions was not assessed (in which case 
response is UNK) or there is unequivocal progression of the non-target lesions (in which 
case response is PD). 
• 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. Even in cases where there is no measurable disease at baseline, 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. In studies where the overall non-target lesion response is not recorded but 
instead the individual status of individual lesions (Absent, Present or Worsened) is 
determined, if there is unequivocal progression of non-target lesions then at least one of 
the non-target lesions must be assigned a status of “Worsened”. Similarly, an individual 
non-target lesion should only be assigned a “Worsened” status if there is unequivocal 
progression of non-target lesions overall. 
• 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 lesion1 
• 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  10mm for the first time in the study plus 
5mm 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 
Incomplete response/SD3 
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 
This overall lesion response also applies when there are no non-target lesions identified at baseline. 
1. Once confirmed PR was achieved, all these assessments are considered PR. 
2. As defined in Section 14.1.8 
If there are no baseline scans taken at all at baseline then the overall lesion response at each 
assessment should be considered Unknown (UNK). 
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen. 


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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. 
14.1.16 Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.26 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 28 days after the last dose 
of study therapy 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 a 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 


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• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR). 
The protocol should state if randomization or start of treatment is used as start date (baseline). 
This is then used in all definitions. 
If a different minimum follow-up period is required to classify for overall response= ’stable 
disease’, this must be specified in the protocol. 
• PD = progression  12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD). 
If PD in a different follow-up period is considered overall response=’progressive disease’, this 
must be specified in the protocol. 
The protocol should state if discontinuation due to ‘Disease progression’ or death due to study 
indication is considered PD even if this was not accompanied by documentation of PD based 
on tumor measurements. This depends on Phase of the study and the primary endpoint (e.g. 
Phase III studies in which progression-free survival is primary endpoint should consider only 
documented PD, whereas Phase I and II studies may consider all clinical deteriorations PD). 
The following sentence therefore is only applicable if this is specified in the protocol: 
• Patients with symptoms of rapidly progressing disease without radiologic evidence will be 
classified as progression only when clear evidence of clinical deterioration is documented 
and/or patient discontinued due to ‘Disease progression’ or death due to study indication. 
• 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) 
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 
20 cm at baseline and then 14 cm - 15 cm - 14 cm - 16 cm - 16 cm 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 14 cm confirms the PR for this patient. All 


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subsequent assessments are considered PR even if tumor measurements decrease only by 20% 
compared to baseline (20 cm to 16 cm) at the following assessments. 
If the patient progressed but continues study medication, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the Clinical Study Report but not 
included in the best overall response rate. 
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 
• Calculated overall lesion response (based on measurements from either Investigator or 
Central Review) 
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. 
Specify which determination of best overall response will be considered primary (and delete 
the other terms in the text). If a central blinded review is used (e.g. in an open-label study in 
which response is the primary endpoint), the best overall response evaluated by the central 
blinded review will always be considered the primary response. 
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. 
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). 


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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. 
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 contacted, 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 contact. 
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 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 
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 


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failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment. 
14.1.23 Duration of response 
The analysis following variables should be performed with much caution when restricted to 
responders since treatment bias could have been introduces. 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 induce 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 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 an SD the start and end date as well as censoring is defined the same as that for 
time to progression. 
14.1.24 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 


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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 14.1.23. 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 is the worst 
possible outcome as it means the patient that 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. 
Indicate in the protocol whether a subgroup analysis of responders only will be performed in 
addition to the full population analysis (which should be included as default). 
14.1.25 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. 
Start dates 
State in the protocol if date of randomization or date of start of treatment is to be used for all 
definitions. For randomized studies specify exactly where the randomization date comes from, 
e.g. from IVRS, or if start of treatment is used as randomization date. For non-randomized studies 
please specify which treatment start date is taken if more than one treatment is to be given. 
For all “time to event” variables, other than the duration of responses, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of responses the following start date should be used: 


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• 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. 
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. 
If applicable, if patients who discontinued due to ‘Disease progression’ are considered to be PD 
solely based on clinical deterioration, then add the following in the protocol: 
When there is no documentation of radiologic evidence of progression, and the patient 
discontinued for ‘Disease progression’ due to documented clinical deterioration of disease, the 
date of discontinuation is used as date of progression. 
• 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 
corresponds to 9 months. 
• Date of discontinuation is the date of the EOT 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 contact date from that survival follow-up page is used. If no 
survival follow-up is available, the date of discontinuation is used as last contact date. 
In comparative studies with long follow-up period and therefore extended visit schedule, it may 
be useful to collect the survival status at a pre-specified cut-off within a limited timeframe for all 
patients with no documented death. In this case, this requires a contact to be made with the patient 
or with any reliable source of information on the patient’s status, but not requiring a specific visit 
to be scheduled 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 


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If this is applicable for the study, it should be specified in the protocol if new cancer therapy is 
considered an event or endpoints are censored. 
14.1.26 Handling of patients with non-measurable disease only at baseline 
It is possible that patients with just non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. Phase III studies with PFS as 
the primary endpoint). In such cases the handling of response data requires special consideration 
with respect to inclusion in any analysis of endpoints based on the overall response evaluations. 
The protocol should state clearly whether patients with non-measurable disease only at baseline 
will be allowed into the study. If patients with non-measurable disease only are allowed to be 
enrolled then the statistical section should describe clearly how data from these patients will be 
incorporated into the primary analysis and main analyses of the key secondary endpoints. In 
studies where presence or otherwise of measurable disease is expected to have a relatively large 
impact on the primary endpoint, this factor can even be considered as a stratification factor in the 
randomization process. 
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. 
For studies which specifically exclude patients with non-measurable disease only at baseline the 
pre-specified analysis plan should describe how to handle data from these types of patients if they 
are enrolled by error. It is recommended for these types of studies that patients with non- 
measurable disease identified through the local site evaluation be included in the list of protocol 
violations. However, decisions on exclusion from a per protocol analysis should relate to whether 
the patient has measurable disease according to the primary data source. For example, if the 
primary data source is from a central independent review then patients with non-measurable 
disease only according to this central review should be excluded from the relevant per protocol 
analyses. 
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 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 
CR 
No 
CR 
Incomplete response/SD1 
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 


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just 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”. Study teams may also want to 
perform sensitivity analyses excluding patients from the analysis of ORR (e.g. possibly as part 
of a per-protocol type analysis). Similar considerations should be given to other endpoints 
which rely on a clear distinction being made between a PR and an SD response. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with just 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 
14.1.27 Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well is 
addressing 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 analysis 
plan 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 14.1.25, 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 analysis plan 
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 
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) N/A 
(2) Date of discontinuation (visit date at which 
clinical progression was determined) 
Ignored 
Progressed 


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Situation 
Options for end-date (progression or 
censoring?)1 
(1) = default unless specified differently in the 
protocol or analysis plan 
Outcome 
F 
New anticancer therapy given 
(1) Date of last adequate assessment 
(2) Date of secondary anti-cancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) N/A 
Censored 
Censored 
Event 
Ignored 
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 14.1.25. 
2=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.1.25 
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), i.e. censoring at last adequate assessment may be 
used as a default in this case. 
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: 


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• 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 RAP documentation. 
14.1.28 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). 
14.1.29 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP 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 RAP 
documentation before database lock). 
14.1.30 Treatment and study completion CRFs 
If study drug is discontinued, the EOT Page is to be completed with a visit date reflecting the 
date the discontinuation decision was made, and with the ‘Last known date patient took study 
drug’ and one of the following reasons: 
• AE(s) 
• Abnormal laboratory value(s) 
• Abnormal test procedure results(s) 
• Protocol violation 
• Patient withdrew consent 
• Lost to follow-up 
• Administrative problems 
• Death 
• Disease progression 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
For reasons other than progression (and death) it should be checked if this was not in fact 
progression (especially reasons AEs, Abnormal laboratory value (s), Abnormal test procedure 
result and patient withdrew consent). Also it should be checked if patient withdrew consent 
because of safety issues, in which case reasons AEs, Abnormal laboratory value (s), Abnormal 


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test procedure result should be used. In such cases where the reason for discontinuation is AE, 
the AE CRF page must be consistent with the EOT reason provided 
All patients who discontinued study drug will be followed for post a treatment evaluation until 
progression or until a new anticancer therapy is initiated. Patients who discontinued study drug 
for reasons other than documented progression, death or lost to follow-up will be followed for 
progression thereafter (patients who withdrew consent might not be followed with regular 
tumor assessments at the study site, but should ideally be followed until progression outside the 
study site). Ideally, all patients who discontinued study drug for progression without 
documented progression will still be followed with regular tumor assessments (e.g. in case of 
central radiology review).If patient withdraws consent, it must be clearly stated if patient is also 
withdrawing consent from post treatment evaluations and/or post treatment follow-up 
assessments. During that evaluation period, usually only tumor measurements (and/or response 
status) and survival data are collected. In some protocols, the subsequent anti-cancer therapies 
may also be recorded. 
14.1.31 Study evaluation completion 
At the end of the study evaluation period, the study evaluation completion page is filled out 
with the following options: 
• Patient withdrew consent 
• Lost to follow-up 
• Administrative problems (when follow-up for progression has met protocol required 
events, e.g. follow-up stopped at certain number of events or certain time) 
• Death 
• New cancer therapy (optional, to be used when follow-up for progression is stopped in this 
case) 
• Disease progression 
Thereafter, patients will be followed for survival using the survival follow-up pages. If 
information on death becomes available for patients who were lost to follow-up or withdrew 
consent, this may also be entered in the database. The reason for death must be documented 
(and will be coded using MedDRA); it must be also stated if death was due to ‘Study indication’ 
or ‘Other’ reason. 
In comparative studies with long follow-up period and therefore extended visit schedule, it may 
be useful to collect the survival status at a pre-specified cut-off within a limited timeframe for 
all patients with no documented death. In this case, this requires a contact to be made with the 
patient or with any reliable source of information on the patient’s status, but not requiring a 
specific visit to be scheduled. 
Until the specified cut-off point has been reached, the goal is to collect tumor assessments until 
disease progression for all patients regardless of whether the patients are still receiving study 
drug. If patients are not followed for progression, e.g. in a Phase I or II study mainly evaluating 
safety, the evaluation is completed when study drug is completed (in this case only the first 
completion page is used). 


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14.1.32 Medical validation of programmed overall lesion response 
As RECIST 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), these UNK 
assessments may be re-evaluated by clinicians at the Sponsor or designee or by external experts. 
In addition, data review reports will be available to identify assessments for which the 
Investigators’ opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the Investigator response assessment 
will never be overruled. 
If the Sponsor or designee elect to invalidate an evaluation of overall lesion response 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 RAP 
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. 
14.1.33 Programming rules 
The following should be used for programming of efficacy results: 
14.1.34 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. 
14.1.35 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 14.1.25). 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 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 


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14.1.36 Incomplete dates for last contact 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. 
14.1.37 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)’. 
14.1.38 Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
14.1.39 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) 
• New cancer therapy added (optional; only if the protocol specified that PFS/TTP will be 
censored at that date) 
*Adequate assessment is defined in Section 14.1.25. 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=’Administrative problems’ 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 for censor in case of no baseline assessment. 
14.1.40 References (available upon request) 
Dent S, Zee B, Dancey J, et al (2001) Application of a new multinomial phase II stopping rule 
using response and early progression. J Clin Oncol; 19(3): 785-91. 
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer; 45(2): 228-47. 
Ellis S, Carroll KJ, Pemberton K (2008) Analysis of duration of response in oncology trials. 
Contemp Clin Trials; 29(4): 456-65. 
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. Control 
Clin Trials; 9(1): 11-8. 
Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New Guidelines to Evaluate the 
Response to Treatment in Solid Tumors. J Natl Cancer Inst; 92(3): 205-16. 


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14.2 
Appendix 2 - The 2009 American Joint Committee on Cancer 
(AJCC) staging system 
Table 14-6 
The 2009 American Joint Committee on Cancer (AJCC) staging 
system for malignant melanoma 
 
Stage 
Primary tumour (pT) 
Lymph nodes (N) 
Metastases (M) 
IA 
< 1 mm, no ulceration, 
mitoses < 1 mm)2 
IB 
< 1 mm, with ulceration or 
mitoses ‡1mm)2a 
1Æ01-2 mm, no ulceration 
IIA 
1Æ01-2 mm, with ulceration 
2Æ01-4 mm, no ulceration 
IIB 
2Æ01-4 mm, with ulceration 
> 4 mm, no ulceration 
IIC 
> 4 mm, with ulceration 
IIIA 
Any Breslow thickness, 
Micrometastases 
no ulceration 
1-3 nodes 
IIIB 
Any Breslow thickness, 
Micrometastases 
with ulceration 
1-3 nodes 
Any Breslow 
1-3 palpable 
thickness, no ulceration 
metastatic nodes 
Any Breslow thickness, 
No nodes, but in-transit 
no ulceration 
or satellite metastasis ⁄es 
IIIC 
Any Breslow thickness, 
Up to three palpable 
with ulceration 
lymph nodes 
Any Breslow thickness, 
Four or more nodes or matted 
with or without ulceration 
nodes or in-transit disease 
+ lymph nodes 
Any Breslow thickness, 
No nodes, but in-transit or 
with ulceration 
satellite metastasis ⁄es 
IV, M1a 
Skin, subcutaneous or 
distant nodal disease 
IV, M1b 
Lung metastases 
IV, M1c 
All other sites or any other sites 
of metastases 
with raised lactate 
dehydrogenase 
a In the rare circumstances where mitotic count cannot be accurately determined, a Clark level of invasion of 
either IV or V can be used to define T1b melanoma. Every patient with melanoma should be accurately staged 
using the AJCC system; this may include performing a sentinel lymph node biopsy when this is recommended 
by the Specialist Skin Cancer Multidisciplinary Team. Staging should be updated following relapse. 


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14.3 
Appendix 3 - Guidelines for the treatment of study drug 
combination induced skin toxicity 
[Any language regarding the triple combination of LGX818/MEK162/LEE011 in this 
Section is not applicable to the USA and Singapore] 
14.3.1 
Rash 
Skin disorder/rash has been observed in the ongoing studies of single-agent LGX818 and 
MEK162 and thus is recognized as a potential overlapping toxicity associated with the 
concurrent use of both compounds. The majority of these events were CTCAE Grade 1 or 2, 
but also dose-limiting as Grade 3 at the 80mg BID dose for MEK162. 
The results of the STEPP study (Mitchell 2009; Piperdi 2009) support the use of pre-emptive 
skin treatment for patients at risk of treatment induced skin toxicity. In this study, the pre- 
emptive skin treatment regimen reduced the incidence of specific CTCAE Grade ≥ 2 skin 
toxicity by more than 50% as compared to the group who received only reactive skin toxicity 
treatment. In this study, patients will not initially receive prophylactic treatment for skin toxicity 
during Cycle 1. However, prophylactic treatment for skin toxicity may be introduced in 
subsequent cycles of treatment and in new patients if at least one patient has experienced 
CTCAE Grade 3 or greater skin toxicity, or if at least two patients have experienced such 
toxicities that are CTCAE Grade ≥ 2. Prophylactic supportive therapy for skin toxicity (i.e. 
initiated 24 hrs prior to study drug combination) including skin moisturizers, sunscreen (PABA 
free, SPF ≥ 15, UVA/UVB protection), topical steroid (1% hydrocortisone cream), and 
doxycycline (100 mg BID) may be initiated in all patients at the dose levels where these 
toxicities have been observed and may be advised to all further patients. Effective medications 
also include antihistamines, topical corticosteroids and low-dose systemic corticosteroids (the 
latter should be used with caution due to the increased risk of hyperglycemia). 
The treatment algorithm is as follows: 
Mild Rash (CTCAE Grade 1) 
• Treatment with LGX818 and MEK162 or LGX818 and MEK162 and LEE011 should be 
maintained at the current dose. 
• Topical hydrocortisone (1% or 2.5% cream) for macular rash and/or topical clindamycin 
(1%) for pustular rash is recommended. 
• The patient should be reassessed after 2 weeks. 
Moderate Rash (CTCAE Grade 2) 
• Treatment with LGX818 and MEK162 or LGX818 and MEK162 and LEE011 should be 
maintained at the current dose, and the rash should be closely monitored for change in 
severity. 
• Doxycycline or minocycline are not recommended due to phototoxicity and should be 
replaced with oxytetracycline or lymecycline. However, if doxycycline or minocycline are 
used, precaution measurements should be taken (i.e., avoid direct exposure on sun, use of 
sunglasses, sunscreen, ect.). The recommendation is: topical clindamycin (1%) plus either 


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hydrocortisone (2.5% cream) or pimecrolimus (1% cream) plus oxytetracycline (500 mg 
twice daily) or lymecycline (408 mg QD). 
Severe Rash (CTCAE Grade 3-4) 
CTCAE Grade 3 
• The dose of LGX818 and MEK162 or LGX818 and MEK162 and LEE011 should be 
omitted until resolved to CTCAE Grade ≤ 1, in line with protocol recommendations, and 
the rash should be closely monitored for any change in severity. 
• In addition to the interventions recommended for moderate rash, prednisolone may be 
given (with caution due to risk of hyperglycemia) as a reducing dose regimen (25 mg for 7 
days, subsequently decreasing the dose by 5 mg/day every day to 0). 
• If skin toxicity CTCAE Grade 3 is not resolved within 7 days, discontinue patient from 
study drug treatment. 
CTCAE Grade 4 
• If skin toxicity CTCAE Grade 4 occurs the dose of LGX818 and MEK162 or LGX818 
and MEK162 and LEE011 should be omitted and patients discontinued from study drug 
treatment. 
Table 14-7 
Treatment of skin toxicity 
 
Mild Rash (Grade 1) 
Dry Skin 
Nail changes 
Pruritus 
Desquamation 
Acneiform 
Topical hydrocortisone 1% or 2.5% and/or Clindamycin 1% gel 
Moderate Rash (Grade 2) 
Dry Skin 
Nail changes 
Pruritus 
Desquamation 
Acneiform 
Topical clindamycin (1%) plus either hydrocortisone (2.5% cream) or 
pimecrolimus (1% cream) plus oxytetracycline (500 mg twice daily) or 
lymecycline (408 mg QD). 
Severe Rash (Grade 3-4) 
Dry Skin 
Nail changes 
Pruritus 
Desquamation 
Acneiform 
Hydrocortisone 2.5% cream or Clindamycin 1% gel or Pimecrolimus 1% 
cream plus oxytetracycline (500 mg twice daily) or lymecycline (408 mg QD) 
plus prednisolone (with caution due to risk of hyperglycemia) (25 mg for 7 
days, decreasing the dose by 5 mg/day every day). 
Adapted from Thatcher 2009. 
14.3.2 
Hand Foot Skin Reaction 
As HFSR has been reported in some patients during LGX818 treatment, it is recommended that 
patients are educated prior to starting study treatment which activities to avoid and on 
supportive measures for prevention and/or management of HFSR. Recommendations are 
summarized below in Table 14-8. Furthermore, the patient should be treated at the first 
symptoms according the institutional standards of care. A visit at a podiatrist may also be 
recommended at the discretion of the investigator. 


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Table 14-8 
Supportive care for the prevention and management of HFSR 
Stage 
Recommendations 
Prior to treatment 
Educate the patient about the early signs and symptoms of HFSR and discuss the 
importance of early reporting. 
Prevention of HFSR 
Monitor the patient for signs and symptoms of HFSR. Instruct the patient to: 
- Apply emollient cream regulary to hands and feet 
- Avoid skin irritants (e.g. perfumes, alcohol, harsh cleaning agents) 
- Wear cotton socks or gloves to bed to enhance the absorption of creams 
- Avoid tight, irritating or ill-fitting clothing and shoesa 
- Avoid the use of band aides or other types of adhesive bandages or tape 
- Avoid repetitive activity or staying in one position for long periods of time 
- Keep the skin uncovered when possible to minimize perspiration 
- Wear rubber gloves while doing dishes 
- Pat (do not rub) skin dry with towels 
- Avoid extremes of temperature, pressure and friction 
- Avoid performing mechanically stressful manual work 
- Minimise exposure to strong, direct sunlight 
- Elevate affected limbs 
Treatment of HFSR 
1) Ensure that patient follows treatment interruption or dosage reduction guidelines 
2) Monitor the patient for progression/resolution of HFSR 
3) Prescribe analgesics if necessary 
4) Instruct the patient to: 
- Continue the use of prevention strategies 
- Cushion sore skin 
- Submerge hands and feet in cool water baths or apply cold compresses for relief 
a Wear loose-fitting clothing made of soft, natural fabrics and shoes that are wide and comfortable. Avoid tight 
belts, panties and bras. 
This Table is adapted from (van Moos et al 2008). 
14.3.3 
References (available upon request) 
Mitchell EP, Lacouture M, Shearer H (2009) Final STEPP results of prophylacatic versus 
reactive skin toxicity (ST) treatment (tx) for panitumumab (pmab)-related ST in patients (pts) 
with metastatic colorectal cancer (mCRC). J Clin Oncol; 27:18s, (suppl; abstr CRA4027). 
Van Moos R, Thuerlimann B, Chair M , et al (2008) Pegylated liposomal doxorubicin- 
associated hand-foot syndrome: Recommendations of an international panel of experts. Eur J 
Cancer; 1016: 1-10. 
Piperdi B, Mitchell EP, Lacouture M, et at (2009) STEPP, an open-label, randomized study of 
pre-emptive (P) versus reactive (R) skin toxicity (ST) treatment (tx) in metastatic colorectal 
cancer (mCRC) patients (pts) receiving panitumumab (pmab) + FOLFIRI or irinotecan-based 
(Iri) chemotherapy (CT) as second-line tx: Results by CT and KRAS status. ASCO 2009 
Gastrointestinal Cancers Symposium. Poster presentation Abstract No: 394. 
Thatcher N, Nicolson M, Groves RW, et al (2009) Expert Consensus on the Management of 
Erlotinib-Associated Cutaneous Toxicity in the U.K. Oncologist; 14(8): 840-7. 


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14.4 
Appendix 4 - List of concomitant medications prohibited or to be 
used with caution for dual and triple combination 
[Any language regarding the triple combination of LGX818/MEK162/LEE011 in this 
Section is not applicable to the USA and Singapore] 
Table 14-9 
Narrow therapeutic index substrates of CYP3A4*, CYP2B6, CYP2C9 
prohibited or to be administered with caution 
The information presented on sensitive and narrow TI substrates is a compilation of the 
University of Washington Drug-Drug Interaction (DDI) database and FDA DDI guidance. 
This list might not be exhaustive. 
 
Sensitive Substrates 
Narrow TI Substrates 
CYP1A2 
Alosetron, duloxetine, melatonin, ramelteon, 
tacrine, tizanidine 
Theophylline, tizanidine 
CYP3A4* 
budesonide, buspirone, eplerenone, eletriptan, 
felodipine, fluticasone, lovastatin, midazolam, 
saquinavir, sildenafil, simvastatin, triazolam, 
vardenafil 
alfentanil, astemizole(a), cisapride(a), 
cyclosporine, diergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine(a) 
CYP2B6 
bupropion, efavirenz 
Not Applicable 
CYP2C9 
NA 
warfarin, phenytoin 
Reproduced from 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm081177.htm#4* 
prohibited for patients treated with the triple combination 


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Table 14-10 
List of CYP inhibitors and inducers prohibited or to be used with 
caution 
The information presented on inhibitors and inducers is a compilation of the University of 
Washington Drug-Drug Interaction (DDI) database and FDA DDI guidance. This list might 
not be exhaustive 
 
Strong CYP3A4*,5,7 inhibitors (AUC > 5-fold increase) 
Itraconazole 
Ketoconazole 
Mibefradil 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telithromycin 
Troleandomycin 
Voriconazole 
Boceprevir 
Clarithromycin 
conivaptan 
indinavir 
lopinavir 
Grapefruit juice (citrus 
paradisi fruit juice) 
telaprevir 
cobicistat 
Moderate CYP3A4,5,7 inhibitors (AUC ≥ 2-fold increase and < 5-fold increase) 
Amprenavir 
Atazanavir 
Cimetidine 
Ciprofloxacin 
Diltiazem 
dronedarone 
Fluconazole 
erythromycin 
Imatinib 
Schisandra Sphenanthera 
Tofisopam 
Verapamil 
aprepitant 
casopitant 
cyclosporine 
darunavir 
fosamprenavir 
Strong & Moderate CYP3A4 inducers** (AUC ≥ 2-fold increase) 
Avasimide 
Bosentan 
Carbamazepine 
Efavirenz 
Etravirine 
Modafenil 
Nafcillin 
Nevirapine 
Phenobarbital 
Phenytoin 
Rifabutin 
Rifampin (Rifampicin) 
Ritonavir 
St. John's wort 
Talviraline 
Strong & Moderate CYP1A2 inhibitors (AUC ≥ 2-fold increase) 
Clinafloxacin 
Enoxacin 
Etintidine 
Fluvoxamine 
Idrocilamide 
Methoxsalen 
Mexiletine 
Oltipraz 
Oral contraceptives 
Phenylpropanolamine 
Pipemidic acid 
Propranolol 
Rofecoxib 
Thiabendazole 
Zafirlukast 
Zileuton 
CYP1A2 inducers 
Tobacco 
Strong & Moderate CYP2C19 inhibitors (AUC ≥ 2-fold increase) 
Fluconazole 
Fluvoxamine 
Fluoxetine 
Moclobemide 
Omeprazole 
Ticlopidine 
Voriconazole 
CYP2C19 inducers 
Rifampin 
This database of CYP inhibitors and inducers was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table, the University of Washington’s Drug Interaction Database, and the FDA’s 
“Guidance for Industry, Drug Interaction Studies.”* prohibited for patients treated with the dual and triple 
combination 
** prohibited for patients treated with the triple combination 


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Table 14-11 
List of BCRP substrates, BSEP inhibitors, P-gp inhibitors/inducers, and 
MATE1/2, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1 and OATP1B3 substrates to be 
used with caution 
The information presented on transporter substrates, inducers and inhibitors is a compilation 
of the University of Washington Drug-Drug Interaction (DDI) database and FDA DDI 
guidance. This list might not be exhaustive. 
 
Category 
Drug Name 
BCRP substrates 
atorvastatin, daunorubicin, doxorubicin, ethinyl estradiol, hematoporphyrin, imatinib, 
methotrexate6, mitoxantrone, pitavastatin6, rosuvastatin6, SN-38 (irinotecan), 
simvastatin, sulfasalazine, sofosbuvir1, topotecan1, sulfasalazine1 
BSEP 
Vinblastine 
Strong BSEP inhibitors 
Alectinib, atazanavir, bromocriptine, bosentan, clofaziminie, cerivastatin, fusidate, 
glibenclamide, glyburide, nefazadone, paritaprevir, pioglitazone, reserpine, 
rosiglitazone, sulindac, troglitazone (TGZ-sulfate), valinomycin 
NTI substrates of P-gp1 
digoxin, quinidine, paclitaxel, cyclosporine, sirolimus, tacrolimus, fentanyl, phenytoin 
Substrates of P-gp (≥2X 
AUC change)2 
aliskiren, ambrisentan, atorvastatin, atorvastatin acid, azithromycin, cerivastatin, 
colchicine, CP-481,715, cyclosporine, dabigatran, digoxin, docetaxel, domperidone, 
doxorubicin, fentanyl, fexofenadine, lapatinib, linezolid, loperamide, maraviroc, 
nevirapine, paclitaxel, proguanil, quinidine, ranolazine, ritonavir, saquinavir, 
simvastatin, sirolimus, sofosbuvir, tacrolimus, ticagrelor, voclosporin 
Substrates of P-gp 
mentioned in US label3 
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, aprepitant, 
boceprevir, bosentan, carvedilol, carvedilol, caspofungin, ceritinib, citalopram, 
colchicine, cyclosporine, dabigatran, digoxin, doxepin, doxorubicin, eribulin, 
everolimus, fidaxomicin, fluvastatin, fosamprenavir, gatifloxacin, idelalisib, iloperidone, 
indacaterol, irbesartan, lacosamide, lapatinib, levetiracetam, levofloxacin, linagliptin, 
losartan, maraviroc, mirabegron, moxifloxacin, naloxegol, nateglinide, nintedanib, 
olodaterol, pantoprazole, paroxetine, pazopanib, posaconazole, pravastatin, quinine, 
ranolazine, riociguat, risperidone, rivaroxaban, saquinavir, silodosin, simeprevir, 
sirolimus, sitagliptin, sorafenib, telaprevir, tenofovir, ticagrelor, tipranavir, tolvaptan, 
topotecan, umeclidinium, valsartan, vardenafil, vincristine, voriconazole 
P-gp inhibitors 
alogliptin, amiodarone4, azithromycin4, canaglifozin, captopril4, carvedilol4, 
clarithromycin4, conivaptan4, cremophor RH40, curcumin, diltiazem4, dronedarone4, 
elacridar4, erythromycin4, felodipine4, fluvoxamine4, ginko4,5, indinavir4, 
indinavir/ritonavir4, itraconazole4, ketoconazole, lapatinib, lopinavir/ritonavir, 
mibefradil4, milk thisle4,5, mirabegron, nelfinavir4, nifedipine4, nitredipine4, paroxetine4, 
propafenone, quercetin,4, quinidine4, ranolazine4, rifampin4, ritonavir4, 
sequinavir/ritonavir4, schisandra chinesis extract4,5, simepravir, St. John’s wort 
extract4,5, talinolol4, telaprevir4, telmisartan4, ticagrelor4, tipranavir/ritonavir4, tolvaptan4, 
valspodar, vandetanib, verapamil4, voclosporin, Zosuquidar LY335979 
P-gp Inducers 
avasimibe, carbamazepine, efavirenz, genistein2, phenytoin, quercetin2, rifampin, St. 
Johns wort extract5 
OCT1/2 substrates7 
, Amantadine, , 6-beta-hydroxycortisol, carboplatin, cisplatin, cephalexin, cephradine, 
ipratropium, lamivudine, linagliptin, metformin, oxyplatin, oxybutynin, phenformin, 
picoplatin, pilsicainide, pindolol, ranitidine, sorafenib, tropisetron, trospium, 
umeclidinium, zidovudine 
MATE1/2 substrates3,8 
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, glycopyrronium, 
metformin, pindolol, plisicainide, ranitidine, topotecan, varenicline 
OAT1 
Adefovir, captopril, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, 
zalcitabine, zidovudine 
OAT3 
Acyclovir, bumetanide, ciprofloxacin, famotidine, furosemide, methotrexate, 
zidovudine, oseltamivir acid, (the active metabolite of oseltamivir), penicillin G, 
pravastatin, rosuvastatin, sitagliptin 


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Category 
Drug Name 
OATP1B1 substrates 
ambrisentan, anacetrapib asunaprevir, atorvastatin, atrasentan, benzylpenicillin, 
bosentan, bromociptine, caspofungin, cerivastatin, danoprevir, empangliflozin, 
enalapril, ezetimibe, fexofenadine, fimasartan, fluvastatin, maraviroc, methotrexate, 
olmesartan, pitavastatin, pravastatin, repaglinide, rifampicin, rosuvastatin, simvastatin 
acid, SN-38; temocapril, troglitazone, valsartan 
OATP1B3 substrates 
asunaprevir, atrasentan, bosentan, danoprevir, digoxin, docetaxel, empangliflozin, 
enalapril, erythromycin, fexofenadine, fluvastatin, imatinib, methotrexate, olmesartan, 
ouabain, paclitaxel, pitavastatin, pravastatin, rifampicin, rosuvastatin, telmisartan, SN- 
38; thyroxine (T4), valsartan 
Reproduced from 
(fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm) 
1 These drugs have both a narrow therapeutic index and an in vivo DDI outcome ascribed at least in part ascribed to P-gp 
(inhibition or induction) that exceeds a 20% change in AUC. 
2 These drugs have in vivo DDI outcomes (inhibition) which are ≥2x increase in AUC and are at least in part ascribed to 
P-gp. 
3 The US labels for these drugs have specific language on in vivo P-gp substrate status. 
4 Dual P-gp and CYP3A4 inhibitor 
5 Herbal medication. 
6 Have been shown to have DDI in vivo, others are reported as substrates in vitro. 
7 OCT1 and OCT2 share considerable substrate specificity. 
8 MATE1 and MATE2 share considerable substrate specificity. 


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Table 14-12 
List of QT prolonging drugs 
This list might not be exhaustive. 
 
TdP Risk 
Generic Name 
Known1 
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, bepridil, chloroquine, 
cocaine, chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, clarithromycin, 
disopyramide, dofetilide, domperidone, donepezil, dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, fluconazole, gatifloxacine, grepafloxacin, halofantrine, haloperidol, 
ibutilide, levofloxacin, levomethadyl, mesoridazine, methadone, moxifloxacin, ondansetron 
(i.v. only), oxaliplatin, papaverine HCl, pentamidine, pimozide, probucol, procainamide, 
propofol, quinidine, roxithromycin, sevoflurane, sotalol, sparfloxacin, sulpiride, terfenadine, 
thioridazine, vandetanib 
Possible2 
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine ,atazanavir, atomoxetine, 
asenapine, bedaquiline, bortezomib, buprenorphine, capecitabine, ceritinib, clomipramine, 
crizotinib,,clozapine, cyamemazine (cyamepromazine), dabrafenib, dasatinib, degarilix, 
delamanid, desipramine, dexmedetomidine, dolasetron, eribulin, ezogabine, famotidine, 
felbamate, fingolimod, foscarnet, gatifloxacin, gemifloxacin, granisetron, hydrocodone-ER, 
iloperidone, imipramine (melipramine), isradipine, , lapatinib, lenvatinib, leuprolide, 
loperamide, lithium, mifepristone, mirabegron, mirtazapine, moexipril, norfloxacin, 
nortriptyline, ofloxacin, olanzapine, osimirtinib, ondansetron (p.o. only at 4 mg or 8 mg), 
oxytocin, paliperidone, panabinostat, pasireotide, pazopanib, pipamperone, promethazine, 
quetiapine, ranolazine, rilpivirine, risperidone, roxithromycin, sertindole, sorafenib, sunitinib, 
telavancin, tetrabenazine, tizanidine, tolterodine, toremifene, tramadol, trimipramine, 
vardenafil, vemurafenib, venlafaxine, vorinostat, ziprasidone 
Conditional3 
Amantadine, amisulpride, amitriptyline, amoxapine, chloral hydrate, diphenhydramine, 
doxepin, fluoxetine, furosemide (frusemide), galantamine, hydrochlorothiazide, 
Hydroxychloroquine hydroxyzine, indapamide, itraconazole, ivabradine (on non US mkt), 
ketoconazole, metoclopramide, metronidazole, nelfinavir, pantoprazole, paroxetine, 
posaconazole, quinine sulfate, ritonavir, sertraline, solifenacin, telaprevir, torsemide 
(torasemide), trazodone, voriconazole 
1 Known risk: Substantial evidence supports the conclusion that these drugs prolong the QT interval AND are clearly 
associated with a risk of TdP, even when taken as directed in official labeling 
2 Possible risk: Substantial evidence supports the conclusion that these drugs can cause QT prolongation BUT there is 
insufficient evidence at this time that these drugs, when used as directed in official labeling, are associated with a risk of 
causing TdP. 
3 Conditional risk: Substantial evidence supports the conclusion that these drugs are associated with a risk of TdP BUT only 
under certain conditions (e.g. excessive dose, hypokalemia, congenital long QT or by causing a drug-drug interaction that 
results in excessive QT interval prolongation). 


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14.5 
Appendix 5 – Statistical methodology LGX818 and MEK162 dual 
combination 
14.5.1 
Prior Distributions of 5 parameter dual combo (LGX818+MEK162) 
model 
LGX818 (cps): The initial prior parameters for the capsule of the single agent are as specified 
in study [CLGX818X2101]. Detailed derivation of this prior distribution can be found in the 
protocol of CLGX818X2101, Section 10.4.2. 
Using a meta-analytic predictive approach, an assumption about heterogeneity between trial 
[CLGX818X2101] and the current combination trial is captured in the prior distributions of the 
standard deviation of the model parameters (log(α1),log(β1)), denoted by τ1 and τ2. Both τ1 and 
τ2 were assumed to follow a log-normal distribution with mean log(0.25) and standard deviation 
0.01, assuming moderate between-trial heterogeneity. This new distribution is then used as the 
prior distribution for the model parameters (log(α1),log(β1)). 
MEK162: An informative bivariate normal prior for the model parameters (log(α2),log(β2)) is 
obtained as follows: 
As a first step, a non-informative prior for (log(α2),log(β2)) was defined as follows: 
• The median DLT rate at the reference dose (60mg) was assumed 1/3, i.e. 
mean(log(α2,fasted)) = log(1/2) 
• A doubling in dose was assumed to double the odds of DLT, i.e. mean(log(β2)) = 0 
• The standard deviations of the two parameters were set to 2, such that the bivariate normal 
distribution covers approximately 95% of the probability space. 
• The correlation between the two parameters was set to 0, assuming independence. 
Data from the 15 patients eligible for the DDS of on-going study [ARRAY-162-111] was added 
into a 2-parameter BLRM for single agent. 
The assumption about heterogeneity is captured in the prior distributions of the standard 
deviation of (log(α2),log(β2)), denoted by τ1 and τ2. Both τ1 and τ2 are assumed to follow a log- 
normal distribution with mean log(0.25) and standard deviation 0.01, assuming moderate 
between-trial heterogeneity. 
The updated model parameters are estimated via simulation from the posterior distribution. This 
distribution is then used as the prior distribution for the parameters (log(α2),log(β2)). 
Table 14-13  Data from ARRAY-162-111 
 
Dose of MEK162 (mg, bid) 
No of DLTs / No of evaluable patients 
 
30 
0/3 
45 
0/3 
60 
0/6 
80 
2/3 
A weakly informative prior reflecting the current uncertainty about the toxicity of the 
combination treatment is used for η12. In order to allow for the potentiality of both synergy and 
antagonism of the safety profiles, it was assumed that η12 is normally distributed with median 


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= 0 (no increase on odds of DLT, i.e. independence) and 97.5th percentile = log(20) (20-fold 
increase on odds of DLT). 
The prior distributions of 5 parameter dual combo (LGX818+MEK162) model are provided in 
Table 14-14. 
Table 14-14   Predictive distribution of model parameters 
 
Parameter 
Means 
Standard deviations 
Correlation 
log(α1), log(β1) 
-1.415, 0.463 
1.231, 1.273 
0.003 
log(α2), log(β2) 
-2.326, 1.564 
1.107, 1.368 
-0.535 
η12 
0 
1.528 
N/A 
For LGX818X2101, data up to dose escalation teleconference from 23/Nov/2011 
Predictive: between-trial heterogeneity τ1~lognormal(log(0.25),0.012), τ2~lognormal(log(0.25),0.012) for log(α1), 
log(β1), and τ1~lognormal(log(0.25),0.012), τ2~lognormal(log(0.25),0.012) for log(α2), log(β2) 
A summary of the respective prior distribution of DLT rates for dual combo 
(LGX818+MEK162) is given in Table 14-15. Dose combinations not satisfying the overdose 
criteria, i.e. not eligible at the start of the study, are displayed in bold. 
Note: the model was re-evaluated before the first dose escalation meeting with the available 
data from study [CLGX818X2101]. 


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Table 14-15 
Summary of prior probabilities of DLT rates 
LGX818 
(mg) 
Prior probabilities that Pr(DLT) 
is in interval: 
Mean 
SD 
Quantiles 
[0.0, 0.16) [0.16, 
0.35) 
[0.35,1.00] 
2.50% 
50.00% 
97.50% 
MEK162 = 30mg 
50 
0.674 
0.206 
0.12 
0.147 
0.166 
0 
0.086 
0.616 
100 
0.379 
0.29 
0.331 
0.288 
0.226 
0.018 
0.226 
0.824 
150 
0.231 
0.199 
0.571 
0.472 
0.32 
0.021 
0.433 
0.999 
200 
0.203 
0.152 
0.644 
0.551 
0.347 
0.017 
0.573 
1 
250 
0.198 
0.124 
0.679 
0.595 
0.361 
0.011 
0.677 
1 
300 
0.198 
0.105 
0.697 
0.621 
0.37 
0.007 
0.754 
1 
MEK162 = 45mg 
50 
0.615 
0.231 
0.154 
0.173 
0.18 
0.001 
0.109 
0.668 
100 
0.365 
0.254 
0.381 
0.319 
0.256 
0.014 
0.249 
0.891 
150 
0.255 
0.165 
0.58 
0.489 
0.342 
0.011 
0.466 
0.999 
200 
0.238 
0.123 
0.639 
0.559 
0.37 
0.006 
0.616 
1 
250 
0.238 
0.098 
0.664 
0.596 
0.385 
0.003 
0.722 
1 
300 
0.242 
0.083 
0.675 
0.616 
0.395 
0.001 
0.798 
1 
MEK162 = 60mg 
50 
0.453 
0.297 
0.25 
0.242 
0.202 
0.016 
0.182 
0.754 
100 
0.313 
0.221 
0.466 
0.379 
0.289 
0.013 
0.316 
0.946 
150 
0.255 
0.137 
0.608 
0.521 
0.36 
0.006 
0.532 
1 
200 
0.252 
0.102 
0.645 
0.577 
0.386 
0.002 
0.68 
1 
250 
0.259 
0.082 
0.66 
0.603 
0.401 
0.001 
0.78 
1 
300 
0.267 
0.068 
0.665 
0.618 
0.412 
0 
0.846 
1 
Prior specifications of LGX818 New Regimen 
If a different regimen (BID and/or every-other-day) for LGX818 is explored in this study, then 
two models will be fitted independently for the different dosing regimens. The dose escalation 
for the originally planned regimen will be guided by the model described previously. The dose 
escalation for the new regimen (NR) will be guided by a model using the same mathematical 
relationship as the one for the originally planned regimen but with different prior distributions 
based on a meta-analytic predictive approach. Details are given in Section 14.5.3.1. 
Prior specifications for the MEK162 smaller tablet / new MEK162 tablet variant 
if to be evaluated for MTD/RP2D in MEK162X2110 patients 
If it is decided that the MTD/RP2D of the LGX818 and MEK162 combination will need to be 
established with one or both of the two new MEK162 tablet variants, then all updated DLT data 
from the patients treated with the original tablet will be incorporated into a weakly informative 
prior distribution for MEK162 (smaller tablet /new tablet variant) using a meta-analytic 
predictive approach. Between variant variability will be assessed using the data from 
[CMEK162A2101] and [CMEK162X2108] and a down-weighting factor will be used to down- 


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weight the original tablet data. The assumption about the heterogeneity between the two tablet 
variants will be captured in the prior distributions of the standard deviations of (log(α),log(β)), 
denoted by τ(τ1, τ2). A mixture prior with high or low tox components may be used to add 
robustness to the model. The equivalent dose of the MEK162 smaller tablet and/or new 
MEK162 tablet variant with respect to the original MEK162 tablet will be calculated based on 
the bioavailability ratio from relative bioavailability study or relative PK from first dose cohort 
prior to first DETC. More details of this process will be provided at the dose-escalation 
teleconference and will be reported in the statistical appendix, Section 16.1.9 of the CSR. 
14.5.2 
Data from the ongoing study LGX818X2101 
Table 14-16   Data from LGX818X2101- as of 23/Nov/2011 
Dose of LGX818 (mg) 
Nr. DLTs / Nr. evaluable patients 
100 (micro-emulsion) 
1/4 
14.5.3 
LGX818 change in regimen 
If a different regimen (BID and/or every-other-day) for LGX818 is explored in this study, then 
two models will be fitted independently for the different dosing regimens. The dose escalation 
for the originally planned regimen will be guided by the model described on Section 10.4.2.1. 
The dose escalation for the new regimen (NR) will be guided by a model using the same 
mathematical relationship as the one for the originally planned regimen but with different prior 
distributions based on a meta-analytic predictive approach. 
The parameters in the model for the new regimen (NR) will be denoted by γ1, δ1 for the LGX818 
NR, by γ 2, β2 for MEK162 BID, and by ηNR for the interaction parameter. The respective total 
daily doses will be denoted by b1 and b2, respectively. This model can thus be expressed as: 
logit(µ1(b1)) = log(γ 1) + δ 1log(b1/b1*) 
logit( µ2(b2)) = log(γ 2) + δ 2log(b2/b2*) 
Odds( µ12(b1,b2))) = µ12(b1,b2)/(1- µ12(b1,b2)) 
= exp(ηNRb1/b1*b2/b2*)(µ1(b1)+ µ2(b2) – µ1(b1)µ2(b2))/((1- µ1(b1))(1- µ2(b2))), 
where b1*= 100mg (NR) and b2*= 60mg (BID). 
14.5.3.1 Prior specifications for LGX818 new regimen 
At the time when a NR is introduced, the prior distribution for the parameters γ1, δ1, γ2, δ2 and 
ηNR will be derived in the following way: 
γ1, δ1: 
The posterior means, standard deviations and correlation of log(α1), log(β1) incorporating all 
the data available at the time when a NR is introduced will be found via simulation. 
The assumption about heterogeneity will be captured in the prior distributions of the standard 
deviation of (log(γ1),log(δ1)), denoted by τ1 and τ2. Both τ1 and τ2 follow a log-normal 
distribution with mean log(0.2) and standard deviation 0.01, assuming small to moderate 
between-regimen heterogeneity. 


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The updated model parameter will be estimated via simulation from the predictive distribution. 
Means, standards deviations and correlation of this distribution will then be used as the prior 
distribution for the parameters (log(γ1),log(δ1)). 
γ2, δ2: 
since the parameters γ2, δ2 relate to the single-agent (the marginal) dose-toxicity relationship of 
MEK162, for which the same regimen will be used, no heterogeneity is expected. Therefore, 
the prior for γ2, δ2 will simply be the posterior means, standard deviations and correlation of 
log(α2), log(β2) incorporating all the data available at the time when a BID regimen is introduced, 
found via simulation. 
ηNR: 
the posterior mean and standard deviation of η, denoted by mean(η|data), sd(η|data), 
incorporating all the data available at the time when a NR is introduced will be found via 
simulation. Based on the assumption of small to moderate between-regimen heterogeneity, the 
prior distribution of ηNR can be found analytically, as a normal distribution with mean = 
mean(η|data) and standard deviation = (sd(η|data)2. + 2*0.22)0.5. 
14.5.4 
Operating characteristics of the Bayesian Logistic Regression Model 
and hypothetical dose escalation scenarios 
14.5.4.1 The Bayesian logistic regression model 
An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will guide the dose escalation of the combination treatment 
to its MTD(s)/RP2D(s). 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. 
A 5-parameter BLRM (refer to the protocol Section 10.4.2 for detail) for combination treatment 
will be fitted on first 28 day dose limiting toxicity data (i.e. absence or presence of DLT) 
accumulated throughout the dose escalation to model the dose-toxicity relationship of LGX818 
and MEK162 when given in combination. To check the performance of the model, the 
document summarizes the simulation results and some hypothetical dose escalation scenarios. 
Details regarding dose recommendation are described in Section 10.4.2 of the protocol. 
14.5.5 
Simulated operating characteristics 
14.5.5.1 Hypothetical scenarios 
In order to show how the Bayesian combination model reacts, the following hypothetical 
scenarios were investigated: 
• Scenario 1: no increases in odds of DLT, i.e., the simulation parameter values for the 
BLRM are set to the mean values of the prior. 
• Scenario 2: is scenario 1 + 50% increase in odds of DLT, i.e., 50% increase in odds of 
DLT. 


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• Scenario 3: is scenario 1 + 100% increase in odds of DLT, i.e., 100% increase in odds of 
DLT. 
• Scenario 4: is scenario 1 but with constant interaction across doses. 
• Scenario 5: is scenario 2 but with constant interaction across doses. 
Scenarios 4 and 5 represent stress tests since the underlying interaction is assumed constant 
across doses and not dose-dependent (as assumed in the model). 


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Table 14-17 
True underlying probabilities of DLT for Scenario 1 
PFIZER CONFIDENTIAL 
 
 
 
 
LGX818 -QD (mg) 
MEK162 - BID (mg) 
15 
30 
45 
60 
30 
0.035 
0.039 
0.06 
0.126 
50 
0.076 
0.081 
0.103 
0.169 
100 
0.203 
0.213 
0.239 
0.304 
150 
0.331 
0.349 
0.38 
0.443 
200 
0.445 
0.469 
0.504 
0.564 
250 
0.539 
0.568 
0.606 
0.662 
300 
0.615 
0.648 
0.686 
0.737 
350 
0.676 
0.711 
0.749 
0.795 
400 
0.725 
0.761 
0.797 
0.839 
450 
0.765 
0.8 
0.835 
0.872 
Bold values indicate dose combinations in the targeted toxicity interval [16%, 35%) 
Table 14-18 
True underlying probabilities of DLT for Scenario 2 
LGX818 -QD (mg) 
MEK162 - BID (mg) 
15 
30 
45 
60 
30 
0.036 
0.041 
0.066 
0.141 
50 
0.08 
0.089 
0.118 
0.2 
100 
0.22 
0.249 
0.298 
0.396 
150 
0.366 
0.421 
0.491 
0.594 
200 
0.495 
0.57 
0.651 
0.744 
250 
0.601 
0.686 
0.767 
0.844 
300 
0.684 
0.772 
0.845 
0.904 
350 
0.748 
0.833 
0.896 
0.941 
400 
0.798 
0.877 
0.93 
0.963 
450 
0.837 
0.909 
0.952 
0.977 
Bold values indicate dose combinations in the targeted toxicity interval [16%, 35%) 
Table 14-19 
True underlying probabilities of DLT for Scenario 3 
LGX818 -QD (mg) 
MEK162 - BID (mg) 
15 
30 
45 
60 
30 
0.037 
0.043 
0.07 
0.151 
50 
0.083 
0.095 
0.13 
0.224 
100 
0.232 
0.277 
0.345 
0.466 
150 
0.391 
0.474 
0.572 
0.692 
200 
0.531 
0.639 
0.742 
0.838 
250 
0.643 
0.758 
0.849 
0.917 
300 
0.729 
0.839 
0.912 
0.957 
350 
0.793 
0.892 
0.948 
0.978 
400 
0.841 
0.927 
0.969 
0.988 
450 
0.876 
0.95 
0.981 
0.994 
Bold values indicate dose combinations in the targeted toxicity interval [16%, 35%) 


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Table 14-20 
True underlying probabilities of DLT for Scenario 4 
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LGX818- QD (mg) 
MEK162 - BID (mg) 
15 
30 
45 
60 
30 
0.035 
0.038 
0.058 
0.121 
50 
0.075 
0.078 
0.097 
0.157 
100 
0.196 
0.198 
0.215 
0.267 
150 
0.316 
0.319 
0.333 
0.377 
200 
0.422 
0.424 
0.436 
0.474 
250 
0.51 
0.512 
0.522 
0.554 
300 
0.582 
0.583 
0.592 
0.619 
350 
0.64 
0.641 
0.649 
0.672 
400 
0.687 
0.688 
0.695 
0.715 
450 
0.726 
0.727 
0.733 
0.75 
Bold values indicate dose combinations in the targeted toxicity interval [0.16, 0.35) 
Table 14-21 
True underlying probabilities of DLT for Scenario 5 
LGX818 -QD (mg) 
MEK162 - BID (mg) 
15 
30 
45 
60 
30 
0.051 
0.056 
0.084 
0.171 
50 
0.108 
0.113 
0.139 
0.218 
100 
0.267 
0.271 
0.291 
0.353 
150 
0.41 
0.412 
0.428 
0.476 
200 
0.523 
0.525 
0.537 
0.574 
250 
0.61 
0.611 
0.621 
0.651 
300 
0.676 
0.677 
0.685 
0.709 
350 
0.727 
0.728 
0.735 
0.755 
400 
0.767 
0.768 
0.774 
0.79 
450 
0.799 
0.8 
0.804 
0.819 
Bold values indicate dose combinations in the targeted toxicity interval [0.16, 0.35) 
14.5.5.2 Simulation parameters 
500 trials were used to simulate each scenario and the total minimum number of DLT to control 
the declaration of MTD was fixed to one. 
The maximal dose to jump to was orthogonal and follows the protocol specifications 
(Section 10.4.2.1 of the protocol): 


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Table 14-
Preference matrix 
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LGX818 – QD (mg) 
MEK162 - BID (mg) 
15 
30 
45 
60 
50 
1 
2 
3 
4 
100 
2 
3 
4 
5 
150 
3 
4 
5 
6 
200 
4 
5 
6 
7 
250 
5 
6 
7 
8 
300 
6 
7 
8 
9 
350 
7 
8 
9 
10 
400 
8 
9 
10 
10 
450 
9 
10 
10 
10 
The number of patients to enroll in each cohort and stopping rules used to declare MTD were 
defined as: 
• Minimum cohort size: 3 
• Minimum number of patients enrolled: 18 
• Maximum number of patients enrolled: 60 
• Minimum number of patients enrolled at a given dose combination in order to declare 
MTD: 6 
14.5.5.3 Metrics 
Operating characteristics were reviewed for the simulations to compare the relative 
performance under each true scenario. The metrics reviewed were: 
I. Average proportion of patients receiving a target dose combination on study (I) 
II. Average proportion of patients receiving a dose combination with true P(DLT) ≥ 35% on 
study (II) 
III. Average proportion of patients receiving a dose combination with true P(DLT) < 16% on 
study (III) 
IV. Probability of recommending a target dose combination as the MTD (correct final 
decision) (IV) 
V. Probability of recommending a dose combinations with true P(DLT) ≥ 35% as the MTD 
(patient risk) (V) 
VI. Probability of recommending dose combination with true P(DLT) < 16% as the MTD (VI) 
14.5.5.4 Results 
Table 14-23 presents the model for the 5 different scenarios studied, additionally showing how 
many of the trials were stopped before declaring MTD when all dose combinations were 
considered too toxic. 


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Table 14-
Results 
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Scenario 
Metric 
I 
II 
III 
IV 
V 
VI 
Stopped 
1 
0.681 
0.035 
0.286 
0.882 
0.016 
0.076 
0.026 
2 
0.532 
0.147 
0.32 
0.716 
0.126 
0.122 
0.036 
3 
0.552 
0.099 
0.35 
0.78 
0.046 
0.136 
0.038 
4 
0.474 
0.155 
0.273 
0.496 
0.382 
0.088 
0.034 
5 
0.613 
0.133 
0.252 
0.736 
0.152 
0.058 
0.054 
In summary, the simulated operating characteristics show: 
• (Metric IV) that the identified MTD falls within the targeted interval in more than 72% of 
the cases, except for scenario 4. 
• (Metric V) that on average, less than 15% of patients are treated at overly toxic doses, 
excluding scenario 4. 
• (Metric I) The average proportion of patients receiving a target dose combination on study 
is 47% to 68%. 
• Scenario 4 needs careful consideration, since the true underlying probability of DLT 
(15.7%) for the combination MEK162 60mg + LGX818 50mg is very close to the lower 
boundary of the targeted toxicity [16%, 35%). Unsurprisingly, this combination is 
therefore identified relatively often as an MTD. Had this combination been counted as a 
correct MTD as well, then metric IV improves to 56.8%. 
14.5.6 
Hypothetical dose escalation scenarios 
In order to show how the Bayesian model reacts, different hypothetical dose escalation 
scenarios were investigated (Table 14-24). 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. 
It is assumed for most scenarios that each cohort has exactly 3 evaluable patients. Scenario 20 
illustrates the ability for the model to handle cohorts of different size. Dose escalation follows 
the rule listed in Section 6.2.4. 
Overall, in the early cohort scenarios, the model is showing appropriate behaviors, in agreement 
with clinical sense and decision-making process: progressive increase of the combination doses 
if no DLT is observed (e.g., scenarios 1, 4, 10), staying at the same dose level and opening of a 
new cohort at the same dose combination when 1 DLT is reported (e.g., scenario 2), and 
decrease when more than 1 DLT is reported in a cohort (e.g., scenarios 5,6). 


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Table 14-24 
Hypothetical dose escalation scenarios 
Scenario 
Dose combination 
MEK162 / LGX818 
Npat 
Ntox 
Next dose 
combination 
(NDC) 
P(Target) 
NDC 
P(over) 
NDC 
Median 
DLT rate 
(NDC) 
1 
45/50 
3 
0 
60/50 
0.279 
0.096 
0.119 
2 
45/50 
3 
1 
45/50 
0.398 
0.232 
0.211 
3 
45/50 
3 
2 
stop 
4 
45/50 
45/100 
3 
3 
0 
0 
60/100 
0.240 
0.126 
0.107 
5 
45/50 
45/100 
3 
3 
0 
1 
45/50 
0.224 
0.034 
0.084 
6 
45/50 
45/100 
3 
3 
0 
2 
45/50 
0.308 
0.095 
0.123 
7 
45/50 
45/100 
45/50 
3 
3 
3 
0 
1 
0 
45/100 
0.397 
0.243 
0.214 
8 
45/50 
45/100 
45/50 
3 
3 
3 
0 
1 
1 
45/50 
0.407 
0.064 
0.152 
9 
45/50 
45/100 
45/50 
3 
3 
3 
0 
1 
2 
45/50 
0.552 
0.203 
0.237 
10 
45/50 
45/100 
60/100 
3 
3 
3 
0 
0 
0 
60/150 
0.158 
0.204 
0.084 
11 
45/50 
45/100 
60/100 
3 
3 
3 
0 
0 
1 
60/100 
0.399 
0.185 
0.189 
12 
45/50 
45/100 
60/100 
3 
3 
3 
0 
0 
2 
45/100 
0.480 
0.241 
0.238 
13 
45/50 
45/100 
45/150 
3 
3 
3 
0 
0 
0 
45/200 
0.154 
0.115 
0.058 
14 
45/50 
45/100 
45/150 
3 
3 
3 
0 
0 
1 
45/100 
0.310 
0.040 
0.121 
15 
45/50 
45/100 
45/150 
3 
3 
3 
0 
0 
2 
45/100 
0.432 
0.135 
0.181 
16 
45/50 
45/100 
45/150 
45/100 
3 
3 
3 
3 
0 
0 
2 
0 
60/100 
0.375 
0.177 
0.179 
17 
45/50 
45/100 
45/150 
45/100 
3 
3 
3 
3 
0 
0 
2 
1 
45/100 
0.542 
0.169 
0.222 
18 
45/50 
45/100 
45/150 
45/100 
3 
3 
3 
3 
0 
0 
2 
2 
45/50 
0.283 
0.042 
0.105 


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Scenario 
Dose combination 
MEK162 / LGX818 
Npat 
Ntox 
Next dose 
combination 
(NDC) 
P(Target) 
NDC 
P(over) 
NDC 
Median 
DLT rate 
(NDC) 
19 
45/50 
45/100 
60/100 
60/150 
3 
3 
3 
3 
0 
0 
0 
0 
60/300 
0.076 
0.115 
0.011 
20 
45/50 
45/100 
60/100 
60/150 
3 
3 
3 
6 
0 
0 
0 
3 
60/100 
0.467 
0.083 
0.174 
14.5.7 
Power for analysis of key secondary variables 
Not applicable. 
14.5.8 
References (available upon request) 
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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14.6 
Appendix 6 - Operating characteristics of the combination 
Bayesian logistic regression model and hypothetical dose 
escalation scenarios LGX818 and MEK162 and LEE011 triple 
combination 
[This Section is not applicable to the USA and Singapore] 
An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will guide the dose-escalation of the combination treatment 
to its MTD(s)/RP2D(s). 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 et al 2007) 
and is one of the key elements of the FDA’s Critical Path Initiative. 
A 10-parameter BLRM for combination treatment will be fitted on first 28 day dose limiting 
toxicity data (i.e. absence or presence of DLT) accumulated throughout the dose-escalation to 
model the dose-toxicity relationship of LGX818, MEK162 and LEE011 when given in 
combination. To check the performance of the model, the document summarizes some 
hypothetical dose escalation scenarios. 
14.6.1 
Statistical Model 
Refer to Section 10.4.2 for the form of the model. Note that the 10 parameter model for the 
triple combination (LGX818+MEK162+LEE011) is an extension of 5 parameter model used 
for the dual combination (LGX818+MEK162). When the dose of LEE011 equals to 0, the 10 
parameter model reduces to the existing 5 parameter model. 
The Bayesian approach requires the specification of prior distributions for the model parameters. 
((log(α1),log(β1)), (log(α2),log(β2)), (log(α4),log(β4))), η12, η14, η24, η124 
The prior information for parameters (log(αx),log(βx)) (where x=1, 2, 4) come from prior 
available dose-DLT information of LGX818, MEK162 and LEE011. 
14.6.2 
Prior Specification 
The prior derivation for the 5 parameter dual combo (LGX818+MEK162) model was described 
in the original protocol as shown in Appendix 5 (Section 14.5). 
14.6.2.1 Prior distribution for log(α4),log(β4) (LEE011 single agent component) 
For this trial, historical data from the ongoing study CLEE011X2101 (first-in-human LEE011 
oncology study) were used to derive an informative prior for the (log(α4),log(β4)) (see Table 
14-25). 
1. The informative bivariate normal prior for the model parameters (log(α4),log(β4)) was 
obtained as follows: 
• The median DLT rate at the LEE011 reference dose (400 mg, 3 weeks on 1 week off) 
was assumed 1/10 i.e. mean(log(α4)) = log(1/9). 
• A doubling in dose was assumed to double odds of DLT, i.e. mean(log(β4)) = 0. 
• The standard deviation of log(α4) was set to 2 and the standard deviation of log(β4) to 
1, which allows for considerably prior uncertainty for the dose-toxicity profile. 


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• The correlation between log(α4) and log(β4) was set to 0. 
2. Data from 53 patients (treated with LEE011 3 week on 1 week off) eligible for the dose 
determining set of the study [CLEE011X2101] were used to update the dose-toxicity 
profile (See Table 14-25). 
Three percentiles (2.5, 50, 97.5) of the posterior distribution are used to find the 5 parameters 
of the bivariate-normal distribution that is in best agreement with the percentiles for each dose 
level. 
3. Heterogeneity between the historical and current study was incorporated by between-trial 
standard deviations and τ41 and τ42 for log(α4) and log(β4). Both τ41 and τ42 were set to 
follow a log-normal distribution. Mean log(0.25) and standard deviation 0.01 was chosen 
for τ41 and mean log(0.125) and standard deviation 0.01 was chosen for τ42 which 
correspond to moderate between-trial variability. 
Table 14-25 
Data from CLEE11X2101 
 
Dose of LEE011 (mg, 3 weeks on, 1 week off) 
No of DLTs / No of evaluable patients 
50 
1/4 
70 
0/2 
140 
0/3 
260 
0/4 
280 
1/4 
350 
0/5 
400 
1/4 
600 
0/4 
750 
1/7 
900 
1/13 
1200 
2/3 
 
 
Table 14-26 
Prior, posterior and predictive distribution of (log(alpha4),log(beta4)) 
 
Parameter 
Means 
Standard deviations 
Correlation 
Prior for (log(α4),log(β4)) 
(log(1/9), 0) 
(2, 1) 
0 
Normalized Posterior for 
(log(α4),log(β4)) 
(-2.075, -0.744) 
(0.396, 0.521) 
-0.130 
Predictive for (log(α4),log(β4)) 
(-2.066, -0.749) 
(0.527, 0.563) 
-0.116 
Interaction 
As shown above, the distribution of η12 is inherited from existing LGX818 and MEK162 dual- 
combo model. A non-informative prior reflecting the current uncertainty about the toxicity of 
the combination treatment is used for η14, η24, η124. There is no interaction expected between 
MEK162 and LEE011, we set the median of η24 to be log (1.02) which assumes a 2% increase 
of odds. This is a conservative way to set the prior. The 97.5 percentile of η24 is set to be log 
(2.2) which assumes a 1.2 fold increase of odds. LGX818 and LEE011 have potential positive 
interaction. Hence we set the median of η14 to be log (1.1) which assumes a 10% increase in 
odds of toxicity. The 97.5 percentile of η14 is set to be log (3), which assumes a 2 fold increase 


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of odds. We also set a conservative prior for 3 way interaction. The median of η124 is set to be 
log (1.02). The 97.5 percentile is set to be log (2.2). 
14.6.2.2 Summary 
The prior distribution of the parameters is summarized in Table 14-27. The prior distribution of 
the DLT rates for provisional doses is summarized in Table 14-28. Note that the posterior 
probability of excessive toxicity of the proposed starting dose for triple combination 
(LGX818+MEK162+LEE011) is 10.2% which satisfies EWOC criteria. 
Table 14-27 
Prior distribution of model parameters 
 
Parameter 
Means 
Standard deviations 
Correlation 
(log(α1),log(β1)) 
(-2.917, -1.820) 
(0.986, 1.041) 
0.233 
(log(α2),log(β2)) 
(-2.326, 1.564) 
(1.107, 1.368) 
-0.535 
(log(α4),log(β4)) 
(-2.066, -0.749) 
(0.527, 0.563) 
-0.116 
η12 
0 
1.528 
NA 
η14 
0.095 
0.512 
NA 
η24 
0.020 
0.392 
NA 
η124 
0.020 
0.392 
NA 
Table 14-28 
Summary of prior distribution of DLT rates for triple combo 
(LGX818+MEK162+LEE011) including current DLT data (up to Apr 16, 2013) from dual 
combo (LGX818+MEK162) 
 
LEE011 
(mg, 3 week 
on, 1 week) 
Prior probabilities that Pr(DLT) is in 
interval 
Mean 
SD 
Quantiles 
[0.0, 0.16) 
[0.16, 0.35) 
[0.35,1.00] 
2.50% 
50.00% 
97.50% 
MEK162 45mg BID, LGX818 450mg QD 
100 
0.662 
0.236 
0.102 
0.149 
0.145 
0.006 
0.102 
0.551 
200 
0.552 
0.216 
0.232 
0.218 
0.226 
0.004 
0.132 
0.809 
400 
0.468 
0.14 
0.392 
0.337 
0.341 
0.001 
0.194 
0.986 
600 
0.44 
0.098 
0.462 
0.411 
0.396 
0 
0.265 
0.999 
800 
0.428 
0.075 
0.498 
0.455 
0.424 
0 
0.342 
1 
MEK162 45mg BID, LGX818 600mg QD 
100 
0.632 
0.204 
0.164 
0.174 
0.195 
0.002 
0.097 
0.72 
200 
0.543 
0.169 
0.288 
0.253 
0.281 
0.001 
0.129 
0.926 
400 
0.472 
0.106 
0.423 
0.373 
0.381 
0 
0.202 
0.998 
600 
0.447 
0.073 
0.481 
0.439 
0.423 
0 
0.291 
1 
800 
0.434 
0.056 
0.51 
0.476 
0.443 
0 
0.39 
1 
14.6.2.3 Hypothetical dose escalation scenarios for triple combo 
(LGX818+MEK162+LEE011) 
The BLRM model should make reasonable decisions during a study based on the observed 
toxicities particularly in early cohorts. After completion of a given cohort, the decision to dose 
escalate and actual dose chosen for the subsequent cohort will depend on the recommendation 
of the BLRM EWOC principle and medical review of all relevant data available up to date. 


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Table 14-29 shows some scenarios of dose levels recommended by the 10-parameter BLRM 
for the specified DLT observations. 
Note that the next dose level is selected in concordance with the provisional dose levels of 
LGX818 and LEE011 specified in the protocol, to mimic possible on-study escalation steps. 
MEK162 is maintained at 45 mg BID. Since the main goal of the dose escalation is to escalate 
LEE011, LGX818 is fixed at 450mg in the table. 
Table 14-29  Dose decisions recommended by BLRM 
 
Scenario 
LEE011 
(mg, 3 week 
on, 1 week off) 
Npat 
Ntox 
Next dose level LEE011 
(mg, 3 week on, 1 week off) 
P(Target) P(over) 
Median 
DLT rate 
1 
100 
3 
0 
200 
0.193 
0.109 
0.079 
2 
100 
3 
1 
100 
0.399 
0.155 
0.178 
3 
100 
3 
2 
50 
0.505 
0.227 
0.233 
4 
100 
6 
1 
200 
0.308 
0.221 
0.172 
5 
100 
3 
0 
400 
0.131 
0.130 
0.042 
200 
3 
0 
6 
100 
3 
0 
200 
0.367 
0.181 
0.178 
200 
3 
1 
7 
100 
3 
0 
100 
0.527 
0.126 
0.200 
200 
3 
2 
8 
100 
3 
0 
300 
0.281 
0.188 
0.147 
200 
6 
1 
10 
100 
3 
0 
400 
0.221 
0.225 
0.131 
200 
8 
1 
11 
100 
3 
0 
800 
0.072 
0.104 
0.007 
200 
3 
0 
400 
3 
0 
12 
100 
3 
0 
400 
0.326 
0.242 
0.191 
200 
3 
0 
400 
3 
1 
13 
100 
3 
0 
200 
0.505 
0.105 
0.188 
200 
3 
0 
400 
3 
2 
14 
100 
3 
0 
600 
0.233 
0.229 
0.139 
200 
3 
0 
400 
6 
1 
The BLRM model is performing reasonably for the hypothetical dose escalation scenarios. 
Within Table 14-29, it can be seen that the model leads to decisions that are in agreement with 
clinical sense. When no DLTs are observed in a cohort, the decision is to escalate the dose. 
When 1 DLT is observed in one cohort, the decision is to stay in the current dose level, or dose 
escalation depending on the size of the cohort. When more than 1 DLT is observed in one cohort, 
the decision is to dose de-escalation. 
14.6.3 
References (available upon request) 
EMEA (2006) Guideline on small populations (Internet) Available from: 
<emea.europa.eu.docs/en_GB/document_library/Scientific_guidiline/2009/09/WC500003615. 
pdf>. 


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Ho C, Sangha R, Beckett L, et al (2011) Escalating weekly doses of cetuximab and conelation 
with skin toxicity: a phase I study. Invest New Dmgs; 29: 680-7. 
Rogatko A, Schoeneck D, Jonas W, et al (2007) Translation of innovative designs into phase I 
trials. J Clin Oncol; 25: 4982-6. 
 
14.7 
Appendix 7: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
14.7.1 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occunence in a patient or clinical study patient, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnonnal laborato1y finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• 
 Any abnonnal laborato1y test results (hematology, clinical cheinistiy, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator Any abnonnal laborato1y test 
results that meet any of the conditions below must be recorded as an AE: 
• 
Is associated with accompanying symptoms; 
• 
Requires additional diagnostic testing or medical/surgical intervention; 
• 
 Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
dmg ti·eatinent, or other therapy. 
• 
 Exacerbation of a chronic or intennittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study ti·eatinent adininisti·ation even 
though it may have been present before the staii of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected dmg-dmg interaction. 
• 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concoinitant medication. Overdose per se will not be repo1ied as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-haiming intent. Such overdoses should be repo1ied regardless of 
sequelae. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reoo1ied as an AE or SAE if they fulfill the definition of an AE or SAE and meet the 


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requirements as per Section 8.1.8.1. Also, "lack of efficacy" or "failure of expected 
phannacological action" does not constitute an AE or SAE. 
 
Events 
Meeting the AE Definition 
• 
 Any clinically significant abnonnal laborato1y findings or other abnonnal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the patient's condition. 
• 
 The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
patient's condition. 
• 
 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
 Situations in which an untoward medical occunence did not occur (social and/or 
convenience admission to a hospital). 
• 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the sta1t of the study that do not worsen. 
• 
 Worsening of signs and symptoms of the malignancy under study should be 
recorded as AEs in the appropriate section of the CRF. Disease progression 
assessed by measurement of malignant lesions on radiographs or other methods 
should not be repo1ted as AEs. 
14.7.2 
Definition of an SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 


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An SAE is defined as any untoward medical occurrence that, at any dose: 
a.  Results in death 
b. Is life-threatening 
The te1m "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician's office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether "hospitalization" occmTed or was necessaiy, the AE should be considered 
senous. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The te1m disability means a substantial dismption of a person's ability to conduct 
n01mal life functions. 
• 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diaiThea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial dismption. 
e.  Is a congenital anomaly/birth defect 
f. Other situations: 
• 
 Medical or scientific judgment should be exercised in deciding whether SAE 
repo1iing is appropriate in other situations such as impo1iant medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopai·dize the patient or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
• 
 Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 


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convulsions that do not result in hospitalization, or development of drng dependency 
or dmg abuse. 
• 
 Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
active collection period. Hospitalization due to signs and symptoms of disease 
progression should not be repo1ied as an SAE. If the malignancy has a fatal 
outcome during the study or within the active collection period, then the event 
leading to death must be recorded as an AE on the CRF, and as an SAE with 
CTCAE Grade 5 (see the Assessment of Intensity section). 
 
 
14.7.3 
Recording/Reporting and Follow-up of AEs and/or SAEs 
AE and SAE Recording/Reporting 
 
The table below summarizes the requirements for recording adverse events on the CRF and 
for repo1iing serious adverse events on the CT SAE Repo1i Fo1m to Pfizer Safety. These 
requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse events 
(AEs); and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Repo1i Fo1m for repo1iing of SAE infonnation is not 
the same as the AE page of the CRF. When the same data are collected, the fo1ms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
tenninology and the same AE te1m should be used on both the CRF and the CT SAE 
Repo1i Fo1m for repo1iing of SAE infonnation. 
 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
SAE 
All 
All 
Nonserious AE 
All 
None 
Exposure to the study 
intervention under study 
All AEs/SAEs associated 
with exposure during 
All (and EDP supplemental 
fonn for EDP) 
during pregnancy or 
breastfeeding, and 
occupational exposure 
pregnancy or breastfeeding 
Occupational exposure is not 
recorded. 
Note: Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure. 


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•  When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laborato1y repo1ts, and diagnostic 
repo1ts) related to the event. 
• The investigator will then record all relevant AE/SAE infonnation in the CRF. 
• It is not acceptable for the investigator to send photocopies of the patient's medical 
records to Pfizer Safety in lieu of completion of the CT SAE Repo1t Fonn/AE/SAE 
CRFpage. 
• There may be instances when copies of medical records for ce1tain cases are 
requested by Pfizer Safety. In this case, all patient identifiers, with the exception of 
the patient number, will be redacted on the copies of the medical records before 
submission to Pfizer Safety. 
•  The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical infonnation. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE repo1ted during 
the study and assign it to 1 of the following categories: 
GRADE Clinical Description of Severity 
1 
MILD adverse event 
2 
MODERATE adverse event 
3 
SEVERE adverse event 
4 
LIFE-THREATENING consequences; urgent intervention indicated 
5 
DEATH RELATED TO adverse event 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and 
each occunence of each AE/SAE. 
•  A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be rnled out. 
• The investigator will use clinical judgment to detennine the relationship. 


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• 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration, will be considered and investigated. 
 
• 
 The investigator will also consult the IB and/or product infonnation, for marketed 
products, in his/her assessment. 
• 
For each AE/SAE, the investigator !!!!ll! document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
 
• 
There may be situations in which an SAE has occuned, and the investigator has 
minimal infonnation to include in the initial repo1t to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor. 
 
• 
The investigator may change his/her opinion of causality in light of follow-up 
infonnation and send an SAE follow-up repo1t with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when detennining regulato1y 
repo1ting requirements. 
• 
 If the investigator does not know whether or not the study treatment caused the 
event, then the event will be handled as "related to study treatment" for repo1ting 
purposes, as defined by the sponsor. In addition, if the investigator detennines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and repo1t such an 
assessment in the dedicated section of the CT SAE Repo1t Fonn and in accordance 
with the SAE repo1ting requirements. 
 
 
Follow-up of AEs and SAEs 
• 
 The investigator is obligated to perfonn or anange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laborato1y tests or investigations, 
histopathological examinations, or consultation with other healthcare providers. 
• 
New or updated info1mation will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the infonnation. 


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14.7.4 
Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via CT SAE Report Form 
• 
Facsimile trnnsmission of the CT SAE Repo1i Fo1m is the prefened method to 
transmit this info1mation to Pfizer Safety. 
• 
 In circlllllstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Fonn sent by overnight mail or 
com .er serv.ce. 
-i 
i 
• 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Repo1i Fo1m pages within the designated repo1iing 
time frames. 
14.8 
Appendix 8: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Potential Cases of Drug-Induced Liver Injury 
 
Humans exposed to a drng who show no sign of liver injmy (as dete1mined by elevations in 
transaminases) are te1med "tolerators," while those who show transient liver injmy, but adapt 
are te1med "adaptors." In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome. These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injmy, commonly refened to as DILi. Patients who experience a 
transaminase elevation above 3 x ULN should be monitored more frequently to detennine if 
they are an "adaptor" or are "susceptible." 
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations (>2 x 
ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT is/are 
still elevated above 3 x ULN (ie, AST/ALT and TBili values will be elevated within the same 
laborato1y sample). In rare instances, by the time TBili elevations are detected, AST/ALT 
values might have decreased. This occmTence is still regarded as a potential DILi. Therefore, 
abnonnal elevations in either AST OR ALT in addition to TBili that meet the criteria outlined 
below are considered potential DILI (assessed per Hy's law criteria) cases and should always 
be considered important medical events, even before all other possible causes of liver injmy 
have been excluded. 
The threshold of laborato1y abnonnalities for a potential DILI case depends on the patient's 
individual baseline values and underlying conditions. Patients who present with the following 
laborato1y abno1malities should be evaluated fmiher as potential DILI (Hy's law) cases to 
definitively detennine the etiology of the abnonnal laborato1y values: 
• 
 Patients with AST/ALT and TBili baseline values within the n01mal range who 
subsequently present with AST OR ALT values >3 x ULN AND a TBili value 
>2 x ULN with no evidence ofhemolysis and an alkaline phosphatase value <2 x ULN 
or not available. 


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• For patients with baseline AST OR ALT OR TBili values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on 
which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever 
is smaller). 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller). 
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The patient should return to the investigator site and be evaluated as soon as possible, preferably 
within 48 hours from awareness of the abnormal results. This evaluation should include 
laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected cases of Hy’s 
law, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, GGT, 
PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given to 
drawing a separate tube of clotted blood and an anticoagulated tube of blood for further testing, 
as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. 
A detailed history, including relevant information, such as review of ethanol, 
acetaminophen/paracetamol (either by itself or as a coformulated product in prescription or 
over-the-counter medications), recreational drug, supplement (herbal) use and consumption, 
family history, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and potential occupational exposure to 
chemicals, should be collected. Further testing for acute hepatitis A, B, C, D, and E infection 
and liver imaging (e.g., biliary tract) and collection of serum samples for 
acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no other 
reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) cases 
are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of reasonable 
investigations have been received and have excluded an alternative etiology. 


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14.9 
Appendix 9: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AEs 
• 
Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
• 
New PR interval prolongation >280 msec. 
• 
New prolongation of QTcF to >480 msec (absolute) or by60 msec from baseline. 
• 
New-onset atrial flutter or fibrillation, with contrnlled ventricular response rate: ie, 
rate <120 bpm. 
• 
New-onset type I second-degree (Wenckebach) AV block of>30 seconds' duration. 
• 
 Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes. 
ECG Findings That May Qualify as Serious Adverse Events (SAEs) 
• 
QTcF prolongation >500 msec. 
• 
New ST-T changes suggestive of myocardial ischemia. 
• 
New-onset left bundle branch block (QRS >120 msec). 
• 
New-onset right bundle branch block (QRS >120 msec). 
• 
Symptomatic bradycardia. 
• 
Asystole: 
In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole3.0 seconds or any escape rate <40 bpm, or with an escape rhythm that 
is below the AV node; 
In awake, symptom-free patients with atrial fibrillation and bradycardia with 1 or 
more pauses of at least 5 seconds or longer; 
Atrial flutter or fibrillation, with rapid ventricular response rate: rapid= rate 
>120 bpm. 
• 
Sustained supraventricular tachycardia (rate>120 bpm) ("sustained"= sho1i 
duration with relevant symptoms or lasting>1 minute). 


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• Ventricular rhythms >30 seconds' duration, including idioventricular rhythm (hea1t 
rate <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR>100 bpm (such as 
torsades de pointes)). 
• Type II second-degree (Mobitz II) AV block. 
• Complete (third-degree) heait block. 
ECG Findings That Qualify as SAEs 
• Change in pattern suggestive of new myocardial infarction. 
• Sustained ventricular tachyarrhythmias (>30 seconds' duration). 
• Second- or third-degree AV block requiring pacemaker placement. 
• Asystolic pauses requiring pacemaker placement. 
• Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion. 
• Ventricular fibrillation/flutter. 
• At the discretion of the investigator, any aIThythmia classified as an adverse 
expenence. 
The enumerated list of major events of potential clinical concem are recommended as "ale1ts" or notifications 
from the core ECG laborat01y to the investigator and Pfizer study team, and not to be considered as all 
inclusive of what to be reported as AEs/SAEs. 
 
14.10 
Appendix 10: Alternative Measures During Public Emergencies 
 
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of the 
COVID-19 global pandemic and will become effective for other public emergencies only upon 
written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
14.10.1 Eligibility 
Emollment for this study was closed prior to the COVID-19 pandemic. 
 
14.10.2 Telehealth Visits 
In the event that in-clinic study visits cannot be conducted, eve1y effort should be made to 
follow up on the safety of study patients at scheduled visits per the Visit Schedules and 


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Assessments (Section 7, Table 7-2) or unscheduled visits. Telehealth visits may be used to 
continue to assess patient safety and collect data points. Telehealth includes the exchange of 
healthcare information and services via telecommunication technologies (e.g., audio, video, 
video-conferencing software) remotely, allowing the patient and the investigator to 
communicate on aspects of clinical care, including medical advice, reminders, education, and 
safety monitoring. The following assessments must be performed during a telehealth visit: 
• Review and record study treatment(s), including compliance and missed doses. 
• Review and record any AEs and SAEs since the last contact. Refer to Section 8.1. 
• Review and record any new concomitant medications or changes in concomitant 
medications since the last contact. 
• Review and record contraceptive method and results of pregnancy testing. Confirm that 
the patient is adhering to the contraception method(s) required in the protocol. Refer to 
Section 7.2.2.5.5 and Section 14.10.3.1 of this appendix regarding pregnancy tests. 
 
Study patients must be reminded to promptly notify site staff about any change in their health 
14.10.3 Alternative Facilities for Safety Assessments 
14.10.3.1 Laboratory Testing 
If a study patient is unable to visit the site for protocol-specified safety laboratory evaluations, 
testing may be conducted at a local laboratory if permitted by local regulations. The local 
laboratory may be a standalone institution or within a hospital. The following safety laboratory 
evaluations may be performed at a local laboratory: 
• Refer to Section 7.2.2.5 for the list of safety laboratory evaluations, including pregnancy 
testing, required per protocol. 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/ 
accreditations for filing at the site. Laboratory test results are to be provided to the site staff as 
soon as possible. The local laboratory reports should be filed in the patient’s source 
documents/medical records. Relevant data from the local laboratory report should be recorded 
on the CRF. 
 
If a patient requiring pregnancy testing cannot visit a local laboratory for pregnancy testing, a 
home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be used by the 
patient to perform the test at home, if compliant with local regulatory requirements. The 
pregnancy test outcome should be documented in the patient’s source documents/medical 
records and relevant data recorded on the CRF. Confirm that the patient is adhering to the 
contraception method(s) required in the protocol. 
 
14.10.3.2 Imaging 
If the patient is unable to visit the study site for safety imaging assessments (e.g., ECHO or 
MUGA), the patient may visit an alternative facility to have the safety imaging assessments 
performed. Qualified study site personnel must order, receive, and review results. 


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14.10.3.3 Electrocardiograms 
If the patient is unable to visit the study site for ECGs, the patient may visit an alternative facility 
to have the ECGs performed. Qualified study site personnel must order, receive, and review 
results. 
 
14.10.3.4 Study Treatment 
If the safety of a trial patient is at risk because they cannot complete required evaluations or 
adhere to critical mitigation steps, then discontinuing that patient from study treatment must be 
considered. 
 
Study drugs may be shipped by courier to study patients if permitted by local regulations and 
in accordance with storage and transportation requirements for the study drugs. Pfizer does not 
permit the shipment of study drugs by mail. The tracking record of shipments and the chain of 
custody of study drugs must be kept in the patient’s source documents/medical records. 
The following is recommended for the administration of study drugs for patients who have 
active [confirmed (positive by regulatory authority-approved test) or presumed (test 
pending/clinical suspicion)] SARS-CoV2 infection: 
• For symptomatic patients with active SARS-CoV2 infection, study drugs should be 
delayed for at least 14 days from the start of symptoms. This delay is intended to allow 
the resolution of symptoms of SARS-CoV2 infection. 
• Prior to restarting treatment, the patient should be afebrile for 72 hours, and SARS-CoV2- 
related symptoms should have recovered to ≤ Grade 1 for a minimum of 72 hours. Notify 
the study team when treatment is restarted. 
• Continue to consider potential drug-drug interactions as described in protocol Section 6.4 
for any concomitant medication administered for treatment of SARS-CoV2 infection. 
 
14.10.4 Home Health Visits 
A home health care service may be utilized to facilitate scheduled visits per the Visit schedule 
and assessments. Home health visits include a healthcare provider conducting an in-person 
study visit at the patient’s location, rather than an in-person study visit at the site. The following 
may be performed during a home health visit: 
• Physical exam including dermatological lesions and vital signs 
• Review and record study treatment(s), including compliance and missed doses. 
• Review and record any AEs and SAEs since the last contact. Refer to Section 8.1. 
• Review and record any new concomitant medications or changes in concomitant 
medications since the last contact. 


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• Review and record contraceptive method and results of pregnancy testing. Confirm that 
the patient is adhering to the contraception method(s) required in the protocol. Refer to 
Section 7.2.2.5.5 and Section 14.10.3.1 of this appendix regarding pregnancy tests. 
 
14.10.5 Adverse Events and Serious Adverse Events 
If a patient has COVID-19 during the study, this should be reported as an AE or SAE and 
appropriate medical treatment provided. Temporary discontinuation of the study treatment may 
be medically appropriate until the patient has recovered from COVID-19. 
 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 
 
14.10.6 Efficacy Assessments 
If the patient is unable to visit the study site for imaging assessments (e.g., CT, MRI, X-ray, 
FDG-PET), the patient may visit an alternative facility to have the imaging assessments 
performed. Qualified study site personnel must order, receive, and review results. 

SAP_001.pdf: 
 
 
 
Oncology Early Clinical Development 
 
 
LGX818/MEK162 
 
Clinical Trial Protocol CMEK162X2110 (C4221005) 
 
 
A Phase Ib/II, multicenter, open-label, dose escalation 
study of LGX818 in combination with MEK162 in adult 
patients with BRAF V600 - dependent advanced solid 
tumors 
 
STATISTICAL ANALYSIS PLAN 


LGX818 + MEK162 + LEE011 
Confidential 
Pfizer Inc. 
C4221005 (CMEK162X2110) Statistical Analysis Plan 
Version 2.2 
2 
Confidential 
 
 
 
Table of contents 
Table of contents ...................................................................................................... 2 
List of tables ......................................................................................................................... 4 
List of abbreviations ............................................................................................................. 5 
1 
Introduction .......................................................................................................................... 8 
1.1 
Study design ............................................................................................................. 8 
1.2 
Objectives and endpoints ....................................................................................... 10 
1.3 
Data Analysis ......................................................................................................... 13 
1.4 
Analysis not according to the protocol .................................................................. 13 
1.5 
CSR related reporting events ................................................................................. 13 
2 
Definitions and general methodology ................................................................................ 14 
2.1 
General definitions ................................................................................................. 14 
2.1.1 
Study drug and study treatment ............................................................. 14 
2.1.2 
Assessment windows, baseline and post baseline definitions, 
missing data handling ............................................................................ 16 
2.2 
Analysis sets ........................................................................................................... 23 
2.3 
Interim analyses ..................................................................................................... 25 
3 
Statistical methods used in reporting ................................................................................. 25 
3.1 
Intra-patient dose escalation ................................................................................... 25 
3.2 
Patient disposition, background and demographic characteristics ......................... 25 
3.2.1 
Patient disposition ................................................................................. 25 
3.2.2 
Protocol deviations ................................................................................ 26 
3.2.3 
Background and demographic characteristics ....................................... 26 
3.2.4 
Medical History ..................................................................................... 26 
3.2.5 
Prior antineoplastic therapy ................................................................... 26 
3.2.6 
Diagnosis and extent of cancer .............................................................. 27 
3.2.7 
Other baseline characteristics ................................................................ 27 
3.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) ............................................................................................................ 27 
3.3.1 
Study medication ................................................................................... 27 
3.3.2 
Concomitant medication ........................................................................ 29 
3.4 
Analysis of the primary variable(s) ........................................................................ 30 
3.4.1 
Primary variable(s) ................................................................................ 30 
3.4.2 
Statistical model .................................................................................... 31 
3.5 
Efficacy evaluation (Secondary Objectives) .......................................................... 35 
3.5.1 
RECIST related endpoints ..................................................................... 35 


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3.5.2 
Non RECIST related endpoints ............................................................. 37 
3.5.3 
Models and method of analysis ............................................................. 37 
3.6 
Safety evaluation .................................................................................................... 39 
3.6.1 
Adverse event ........................................................................................ 39 
3.6.2 
Dermatologic examination .................................................................... 40 
3.6.3 
Ophthalmic examination ....................................................................... 40 
3.6.4 
Laboratory data ...................................................................................... 40 
3.6.5 
Vital signs, weight and physical examinations ...................................... 42 
3.6.6 
WHO/ECOG performance status .......................................................... 43 
3.6.7 
Electrocardiograms ................................................................................ 43 
3.6.8 
Other safety analyses ............................................................................. 43 
3.6.9 
Tolerability ............................................................................................ 43 
3.6.10 
COVID-19 Study disruptions ................................................................ 44 
3.7 
Pharmacokinetic data ............................................................................................. 44 
3.7.1 
Descriptive statistics .............................................................................. 44 
3.7.2 
Modeling of PK data .............................................................................. 45 
3.7.3 
PK/efficacy analyses ............................................................................. 46 
3.8.1 
Introduction ........................................................................................... 46 
3.8.2 
Outline of the data analysis .................................................................... 46 
CCI 
3.8.4 
Biomarker analysis data set ................................................................... 47 
 
 
 
 
3.8.8 
Next Generation Sequencing ................................................................. 51 
CCI 
3.8.10 
Relationship between biomarkers and PK parameters ........................... 51 
3.8.11 
Association between biomarkers and clinical outcome ......................... 51 
4 
Final Analysis Appendices ................................................................................................. 51 
4.1.1 
Tables .................................................................................................... 51 
4.1.2 
Listings .................................................................................................. 60 
4.1.3 
Figures ................................................................................................... 61 
5 
References .......................................................................................................................... 62 
6. 
Change control ................................................................................................................... 62 
CCI 
CCI 
CCI 


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List of tables 
Table 1-1 
Objectives and related endpoints ........................................................... 10 
Table 2-1 
Time windows ....................................................................................... 19 
Table 2-2 
Time windows for PK analyses ............................................................. 20 
Table 4-11 
AE start date imputation example scenarios .......................................... 22 
Table 4-12 
AE end date imputation example scenarios ........................................... 22 
Table 3-1 
Prior used for CMEK162X2110 triple combo (LGX818 + 
MEK162 + LEE011) ............................................................................. 34 
Table 3-2 
Laboratory parameters to be presented in grade shift tables based 
on CTC grade ........................................................................................ 41 
Table 3-3 
Laboratory parameters to be presented in shift tables based on local 
laboratory normal ranges ....................................................................... 42 
Table 3-4 
Notable vital signs ranges ...................................................................... 42 
Table 3-5 
Definition of PK parameters .................................................................. 44 
CCI 
 
Table 3-7 
Coding of compartment and staining level for IHC .............................. 48 
Table 3-8 
Compartment and statistic for IHC ........................................................ 49 
CCI 
 


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List of abbreviations 
ADI 
Actual dose intensity 
AE 
Adverse Event 
ALT/SGPT 
Alanine transaminase/glutamic pyruvic transaminase 
aPTT 
Activated partial thromboplastin time 
AST/SGOT 
Aspartate transaminase/glutamic oxaloacetic transaminase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BCRP 
Breast Cancer Resistance Protein 
BID 
Bis In Diem/ twice daily 
BLRM 
Bayesian Logistic Regression Model 
BOR 
Best Overall Response 
BRAF 
V-raf murine sarcoma viral oncogene homolog B1 
BRAFi 
BRAF inhibitor 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
Cmax 
Maximum plasma concentraion 
CK/ CPK 
Creatine kinase / Creatine phosphokinase 
CR 
Complete Response 
CRC/ mCRC 
Colorectal cancer/ metastatic CRC 
CRF 
Clinical Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTT 
Clinical Trial Team 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
DCR 
Disease Control Rate 
DDS 
Dose Determining Set 
DLT 
Dose Limiting Toxicity 
DOR 
Duration Of Response 
ECG 
Electrocardiogram 
eCRF 
Electronic case report/record form 
EGFR 
Epidermal growth factor receptor 
EOT 
End Of Treatment 
EPT 
Early Program Team 
ERK 
Extracellular signal Regulated Kinase 
EWOC 
Escalation With Overdose Control 
FAS 
Full Analysis Set 
FU 
Follow Up 


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HDL 
High-density lipoprotein 
ICF 
Informed Consent Form 
IHC 
Immunohistochemistry 
KRAS 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LVEF 
Left ventricular ejection fraction 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
Mitogen-activated protein kinase 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NRAS 
Neuroblastoma RAS viral oncogene homolog 
OAT 
Organic anion transporter 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Pharmacodynamic / Progressive Disease 
PDI 
Planned dose intensity 
PFS 
Progression-Free Survival 
P-gp 
Permeability glycoprotein 
PI3K 
Phosphatidylinositol 3' Kinase 
PIK3CA 
Phosphatidylinositol 3' Kinase Catalytic Alphapolypeptide 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Prothrombin time 
PTEN 
Phosphatase and Tensin Homolog gene 
QD 
Quaque Die/ once daily 
QOD 
Every other day 
QTcB 
QT interval adjusted according to Bazett 
QTcF 
QT interval adjusted according to Fredericia 
RAF 
V-raf murine sarcoma viral oncogene 
RAP 
Report and Analysis Plan 
RBC 
Red Blood Cell 
RDI 
Relative dose intensity 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended Phase II Dose 
RT-PCR 
Reverse-transcriptase polymerase chain reaction 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOD 
Sum of Diameters 
t½ 
Terminal elimination half-life 
tmax 
Time to reach maximum plasma concentration 


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TSH 
Thyroid-stimulating hormone 
TTR 
Time To (overall) Response 
VAP 
Validation and Analysis Planning 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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1 
Introduction 
This document provides the detailed statistical methodology for the analysis of data for initial 
interim Clinical Study Report (CSR) of the study CMEK162X2110 (C4221005) as well as the 
final CSR. 
An initial interim CSR will be prepared based on all Phase Ib/Phase II patient data from the 
dual study drug combination. The cut-off for reporting will be either LPFV + 18 months or 
when 80% of the patients can be assessed for progression free survival (PFS), whichever 
occurs first. Additional data for patients continuing to receive the MEK162 and LGX818 dual 
combination beyond the cutoff point for the initial reporting, as allowed by the protocol, and 
the Phase Ib/II data from the LGX818 and MEK162 and LEE011 triple combination will be 
summarized in a final CSR once all patients have discontinued the study. Although this SAP 
provides comprehensive detail on analyses performed throughout the lifetime of the study, 
only analyses included in the appendices for the final CSR (Section 4: Final Analysis 
Appendices) will be performed for the final analysis. For the presentation of results in the 
final analysis, LGX818, MEK162, and LEE011 will be referred to by their respective generic 
names: encorafenib, binimetinib, and ribociclib. 
In this document, the dual and triple combination refers to the combination of LGX818 and 
MEK162, and LGX818 and MEK162 and LEE011, respectively, when not specified. 
The purpose of the CSRs is to report the estimated maximum tolerated dose (MTD) and/or 
recommended phase II dose (RP2D), characterize the dose limiting toxicities (DLT), safety 
profile and efficacy of LGX818/MEK162 and LGX818/MEK162/LEE011 combinations in 
patients with solid tumors harboring a BRAF V600 mutation. 
In addition, the CSR also report the assessment of clinical efficacy and safety of the LGX818 
and MEK162 combination in patients with BRAF V600 mutant metastatic colorectal cancer 
(mCRC), patient with BRAF V600 mutant metastatic melanoma, who have progressed after 
prior selective BRAF inhibitor and patient with BRAF V600 mutant metastatic melanoma, 
who are naïve to prior selective BRAF inhibitor treatment. 
An interim analysis is planned for the phase II part of patients with BRAF V600 mutant 
mCRC, when 50% of the total sample size (14 patients) have completed four cycles of 
treatment, to allow stopping early for futility when there is no treatment effect. 
Note that obvious corrections will be made at the time of analysis to address minor formatting 
or spelling mistakes present in the SAP without the need to amend this document. 
1.1 
Study design 
This is a multi-center, open-label, dose finding, Phase Ib dose escalation study to estimate the 
MTD(s) and/or RP2D(s) for the combination of LGX818 and MEK162 and triple combination 
of LGX818 and MEK162 and LEE011, followed each independently by a Phase II part to 
assess the clinical efficacy and to further assess the safety of the combinations in selected 
patient populations. 


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Oral LGX818 and MEK162 will be administered once daily and twice daily, respectively, on 
a continuous schedule. Oral LGX818 and MEK162 and LEE011 will be administered once 
daily on a continuous schedule (LGX818), twice daily on a continuous schedule (MEK162) 
and once daily three week on, one week off (LEE011), respectively. Patient will be treated 
until progression of disease, unacceptable toxicity develops, or withdrawal of infored consent, 
whichever occurs first. Continued treatment beyond progression of disease will be allowed 
under certain circumstances. 
Figure 1-1 
Study design schematic 
 
 
Dose escalation (Phase Ib) 
The dose escalation part of the trial will be conducted in adult patients with BRAF V600- 
dependent advance solid tumors. This part of the trial is expected to enroll at least 18 patients 
for the dual combination and at least 12 patients for the triple combination. For the purposes 
of the dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled patients. The 
successive cohorts of patients will receive increasing doses of the combinations. The first 
cohort for the dual combination will be treated with the starting combination doses of 50 mg 
once daily (qd) for LGX818 and 45 mg twice daily (bid) for MEK162. The first cohort for the 
triple combination will be treated with the starting combination doses of 200 mg once daily 
(qd) for LGX818, 45 mg twice daily (bid) for MEK162 and 100 mg once daily (qd) for 
LEE011 (3 weeks on/1 week off regimen). 
Once all patients in a dose cohort have completed 28 days (1 cycle) of treatment and an 
assessment of their dose limiting toxicity (DLT) status is performed, the adaptive Bayesian 
logistic regression model (BLRM) will be updated. At each decision time point, the adaptive 
BLRM provides the upper boundary for the combinations that meet the escalation with 
overdose control (EWOC) criteria. The clinical synthesis of the available toxicity information, 


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pharmacokinetic (PK), CCI 
 and efficacy, as well as the recommendations 
from the adaptive BLRM are used to determine the dose combination for the next cohort(s). 
The Sponsor and investigators will decide on next dose levels and dosing schedule(s) to be 
explored at the dose escalation teleconference. 
Various dose levels will be explored until the MTD is determined and/or until a consensus 
between the Sponsor and Investigators is reached and it is considered that there is no benefit 
of further increasing the dose. At this time the RP2D, a dose less than or equal to the MTD, 
will be estimated based on a review of the totality of the available study data. At least 6 
patients eligible for the dose determining analysis set (DDS) must be treated at the dose(s) 
declared to be the MTD/RP2D. More than one dose-combination may be identified as a MTD, 
and more than one RP2D may be established for further evaluation in the phase II part of the 
study. In the case that all dose combinations are considered to be too toxic by the adaptive 
BLRM after the first cohort, no MTD/RP2D can be defined. 
Phase II 
Following MTD/RP2D declaration, for the dual combination patients will be enrolled in three 
Phase II arms. 
• Phase II Arm 1 will assess the disease control rate (DCR) of the dual combination in 
patients with BRAF V600 mutant mCRC. 
• Phase II Arm 2 will assess the objective response rate (ORR) of the dual combination 
in patients with BRAF V600 mutant melanoma who have progressed after prior 
selective BRAF inhibitor treatment. 
• Phase II Arm 3 will assess the ORR of the dual combination in metastatic BRAF 
mutant melanoma patients who are naïve to prior treatment with a selective BRAF 
inhibitor. 
Following MTD/RP2D declaration, for the triple combination patients will be enrolled in an 
additional Phase II arm. 
• Phase II Arm A will assess the objective response rate (ORR) of the triple combination in 
patients with locally advanced or metastatic BRAF V600 mutant melanoma who are naïve 
to previous treatment with a selective BRAF inhibitor. 
Phase II arms will also assess the safety of the combinations. 
If more than one dose combination or dosing schedule has been defined as MTD/RP2D, The 
Sponsor may decide to open the Phase II arms for more than one MTD/RP2D and/or start the 
Phase II arms with different dose combinations or schedules. 
1.2 
Objectives and endpoints 
The study objectives and corresponding endpoints are shown in Table 1-1. 
Table 1-1 
Objectives and related endpoints 
Objective 
Endpoint 
 


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Primary 
Phase Ib: To estimate the MTD(s) and/or 
RP2D(s) of oral LGX818 in combination with 
oral MEK162, and of oral LGX818 in 
combination with oral MEK162 and oral 
LEE011 in patients with BRAF V600- 
dependent advanced solid tumors 
 
Phase Ib: Incidence of Dose Limiting 
Toxicities 
 
Phase II: To assess clinical efficacy of the 
LGX818 and MEK162 dual combination and 
LGX818 and MEK162 and LEE011 triple 
combination in the respective Phase II 
populations: 
 
Arm 1: metastatic BRAF V600 mutant mCRC 
patients (dual combination) 
 
Arm 2: metastatic BRAF V600 mutant 
melanoma patients who have progressed 
after prior selective BRAFi treatment (dual 
combination) 
 
Arm 3/ Arm A: metastatic BRAF V600 mutant 
melanoma patients who are naïve to prior 
selective BRAFi treatment (dual and triple 
combination). 
Secondary 
Phase Ib + II: 
To characterize the safety and tolerability of 
LGX818 and MEK162 in combination, and 
LGX818 and MEK162 and LEE011 in 
combination 
Phase II arm 1: Disease control rate 
(DCR) as per RECIST v1.1 
 
Phase II arms 2 and 3 / Phase II arm A: 
Objective Response Rate (ORR) as per 
RECIST v1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase Ib + II 
Incidence and severity of AE 
 
Phase Ib 
To determine the single and multiple dose 
PK profile of the LGX818 and MEK162 
combination, and of the LGX818 and 
MEK162 and LEE011 combination 
To assess preliminary clinical anti-tumor 
activity of the LGX818 and MEK162 
combination, and of the LGX818 and 
MEK162 and LEE011 combination 
Phase Ib 
Time vs. plasma concentration, basic PK 
parameters of LGX818 and MEK162 and 
LEE011 and known active metabolite(s) 
 
ORR as per RECIST v1.1 
 
Phase II 
To further assess clinical efficacy of the 
LGX818 and MEK162 dual combination and 
of the LGX818 and MEK162 and LEE011 
triple combination in the Phase II populations 
Phase II 
Progression free survival (PFS), time to 
response (TTR), duration of response 
(DOR) as per RECIST v1.1, and Overall 
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To characterize baseline molecular status of 
molecules relevant to RAF/MEK/ERK and 
EFGR/ Pl3K/AKT signaling in tumor tissue 
Baseline molecular status 
(mutation/amplification/expression) in 
tumor tissue of potential predictive 
markers of tumor response or resistance 
(BRAF, HRAS, KRAS, NRAS, PTEN, 
cKIT, PIK3CA, MAP2K1, MAP2K2, ARAF, 
 
c-MET, RAF1, EGFR) 
 
 
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1.3 
Data Analysis 
Data will be analyzed by the Sponsor and/or designated CRO according to the data analysis 
section 10 of the clinical study protocol [CMEK162X2110] and will be available in CSR 
Appendix 16.1. Impo1tant info1mation will be given in the following sections and details are 
provided as applicable in CSR Appendix 16.1.9. 
The Bayesian modelling of the analysis will be nm using R version 2-13.2 and WinBUGS 
Version 1.4.3 in the MODESIM (production) and GPS II environments. Other statistical 
analysis will be perfo1med using SAS® version 9.2 or higher. 
The following rnles will be followed for reporting results unless stated othe1wise: 
Phase lb dose escalation data: Coho1ts of patients treated with the same dose combination 
and regimen during the dose escalation part will be pooled into a common treatment group. 
All summaries, listings, figures and analyses will be display/perfo1med by treatment group 
unless othe1wise specified. 
Phase II data: Data will be summarized and listed by arm (See Section 2.1.1). 
Phase lb/II combined data: Data will be summarized and listed by ann and treatment group 
(See Section 2.1.1). 
Screen failure patients are those who signed the info1med consent, but never staited the study 
treatment for any reason. For these patients, the only info1mation collected on the eCRF will 
be the screening log and the demography pages. These will not be included in any analysis, 
but will be reported in the CSR as sepai·ate listings. 
1.4 
Analysis not according to the protocol 
The protocol lists the primaiy vai·iable of Phase 2 data as the estimation of trne DCR and 
ORR by ann using a Bayesian design. Instead a frequentist approach will be used for the 
analysis of DCR and ORR of the Phase 2 data presenting the observed value and exact 
confidence interval. 
1.5 
CSR related reporting events 
The following points will guide the production of all or subset of the planned analyses: 
• 
The initial interim CSR (refened to as the initial CSR in protocol) includes all outputs 
described for the dual combination, with the data cut-off of August 31, 2015. This SAP 
describes the analysis for the initial interim CSR. 
• 
The final CSR includes all outputs described for the triple combination and listing for the 
dual combination, with the data cut-off on or after all patients have completed or 
discontinued from the study. 
• 


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2 
Definitions and general methodology 
2.1 
General definitions 
2.1.1 
Study drug and study treatment 
2.1.1.1 
Naming conventions 
Study drug refers to any investigational drug(s) being used for an unapproved indication. 
Study treatment refers to any combination of study drugs(s). 
Study treatment: 
• Dual combination = LGX818 + MEK162 
• Triple combination = LGX818 + MEK162 + LEE011 
Other naming conventions 
“Study parts” or “Study phase”: refers to the sequential parts of the study: 
• Phase Ib (dose escalation) 
• Phase II 
Phase Ib for the dual and triple combination 
• “Cohort” or “Dose Cohort”: group of typically 3 to 6 patients enrolled sequentially at once 
during the dose escalation and intended to receive the same dose of study treatment. 
• “Treatment group”: group of patients intended to receive the same study treatment, for 
instance same dose level of study treatment. A treatment group can include several cohorts 
of patients who have received the same dose level but were recruited at different point in 
the study. 
For example, for dual combination subjects: 
Treat. A = LGX818 50 mg qd and MEK162 45 mg bid 
Treat. B = LGX818 100 mg qd and MEK162 45 mg bid 
… 
All dual combo patients = All dual combination patients 
For example, for triple combination subjects: 
Treat. A = MEK162 45 mg BID and LGX818 200 mg QD and LEE011 100 mg QD 
Treat. B = MEK162 45 mg BID and LGX818 200 mg QD and LEE011 200 mg QD 
… 
All triplet combo patients = All triple combination patients 
Phase II for the dual and triple combination 
• “Phase II arm”: refer to separate groups of patients to be displayed separately according to 
study design even if receiving the same treatment. 
For example, for dual combination subjects: 


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Phase II arm 1, refer to patients with BRAF V600 mCRC 
Phase II arm 2, refer to patients with BRAF V600 mutant melanoma who have 
progressed after prior selective BRAF inhibitor treatment 
Phase II arm 3, refer to patients with BRAF V600 mutant melanoma who are naïve to 
prior selective BRAF inhibitor treatment 
All dual combo patients = All dual combination patients 
For example, for triple combination subjects: 
BRAF mutant melanoma no prior BRAF inhibitor 
All triple combo patients = All triple combination patients 
Phase 1b/II combined for the dual combination 
• The Phase Ib patients in the LGX818 400/450/600 mg treatment groups whose disease 
matches one of the Phase II arms will be combined with Phase II data in the by arm and 
treatment group. 
Arm 1, refers to BRAF V600 mutant mCRC 
Treat. A, refers to LGX818 400/450 mg qd and MEK162 45 mg bid 
Treat. B, refers to LGX818 600 mg qd and MEK162 45 mg bid 
Arm 2, refers to BRAF V600 mutant melanoma who have progressed after prior 
selective BRAF inhibitor treatment 
Treat. A, refers to LGX818 400/450 mg qd and MEK162 45 mg bid 
Treat. B, refers to LGX818 600 mg qd and MEK162 45 mg bid 
Arm 3, refers to BRAF V600 mutant melanoma who are naïve to prior selective 
BRAF inhibitor treatment 
Treat. A, refers to LGX818 400/450 mg qd and MEK162 45 mg bid 
Treat. B, refers to LGX818 600 mg qd and MEK162 45 mg bid 
Phase 1b/II combined for the triple combination 
• The Phase Ib patients in the LEE011 100/200/400/600 mg treatment groups whose disease 
matches the Phase II arm will be combined with Phase II data in the by treatment 
group/arm analyses. 
Arm 1, refers to BRAF mutant melanoma no prior BRAF inhibitor 
Treat. A, refers to LGX818 200 mg QD and MEK162 45 mg BID and LEE011 
100 mg QD 
Treat. B, refers to LGX818 200 mg QD and MEK162 45 mg BID and LEE011 
200 mg QD 
Treat. C, refers to LGX818 200 mg QD and MEK162 45 mg BID and LEE011 
400 mg QD 
Treat. D, refers to LGX818 200 mg QD and MEK162 45 mg BID and LEE011 
600 mg QD 


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2.1.1.2 
Planned/received treatment 
• Intended/planned treatment is the first planned treatment reported in the DAR (e)CRF. For 
combination trial it is the combination of the first planned treatment reported in the DAR 
(e)CRF of each component of the combination. 
• Treatment received is defined as: 
(i) the treatment assigned if it was received at least once, or 
(ii) the first treatment received when starting therapy with study treatment if the assigned 
treatment was never received. 
Each patient will be classified into and analyzed consistently within one (and only one) 
treatment group/arm. 
2.1.2 
Assessment windows, baseline and post baseline definitions, missing 
data handling 
2.1.2.1 
Date of first administration of study drug 
The date of first administration of study drug is derived as the first date when a nonzero dose 
of study drug was administered and recorded on DAR (e)CRF. For the sake of simplicity, the 
date of first administration of study drug will also be referred as start of study drug. 
2.1.2.2 
Date of last administration of study drug 
The date of last administration of study drug is defined as the last date when a nonzero dose 
was administered and recorded on DAR (e)CRF. 
2.1.2.3 
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered and recorded on DAR (e)CRF 
(i.e. earliest date between first LGX818 dose and first MEK162 dose for the dual combination 
and earliest date among first LGX818 dose, first MEK162 dose and first LEE011 dose for the 
triple combination). For the sake of simplicity, the date of first administration of study 
treatment will also be referred as start of study treatment. 
2.1.2.4 
Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment (i.e. latest date between last LGX818 dose and last 
MEK162 dose for the dual combination and latest date among last LGX818 dose, last 
MEK162 dose and last LEE011 dose for the triple combination). 
2.1.2.5 
Last date of exposure to study treatment 
Exposure to study treatment includes the exposure to any of the treatment component 
including any planned rest period between two administrations. As a consequence the last date 


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of exposure to a component of study treatment is the day before the first missed dose of any of 
the component: 
• LGX818 once or twice daily (qd or bid) administration*: last date of exposure = last date 
of administration LGX818 
• MEK162 twice daily (bid) administration: last date of exposure = last date of 
administration MEK162 
• LEE011 once daily (3 weeks on, 1 week off schedule) administration: last date of 
exposure = last date of administration LEE011 + (number of last consecutive days of non 
0 dose /planned consecutive days the patient should have taken the drug)*7 
The last date of exposure to study treatment is the latest of the dates of last exposure of 
components of the combination or death date if earlier. 
* LGX818 every other day (qod) administration: last date of administration LGX818 + 1 day. 
2.1.2.6 
Study day 
The study day for all assessments post-treatment is calculated as the difference between the 
date of the event (e.g., visit date, onset date of an event, assessment date, disease progression, 
etc.) and the start of study treatment, plus one day. The first day of study treatment 
administration is therefore Study Day 1. 
The study day for assessments pre-treatment is calculated as the difference between the date 
of the event (e.g., visit date, onset date of an event, assessment date, disease progression, etc.) 
and the start of study treatment. The day before start of study treatment administration is 
therefore Study Day -1. For the particular case of pre-treatment assessments performed on the 
day of first administration study day will be set to Day 1. 
Unless specified otherwise, the study day is displayed in the data listings. 
Cycle definition 
The cycle number and day within cycle attributed to a visits or assessment will be derived 
according to the following rules: 
• C1D1 (cycle 1 day 1) coincides with the start date of drug/treatment 
• All pre-treatment assessments are displayed as Cycle 0 with a negative day (e.g., Day -1 
for the day before the patient started treatment) or with day 1. 
• Day 1 of a cycle corresponds to the day reported by investigator on the start of cycle log 
form. 
• For all cycles but the last, the end date of a cycle is defined as the day before Day 1 of the 
following cycle as recorded on the cycle log form. 
• The end date of the last cycle is when treatment administration is permanently 
discontinued at the latest of the following days: 
• Date of last administration 


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• 28 days after the first day of the last cycle or day of patient’s death if earlier when 
date of last administration is not known 
• All post-cycles assessments are displayed as follow-up and with, by analogy, Day 1 
representing the first day after the end of the last cycle. 
The duration (in days) of a cycle is defined as the cycle end date – cycle start date + 1. 
Cycle number and day within cycle are computed to be displayed in listings only. 
2.1.2.7 
Baseline 
Baseline is the last available and valid assessment performed or value measured within 14 
days before the first administration of study treatment, unless otherwise stated under the 
related assessment section. Baseline can be the day before first treatment administration or the 
same day as first treatment administration if a pre-dose assessment/value is available (e.g., 
ECG, PK samples, samples for biomarkers). 
If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment will be considered as baseline only if it is actually performed 
before the first dose, as checked using both times. 
If time is not recorded, a specific assessment performed the day of first dose administration 
will be considered as baseline if, according to protocol, it should be performed before the first 
dose. 
Patients with no data on a particular parameter before the first treatment administration will 
have a missing baseline for this parameter. 
2.1.2.8 
On-treatment assessment/event 
An on-treatment assessment/event is defined as any assessment/event obtained in the time 
interval from the date of first administration of study treatment until the date of last 
administration of study treatment (i.e., including combination partner) + 30 days inclusive. 
2.1.2.9 
Scheduled study visit and window for the analysis 
In order to summarize longitudinal data per time point, assessments will be allocated to visits 
using predefined time windows. Unless otherwise specified, when more than one assessment 
is available for a visit, all assessments will be listed under the visit while only the assessment 
closest to the planned day for the visit will be used for summaries and analyses. 
Time windows are provided in Table 2-1. 


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Table 2-1 
Time windows 
Assessment 
Visit 
Time Window 
Planned 
Visit Timing 
Time Window 
Definition 
Efficacy Assessments 
Tumor response 
for imaging 
Screening 
Baseline 
Pre- 
treatment 
D-42 to D-1 for whole 
body bone scans 
assessments 
D-21 to D-1 for all other 
image scans 
C1D28 
Between week 3 and 
week 4 ± 3 days 
C1D28 
D18 to D31 
C2D28 
C2D28 ± 7 days 
D56 
D49 to D63 
C4D28 
C4D28 ± 7 days 
D112 
D105 to D119 
 
 
 
Biomarkers 
every 8 weeks (2 cycles) until disease progression, i.e. C6D28, C8D28 ... 
EOT 
EOT + 14 days± 3 
days 
 
Tumor Biopsy Samples 
Fresh tumor 
biopsy 
Screening 
Baseline 
Pre- 
treatment 
D-14 to D-1 
C1D8 or 
C1D16 
C1D8 ± 3 days or 
C1D16 + 5 days± 3 
D8 or 
D16 
D5 to D11 or 
D13 to D24 
days 
 
 
 
 
 
 
._.. 
 
 
Notes: 
C = cycle, D = Day, 01 = start of study treatment 
All other assessments (i.e. laboratory evaluations etc.) the reported visit will be used 


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Table 2-2 
Time windows for PK analyses 
Assessment 
Visit 
 Time 
Window 
 
PK assessment 
time point 
 
Time Window 
Definition 
Phase Ib (Dose 
C1D1 
-03:00 
< 00:00 pre-dose 
C1D1, [-03:00, 00:00] 
escalation) 
C1D1 
± 00:05 
00:30 post-dose 
C1D1, [00:25, 00:35] 
C1D1 
± 00:15 
01:30 post-dose 
C1D1, [01:15, 01:45] 
C1D1 
± 00:30 
02:30 post-dose 
C1D1, [02:00, 03:00] 
C1D1 
± 00:30 
04:00 post-dose 
C1D1, [03:30, 04:30] 
C1D1 
± 01:00 
06:00 post-dose 
C1D1, [05:00, 07:00] 
C1D1 
± 01:00 
08:00 post-dose 
C1D1, [07:00, 09:00] 
C1D2 
-03:00 
< 00:00 pre-dose 
C1D2, [-03:00, 00:00] 
C1D15 
-03:00 
< 00:00 pre-dose 
C1D15, [-03:00, 00:00] 
C1D15 
± 00:05 
00:30 post-dose 
C1D15, [0:25, 00:35] 
C1D15 
± 00:15 
01:30 post-dose 
C1D15, [01:15, 01:45] 
C1D15 
± 00:30 
02:30 post-dose 
C1D15, [02:00, 03:00] 
C1D15 
± 00:30 
04:00 post-dose 
C1D15, [03:30, 04:30] 
C1D15 
± 01:00 
06:00 post-dose 
C1D15, [05:00, 07:00] 
C1D15 
± 01:00 
08:00 post-dose 
C1D15, [07:00, 09:00] 
C1D16 
-03:00 
< 00:00 pre-dose 
C1D16, [-03:00, 00:00] 
C2D1 
-03:00 
< 00:00 pre-dose 
C2D1, [-03:00, 0:00] 
every cycle Day 1 (pre-dose), up to Cycle 10, i.e. C3D1, C4D1, …, 
C10D1 
Phase II arm 2 + 
C1D1 
-03:00 
< 00:00 pre-dose 
C1D1, [-3:00, 000:00] 
Phase II arm 3 
C1D1 
± 00:05 
00:30 post-dose 
C1D1, [0:25, 000:35] 
(Phase II arm 1, if 
C1D1 
required)*** / 
± 00:15 
01:30 post-dose 
C1D1, [01:15, 01:45] 
Phase II arm A 
C1D1 
± 00:30 
02:30 post-dose 
C1D1, [02:00, 03:00] 
C1D1 
± 01:00 
05:00 post-dose 
C1D1, [04:00, 06:00] 
C1D1 
± 01:00 
08:00 post-dose 
C1D1, [07:00, 09:00] 
C1D2 
-03:00 
< 00:00 pre-dose 
C1D2, [-03:00, 00:00] 
C1D15 
-03:00 
< 00:00 pre-dose 
C1D15, [-03:00, 00:00] 
C1D15 
± 00:05 
00:30 post-dose 
C1D15, [00:25, 00:35] 
C1D15 
± 00:15 
01:30 post-dose 
C1D15, [01:15, 01:45] 
C1D15 
± 00:30 
02:30 post-dose 
C1D15, [02:00, 03:00] 
C1D15 
± 01:00 
05:00 post-dose 
C1D15, [04:00, 06:00] 
C1D15 
± 01:00 
08:00 post-dose 
C1D15, [07:00, 09:00] 
C1D16 
- 03:00 
< 00:00 pre-dose 
C1D16, [-03:00, 00:00] 
C2D1 
-03:00 
< 00:00 pre-dose 
C2D1, [-03:00, 0:00] 
every cycle Day 1 (pre-dose), up to Cycle 10, i.e. C3D1, C4D1, …, 
C10D1 
 
 
Notes: 
C = cycle, D = Day, hh:mm = hours and minutes 
00:00 = time of study treatment intake 


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Assessment 
Visit 
 Time 
Window 
PK assessment 
time point 
Time Window 
Definition 
 
*** first 10 patients in each arm only. 
2.1.2.10 Imputation rule of partial or missing dates/data 
Imputation rule of partial or missing dates 
The following rule will be applied to handle partial dates. When the day is missing, it is 
imputed to the 15th of the month (e.g., DEC2007 imputed to 15DEC2007). When the day and 
month are both missing then the date is imputed to July 1st of that year (e.g., 2007 imputed to 
01JUL2007). All imputed data are flagged in the listings. Rules for imputing dates for adverse 
events (AEs), concomitant medications, and anti-neoplastic therapies are described separately 
in this section. 
For computation of time intervals (e.g. elapse time between initial diagnosis to first 
recurrence/relapse), time interval should be set to missing when the imputation rule leads to a 
negative value. 
As of the date of data cutoff for the purposes of reporting, continuing events (e.g. adverse 
events, concomitant medication, etc.) will be summarized using the cut-off date as the date of 
completion, with an indication within listings that the event is continuing. 
For patients who discontinue the study with ongoing events, the discontinuation date will be 
used as the completion date of the event with the appropriate censoring. 
Handling of missing data 
Unless otherwise specified missing data will not be imputed. Handling of missing data will 
depend on the nature of the data: 
• Baseline characteristics: number of patient with missing data will be reported and 
descriptive statistics will be computed on patients with non-missing data. 
• RECIST best overall response (BOR): patients with missing or unknown BOR will be 
considered as failure in the overall response rate computation (see Section 3.5.1.1) 
• Time-to-event endpoints: appropriate statistical methods will be used to account for 
censored patients (see Section 3.5.1.2) 
• PK and biomarker data, laboratory data, ECG data, vital signs: number of patient with 
missing data will be reported and descriptive statistics will be computed on patients with 
non-missing data. 
Missing data will simply be noted as missing on appropriate tables/listings. 
AE data imputation 
Missing and partial date for AE will be handled according to rules specified below. 
There will be no attempt to impute the following: 
• Completely Missing AE start dates 


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• AE start dates missing the year. 
For partial AE start date, the date imputation will be based on the temporal relation between 
the partial date and start of treatment date. 
For partial AE end date or completely missing end date (AE is ongoing), the date imputation 
will be based on the temporal relation between the partial date, the last contact date and the 
30-day follow date. If the minimum date of the last contact date and 30-day FU date is before 
the AE start date (imputed or not), the imputed AE end date will be set to the AE start date. 
Table 4-11 provides examples of the different considered imputations for AE start date. 
Table 4-12 provides examples of the different considered imputations for AE end date. 
Table 2-3 
AE start date imputation example scenarios 
Partial 
Treatment 
Temporal 
Imputed Date 
AE start date 
start date 
relationship 
compared to 
treatment start 
12mmyyyy 
20OCT2001 
Uncertain 
<blank> 
ddmmm2000 
20OCT2001 
Before 
01JUL2000 
ddmmm2002 
20OCT2001 
After 
01JAN2002 
ddmmm2001 
20OCT2001 
Uncertain 
21OCT2001 
ddSEP2001 
20OCT2001 
Before 
15SEP2001 
ddOCT2001 
20OCT2001 
Uncertain 
21OCT2001 
ddNOV2001 
20OCT2001 
After 
01NOV2001 
Table 2-4 
AE end date imputation example scenarios 
Partial 
Minimum (Last 
Ongoing 
Imputed Date 
AE end date 
contact date, 30- 
day FU date) 
Missing 
20OCT2001 
Yes 
20OCT2001 
ddmmm2000 
20OCT2001 
No 
31DEC2000 
ddmmm2002 
20OCT2001 
No 
31DEC2002 
ddmmm2001 
20OCT2001 
No 
31DEC2001 
ddmmm2001 
20OCT2001 
Yes 
20OCT2001 
ddSEP2001 
20OCT2001 
No 
30SEP2001 
ddOCT2001 
20OCT2001 
No 
31OCT2001 
ddOCT2001 
20OCT2001 
Yes 
20OCT2001 
 
Concomitant medication date imputation 


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The imputation of the start date and end data of concomitant medication will follow the same 
conventions as for AE start date and end date. 
Incomplete date for anti-neoplastic therapies 
Prior therapies 
Start date: 
The same rule which is applied to the imputation of AE/concomitant medication start date. 
End date: 
Imputed date = min (treatment start date -1, last day of the month), if day is missing; 
Imputed date = min (treatment start date -1, 31DEC), if month and day are missing. 
Date of progression: 
Imputed date = min (treatment start date -1, last day of the month), if day is missing; 
Imputed date = min (treatment start date -1, 31DEC), if month and day are missing. 
If the end date or the date of progression is not missing and the imputed start date is after 
the end date or after the date of progression, use the min(end date, date of progression) as 
the imputed start date. 
Post therapies 
Start date: 
Imputed date = max (last date of study drug + 1, first day of the month), if day is missing; 
Imputed date = max (last date of study drug + 1, 01JAN), if day and month are missing. 
End date: No imputation. 
2.2 
Analysis sets 
For inclusion in any analysis set it is required that a patient has correctly consented and has 
received at least one dose of study treatment. For those incorrectly consented patients, they 
will be excluded from all analysis. 
The following analysis sets which will be derived prior to database lock will be used. 
Full Analysis Set 
The FAS includes all patients who received at least one dose of LGX818 or MEK162 or 
LEE011. Patients will be classified according to the planned treatment regimen (dose, 
schedule, tablet variant). 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. 
Note that patients who were screened and are eligible but never started treatment will not be 
included in the FAS. This is considered as an acceptable deviation from the ITT principle in 
the context of the Phase I study in which safety is considered as a primary objective. 


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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. Patients will be analyzed according to the 
planned treatment regimen. 
Safety Set 
The safety set includes all patients who received at least one dose of LGX818 or MEK162 or 
LEE011, and have at least one valid post-baseline safety assessment. The statement that a 
patient had no AEs (on the AE eCRF) constitutes a valid safety assessment. 
Patients will be classified according to treatment received (See Section 2.1.1.2). 
Dose Determining Set (DDS) 
The dose-determining set (DDS) includes all Phase Ib patients from the safety set who either 
completed a minimum exposure requirement and have sufficient safety evaluations or 
discontinued prematurely due to a dose limiting toxicity (DLT). 
A patient is considered to have met the minimum exposure requirement if having received at 
least 75% of the planned combination doses (i.e. 21 out of 28 planned daily doses for QD or 
BID, 11 out of 14 planned doses for an every other day dosing schedule, and 16 days out of 
21 days for 3 week on, 1 week off dosing schedule) of study treatment within the first Cycle 
of dosing. The length of a cycle is 28 days. 
Patients who do not experience DLT during the first cycle will be 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 excluded from this analysis set will be identified through a manual protocol deviation 
(PD) with severity code 18 (“exclude from MTD determining analysis set”) 
Below is a summary of protocol deviations leading to exclusion from analysis sets. Severity 
codes are defined in the Novartis Validation and Analysis Planning (VAP) Module 3. This 
study was previously under the sponsorship of Novartis and transitioned to Pfizer sponsorship 
with PPD oversite, but protocol deviations are still coded according to the Novartis VAP 
Module 3. Patients were excluded from the analysis sets defined above based on the protocol 
deviations entered in the database. 
 
Analysis set 
Protocol deviations [severity codes leading to exclusion] 
Full analysis set 
Patient not correctly consented [8] 
Safety set 
Patient not correctly consented [8] 
Patient has no adverse event record (including no record that 
no event occurred) [5] 
Dose determining set 
Patient not correctly consented [8] 
Patient did not have sufficient safety evaluations for the 
investigator to be able to complete the end of cycle 1 DLT 


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assessment and did not have a DLT [18] 
Minimum exposure requirements not met and did not have a DLT 
[18] 
[8] (exclude from all analysis) / [5] (exclude from all safety analyses) / [18] (exclude from MTD determining 
analysis set) 
 
2.3 
Interim analyses 
Since Phase II Arm 1 was terminated before the planned number of patients was reached, this 
part of the analysis will not be conducted. 
 
3 
Statistical methods used in reporting 
The data will be summarized by treatment group and overall (when appropriate) with respect 
to demographic and baseline characteristics, preliminary efficacy and safety observations and 
measurements, and all relevant PK and PD measurements using descriptive statistics 
(quantitative data) and contingency tables (qualitative data). 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum and maximum will be 
presented. 
Data from participating centers will be combined. Unless otherwise specified, patients of the 
escalation part treated at the MTD with the same dose level but were recruited at different 
point in the study will be pooled into a single treatment group. 
Listings of all raw data will be produced and ordered by treatment group (in Phase Ib) or 
patient group (in Phase II), center, country and patient. Unless otherwise specified, if multiple 
measurements are available for one time point (or period), an average will be provided to 
represent the time point (or time period). Unless specified otherwise, all percentage is with 
respect to big N. 
3.1 
Intra-patient dose escalation 
For patients undergoing intra-patient dose escalation, all data will be summarized and listed 
by initial treatment group they were assigned to. 
3.2 
Patient disposition, background and demographic 
characteristics 
Demographic and other baseline data, including disease characteristics, will be summarized 
descriptively by treatment group in Phase Ib and patient group in Phase II using the FAS. 
3.2.1 
Patient disposition 
The number of patients who were enrolled and treated, as well as those who completed or 
discontinued treatment or the study (along with their reasons for premature discontinuation), 
or were still ongoing at the time of the analysis will be summarized. If treatment 
discontinuation or study evaluation completion due to COVID-19 is reported for any patients, 


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this will also be included in the summary. A listing of study completion by treatment will be 
produced. Patients are considered to be ongoing if they have not discontinued due to any 
reason (e.g., disease progression, AE, withdrawn consent). 
Baseline demographic, reasons for screen failure and serious adverse events will be listed for 
screened failure patients. 
3.2.2 
Protocol deviations 
All protocol deviations will be finalized before database lock. This study was previously 
under the sponsorship of Novartis and transitioned to Pfizer sponsorship with PPD oversite, 
but protocol deviations are still coded according to the Novartis VAP Module 3. Protocol 
deviations and reasons for exclusion from populations will be tabulated. The number and 
percentage of patients in the FAS with any protocol deviations will be tabulated by the 
deviation category (as specified in the Novartis VAP Module 3 documents) and within each 
deviation category, deviations due to COVID-19 will also be summarized. All protocol 
deviations will be listed. 
3.2.3 
Background and demographic characteristics 
Background and demographic characteristics including age, gender, race, ethnicity, height, 
weight, WHO performance status, tumor type, medical conditions, BRAF mutation status, 
geographic region and LDH, etc. will be listed and summarized using descriptive statistics. 
The summaries will be based on the assessments from the screening visit (baseline). 
In addition, the following derived variables derived from the demographic (e)CRF will be 
described: 
• age groups summarized by class (<65, ≥65 years) 
• weight summarized by class (<55, 55-75, ≥75 kg) 
• Body mass index (BMI) calculated as weight/(height**2) (kg/m2) where weight is 
measured in kg and height in m 
• The body surface area (BSA) is calculated using Gehan and George formulae: 
BSA [m2] = 234.94*(height[cm]**0.422)*(weight[kg]**0.515)/10000 
3.2.4 
Medical History 
Past and current medical history will be summarized and listed. Separate summaries will be 
presented for current and past historical medical conditions; these summaries will be 
presented by primary system organ class and preferred term. Medical history/current medical 
conditions will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 18.1. 
3.2.5 
Prior antineoplastic therapy 
Prior anti-neoplastic therapies will be listed, and the latest therapy will be summarized in 
three separate tables for surgery (procedure, residual disease for non-biopsy surgery), 
radiotherapy (location, setting and best overall response) and medications (therapy type, 


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setting, previous treatment with selective BRAF inhibitor and best overall response). In 
addition, the time between end of last therapy and start of treatment will be summarized. 
Last surgery is derived based on procedure date. Last radiotherapy is derived based on end 
date. Last treatment is derived based on the last end date of any of the components of the 
regimen. 
The summary of prior anti-neoplastic medications will be presented by Anatomical 
Therapeutic Chemical (ATC). 
3.2.6 
Diagnosis and extent of cancer 
Diagnosis and extent of cancer will be listed and the summarized by number (%) of patients in 
each of the categories for the following variables: primary site of cancer (includes melanoma 
type and subtype), details of tumor histology/cytology, histological grade, stage at initial 
diagnosis, current stage of cancer, current extent of disease (metastatic sites), and types of 
lesions at baseline. 
In addition, the following continuous and categorized time intervals will be computed and 
summarized: 
• Time since initial diagnosis to first dose of study drug, calculated as (date of study 
treatment start – date of initial diagnosis of primary site + 1)/30.4375. The following 
categories will be used: <6 months, ≥6 to <12 months, ≥12 to <24 months, ≥24 months 
• Time since initial diagnosis to first relapse, calculated as (date of first relapse – date of 
initial diagnosis of primary site + 1)/30.4375. The following categories will be used: <6 
months, ≥6 to <12 months, ≥12 to <24 months, ≥24 months 
• Time since initial diagnosis to most recent recurrence/relapse, calculated as (date of most 
recent recurrence/relapse – date of initial diagnosis of primary site + 1)/30.4375. The 
following categories will be used: <6 months, ≥6 to <12 months, ≥12 to <24 months, ≥24 
• Time since most recent recurrence/relapse to first dose of drug, calculated as (date of 
study treatment start - date of most recent recurrence/relapse + 1)/30.4375. The following 
categories will be used: <1 month, ≥1 to <2 months, ≥2 to <3 months, ≥3 months 
See Section 2.1.2.10 for handling partial missing dates for the intervals. 
3.2.7 
Other baseline characteristics 
All data collected during the baseline evaluation, including child bearing potential, pregnancy 
test results, and exploratory biomarker informed consent will be listed. 
3.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
3.3.1 
Study medication 
Exposure will be summarized overall in terms of: 
• The duration of study treatment exposure, 


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• The cumulative dose, 
• The dose intensity (DI) and/or relative dose intensity (RDI) 
• The percentage of actual days dosed during the treatment period for daily dosed 
compounds 
• The percentage of days received planned doses during the treatment period for daily dosed 
compounds (calculated for Phase II subjects only) 
Exposure will be summarized on the Safety Set. For bid regimen, note that if interruption is 
after a one day reduction, this one day reduction will be considered as start of interruption and 
not as reduction. 
3.3.1.1 
Duration of study treatment exposure 
The following algorithm will be used to compute the duration of study treatment exposure for 
patients who took at least 1 dose of any of the components of the study treatment: 
Duration of exposure (days) = (last date of exposure to any study treatment component) – 
(date of first administration of any treatment component) + 1. 
Both date of first administration of study treatment and last date of exposure to study 
treatment are defined in Section 2.1.2.3 and Section 2.1.2.5, respectively. 
For patients who did not take any drug the duration of drug exposure is by definition equal to 
zero. 
3.3.1.2 
Cumulative dose 
The actual cumulative dose for each study drug is defined as the total dose for this study drug 
given during the study drug exposure and is expressed in mg. For patients who did not take 
any of the drug, the actual cumulative dose is by definition equal to zero. 
The planned cumulative dose is defined as the total dose planned to be given during the study 
treatment exposure and is expressed in mg. 
3.3.1.3 
Dose intensity and relative dose intensity 
The dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 
Planned dose intensity (PDI) (mg/day) = planned cumulative dose (mg) / planned number of 
days patient should have taken the drug (days) 
Actual dose intensity (ADI) (mg/day) = actual cumulative dose (mg) / planned number of 
days patient should have taken the drug (days) 
For patients who did not take any drug the ADI is (by definition) equal to zero. 
ADI and PDI will be expressed in mg/day for LGX818, MEK162 and LEE011. 
Relative dose intensity (RDI) = ADI (mg/day) / PDI (mg /day). 
For patients who did not take any drug the actual RDI is (by definition) equal to zero. 


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The ADI and RDI will be summarized separately for each of the study treatment components 
by using the duration of the study treatment exposure, not the duration of each of the 
components. 
The RDI for each of the study treatment components will be presented also with the following 
categories: <0.5, ≥ 0.5 to < 0.75, ≥ 0.75 to < 0.9, ≥ 0.9 to < 1.1 and ≥ 1.1. 
Dose intensity for the first cycle or by cycle can be computed using cycle length definition 
(see Section 2.1.2.6) as exposure periods. 
3.3.1.4 
Dose change 
Dose delay/interruption: any dose change/delay flagged in the DAR CRF page, satisfying the 
following criteria: 
• 
a reason other than “as per protocol”, 
• 
a zero actual dose, 
• 
occurs between the first and last non-zero doses, 
• 
follows a non-zero actual dose. 
Dose reduction: any dose change/delay flagged in the DAR CRF page, satisfying the 
following criteria: 
• 
a reason other than “as per protocol”, 
• 
a non-zero actual dose below the immediate previous non-zero actual dose 
• 
a non-zero actual dose below the treatment assigned as per safety set 
Dose increment: any dose change/delay flagged in the DAR CRF page, satisfying the 
following criteria: 
• 
a reason other than “as per protocol”, 
• 
a non-zero actual dose above any previous non-zero actual dose 
• 
a non-zero actual dose above the treatment assigned as per safety set 
The following criteria are used to identify an intra-patient dose escalation: 
• 
dose change flag checked with reason “as per protocol” 
• 
planned dose above any previous planned dose. 
3.3.2 
Concomitant medication 
The Safety set will be used for all below mentioned concomitant medication tables. 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment that were administered to a patient preceding or coinciding with 
the study assessment period. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List (WHODRUG 19SEP2014, version 4.3) to allow for categorization by 


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preferred term and by ATC class (note that a medication/therapy can appear with more than 
one ATC class). 
Concomitant medications and significant non-drug therapies taken concurrently with the study 
treatment will be listed and summarized by ATC class, preferred term by contingency tables. 
These summaries will include medications starting on or after the start of study treatment or 
medications starting prior to the start of study treatment and continuing after the start of study 
treatment. 
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed. 
Further anti-neoplastic therapies administered concomitantly with study treatment will be 
listed based on their identification (by the method given in Section 3.2.5) by the protocol 
deviation process. 
Anti-neoplastic therapies since discontinuation of study drug will be listed and tabulated by 
ATC class and preferred term. 
Concomitant medications with a possible PK interaction with LGX818, MEK162 and 
LEE011 will be identified prior to database lock and listed: 
• Inhibitors, inducers and/or substrates of CYP2B6, CYP2C9, CYP3A4, UGT1A1, P-gp, 
BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, CYP1A2 and CYP2C19 will 
be identified, classified and listed. 
See [CMEK162X2110 Protocol Appendix 14-.4] for complete list of inhibitors, inducers and 
substrates which might interact with LGX818 and MEK162 and LEE011. 
3.4 
Analysis of the primary variable(s) 
3.4.1 
Primary variable(s) 
3.4.1.1 
Phase Ib 
Estimation of the MTD of the combination treatment will be based upon the estimation of the 
probability of DLT in Cycle 1 for patients in the DDS. This probability is estimated by the 
model in Section 3.4.2.1. Note that more than one dose-combination of dual combination 
(LGX818 and MEK162) or triple combination (LGX818 and MEK162 and LEE011) may be 
identified as a MTD, and more than one RP2D may be established for further evaluation in 
the phase II part of the study. 
The dose determining set (DDS) will be used for all dose determining analyses. 
3.4.1.2 
Phase II 
Dual combination (LGX818 and MEK162) 
For arm 1, the primary variable is the Disease Control Rate (DCR) at week 16. Estimation of 
the true DCR using a Bayesian design as described in the protocol will not be performed for 


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the CSR. Instead, the observed DCR for patients in the FAS will be presented. The primary 
analysis of the DCR will be based on the local review of overall lesion responses. 
For arms 2 + 3, the primary variable is the Objective Response Rate (ORR), defined as the 
proportion of patients with a best overall response of complete response (CR) or partial 
response (PR). Estimation of the true ORR using a Bayesian design as described in the 
protocol will not be performed for the CSR. Instead, the observed ORR for patients in the 
FAS will be presented. The primary analysis of the ORR will be based on the local review of 
overall lesion responses. 
Triple combination (LGX818 and MEK162 and LEE011) 
For arm A, the primary variable is the Objective Response Rate (ORR). Estimation of the 
true ORR using a Bayesian design as described in the protocol will not be performed for the 
CSR. Instead, the observed ORR for patients in the FAS will be presented. The primary 
analysis of the ORR will be based on the local review of overall lesion responses. 
3.4.2 
Statistical model 
3.4.2.1 
Phase Ib 
An adaptive BLRM guided by the EWOC principle will guide the dose escalation of the 
combination treatment to its MTD(s)/RP2D(s). A 5-parameter BLRM for combination 
treatment will be fitted on the dose-limiting toxicity data (i.e. absence or presence of DLT) 
accumulated throughout the dose escalation, for modeling the dose-DLT relationship of 
LGX818 (capsule formulation) and MEK162 when given in combination. 
The 5 parameter BLRM will be extended to a 10-parameter BLRM to model the dose-DLT 
relationship of LGX818 (capsule formulation) and MEK162 and LEE011 when given in 
combination. 
Summaries of the posterior distribution of model parameters and posterior distribution of DLT 
rates based on the DLT data from all patients enrolled in the study and included in the DDS 
will be produced. 
The 5-parameter BLRM (LGX818 and MEK162 original tablet) 
The 5-parameter BLRM is formulated in the following way: 
Let π1(d1) be the probability of a DLT if LGX818 is given as a single agent at dose d1, and 
π2(d2) be the probability of a DLT if MEK162 is given as a single agent at dose d2. Both drugs 
administered to non-fasted patients. 
The dose-response relationship is then modeled as: 
 
 
 


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where 
 
• logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], π(d) is the probability of a DLT at dose d. 
• π12(d1,d2) is the probability of a DLT given the combination doses. 
• d1* = 100 mg and d2*= 60 mg are the reference doses of LGX818 and MEK162 
respectively. 
• α1, α2, β1, β2 > 0 and -∞ < η12 < ∞, with η12 is the interaction term. 
Note that all five parameters α1, α2, β1, β2 and η12 correspond to the effect of the drugs when 
administered to non-fasted patients. 
 
 
The 5-parameter BLRM (LGX818 and MEK162 smaller tablet / new tablet variant) 
The 5-parameter BLRM is formulated in the following way: 
Let π1(d1) be the probability of a DLT if LGX818 is given as a single agent at dose d1, and 
π3(d3) be the probability of a DLT if MEK162 is given as a single agent at dose d3. 
The dose-response relationship is then modeled as: 
 
 
 
where 
• logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], π(d) is the probability of a DLT at dose d. 
• π13(d1,d3) is the probability of a DLT given the combination doses. 
• d1* = 100 mg and d3*= 60 mg are the reference doses of LGX818 and MEK162 
respectively. 
• α1, α3, β1, β3 > 0 and -∞ < η13 < ∞, with η13 is the interaction term. 
Note that all five parameters α1, α3, β1, β3 and η13 correspond to the effect of the drugs when 
administered to non-fasted patients. 
 
 
The 10-parameter BLRM (LGX818 and MEK162 and LEE011) 
The 10-parameter BLRM is formulated in the following way: 
Let π1(d1) be the probability of DLT if LGX818 is given as a single agent at QD dose d1, 
π2(d2) the probability of DLT if MEK162 is given as a single agent at BID dose d2, and 
π4(d4) the probability of DLT if LEE011 is given as a single agent at 3 weeks on, 1 week 
off dose d4. 
The single agent dose-DLT relationships are then modeled as: 


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LGX818: 
 
MEK162: 
 
LEE011: 
 
The dose-DLT relationships of the dual combinations of LGX818 + MEK162, LGX818 + 
LEE011 and MEK162 + LEE011 are modeled as: 
 
 
 
The dose-DLT relationship of the triple combination is subsequently modeled as: 
 
where logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], d1* = 100mg (QD), d2* = 60mg (BID) and d4* = 
400mg (3 weeks on, 1 week off) are the reference doses of LGX818, MEK162 and LEE011, 
respectively, α1, α2, α4, β1, β2, β4> 0 and -∞ < η12, η14, η24, η124 < ∞ are the interaction terms. 
Starting dose reassessment 
As per [CMEK162X2110-Protocol Amendment 5-Section 6.2.2 Starting dose rationale] for 
LGX818 and MEK162 and LEE011 triple combination, the Bayesian model will be updated 
with the most recent data from the ongoing LEE011 single agent trial [CLEE011X2101] and 
the LGX818 and MEK126 dual combination study [CMEK162X2110], to confirm that the 
proposed starting dose combination is still appropriate (i.e. satisfies the EWOC criterion) 
before the first patient is dosed with the triple combination. 
[CMEK162X2110-Protocol Amendment 5] did not state information for the dual 
combinations of MEK162 and LEE011 or LGX818 and LEE011 will be included. However, 
since these additional studies will provide information on the dose-DLT relationship of the 
dual combinations, the data for MEK162 and LEE011 under on-going study 
[CMEK162X2114] and LGX818 and LEE011 under on-going study [CLEE011X2105] have 
been incorporated. Table 3-1 shows summary of DLT data by study. 


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The information from the on-going studies [CMEK162X2114] and [CLEE011X2105] were 
incorporated through discounting the data directly using the following weight function, w 
[Neuenschwander (2010)]. 
 
 
where n is the sample size of historical data, σ2 and τ2 are the within-trial and between-trial 
variance. The parameters σ and τ for both of the studies, were set at 2 and 0.5 (correspond to 
substantial heterogeneity between trials, i.e. n*∞ = 16), respectively. Thus, the weights (w) for 
studies [CMEK162X2114] and [CLEE011X2105] were 0.421 and 0.615, respectively. Table 
3-1 shows Prior used for the triple combo. 
Table 3-1 
Prior used for CMEK162X2110 triple combo (LGX818 + MEK162 + 
LEE011) 
 
Parameter 
Means 
Standard deviations 
Correlation 
log(α1), log(β1) 
-2.917, -1.820 
0.986, 1.041 
0.233 
log(α2), log(β2) 
-2.326, 1.564 
1.107, 1.368 
-0.535 
log(α4), log(β4) 
-2.027, -0.706 
0.508, 0.511 
-0.149 
η12 
0 
1.528 
NA 
η14 
0.095 
0.512 
NA 
η24 
0.020 
0.392 
NA 
η124 
0.020 
0.392 
NA 
3.4.2.2 
Phase II 
Efficacy will be assessed using the local CT/MRI assessments evaluated under RECIST v1.1. 
The Best Overall Response (BOR) for each patient and individual lesion measurements will 
be listed. The BOR will be summarized using the Disease Control Rate (DCR) for Phase II 
arm 1 and the Objective Response Rate (ORR) for Phase II arms 2 + 3 and Phase II arm A. 
• The ORR is defined as the proportion of patients with a BOR of CR or PR. 
• The DCR is defined as proportion of patients with a BOR of CR or PR or SD. 
Both confirmed and unconfirmed summaries will be provided. 
Patients who withdrew prematurely due to progression of disease without having any post- 
dose tumor assessment will be classified as treatment failures. Similarly, patients who died 
due to their disease without having any post-dose tumor assessment will be classified as 
treatment failures. 
ORR and DCR will be provided with their corresponding 95% exact confidence interval 
according to Clopper-Pearson method [Clopper and Pearson 1934]. 


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3.5 
Efficacy evaluation (Secondary Objectives) 
Phase Ib 
Preliminary clinical anti-tumor activity of the combination in patients with BRAF V600 
dependent advanced solid tumors will be assessed using the Investigator read CT/MRI 
assessments evaluated. 
ORR will be summarized as point estimate and corresponding 95% exact confidence interval 
according to Clopper-Pearson method by treatment group. The BOR for each patient and 
individual lesion measurements will be listed. 
Phase II 
Local read of CT/MRI assessment will be used for all Phase II efficacy assessments of tumor 
activity. 
Progression-free survival (PFS) will be analyzed using Kaplan-Meier estimates [Kaplan and 
Meier 1958] (including graphical representation) with 95% confidence interval for median 
survival. 
Overall survival (OS) will be analyzed using Kaplan-Meier estimates with 95% confidence 
intervals for median survival and survival probabilities for specific time-points (3, 6, 9, 12, 15 
and 18 months) will be presented. 
Time to response (TTR) and duration of overall response (DOR) will be analyzed using 
Kaplan-Meier estimate with 95% confidence interval for median survival. 
If deem necessary, PFS between the Phase II arm 3 and Phase II arm A may be described in 
separate analysis plan documentation and displayed external to the main study CSR. 
The FAS will be used for all efficacy analyses. 
3.5.1 
RECIST related endpoints 
Response and progression evaluation will be performed according to the RECIST guideline 
version 1.1 (as described in detail in [CMEK162X2110 Protocol Appendix 14.1]) whenever it 
applies. 
3.5.1.1 
Best overall response and other binary endpoints 
Best overall response 
The Best overall response (BOR) is the best response recorded from the start of the treatment 
until disease progression/recurrence. 
Only overall tumor assessments reported by investigator and performed before the start of any 
further anti-neoplastic therapies (i.e., any additional secondary anti-neoplastic therapy or 
surgery) will be considered in the assessment of best overall response. 
Confirmation of complete and partial responses (CR and PR, respectively) must be made at 
least 4 weeks apart. Stable disease must occur > 6 weeks after the start of treatment. 


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Patients who are of unknown clinical response will be treated as non-responders. 
3.5.1.2 
Computation of time to event endpoints 
Overall survival 
Overall survival (OS) is defined as the time from 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 
contact. 
As of protocol amendment 10, survival follow-up is no longer performed for patients who 
have discontinued study treatment in the Phase II part of the study. 
Progression free survival 
Progression-free survival (PFS) is defined as the time from the date of first study treatment 
intake to the date of the first documented disease progression or death due to any cause. 
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 tumor 
evaluation with overall lesion response of CR, PR or SD. Patients who begin a new 
antineoplastic therapy prior to disease progression or death will be censored at the last 
adequate tumor evaluation prior to the start of the new antineoplastic therapy. 
As of protocol amendment 10, post-treatment disease progression follow-up is no longer 
performed for patients who have discontinued study treatment in the Phase II part of the 
study. 
Time to (overall) response 
Time to (overall) response (TTR) will be based on “responders” only and is the time between 
the date of first treatment administration and the first documented response (CR or PR). 
Duration of overall response 
Duration of overall response (DOR) will be based on “responders” only and is the time 
between the date of first documented response (CR or PR) and the date of first documented 
progression or death due to underlying cancer. If progression or death due to underlying 
cancer has not occurred, then the patient is censored at the date of last adequate tumor 
assessment. 
3.5.1.3 
Handling of missing data and special cases 
No measurable lesion at baseline 
Evaluation using RECIST criteria implies that patients have measurable lesion at baseline. 


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According to RECIST guidelines, the overall Response should be UNK or PD. In Phase I 
studies when the presence of target lesions is not mandatory for enrollment, in order to avoid 
the presence of too many “UNK” the overall response will be derived based on non-target 
lesions only when no target lesion is available. CR and SD will be assigned if the non-target 
lesion responses are respectively CR, non CR-non PD, respectively, without the appearance of 
a new lesion. 
Analysis of other progression screening methods 
In the efficacy analysis, additional screening methods (e.g., bone scans) are handled 
differently than the regular tumor assessments. 
In addition, if the screening method is not available at a given assessment this does not 
automatically make the overall lesion response “Unknown” at that assessment. 
Change in imaging modality 
As per RECIST, the same imaging method used at baseline should also be used at all 
subsequent assessments. However, for various reasons such as site error (e.g., switch from 
MRI to CT) or renal dysfunction (making contrast a risk), this is not always done. The strict 
implementation of RECIST would mean that any change in the imaging method apart from 
that used at baseline would lead to an overall response of “unknown” at that assessment. 
However, the presence or absence of contrast does not necessarily change the precision of the 
image. To cover that possibility, the following imaging modalities listed under the same bullet 
point below were considered the same for the calculation of change from baseline of the sum 
of diameters of target lesions (SOD): 
• ‘CT with contrast’ and ‘CT without contrast’ 
• ‘Spiral CT with contrast’ and ‘Spiral CT without contrast’ 
• ‘MRI with contrast’, ‘MRI without contrast’, ‘Dynamic contrast – enhanced MRI’ and 
‘Gadolinium-MRI’. 
For other efficacy endpoints, investigator judgment only is considered even if overruling the 
computed response. 
3.5.2 
Non RECIST related endpoints 
Not applicable. 
3.5.3 
Models and method of analysis 
3.5.3.1 
Analyses of time-to-event data 
The following section presents the general methodology used to analyze time-to-event 
variables (e.g., PFS, OS, TTR and DOR) for Phase II efficacy assessments of tumor activity. 
OS will be analyzed using Kaplan-Meier estimates with confidence intervals for median 
survival and survival probabilities for specific time-points (3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 
33, 36, 39, 42, 45, and 48 months). 


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PFS will be analyzed using Kaplan-Meier estimates (including plots) with 95% confidence 
interval for median survival and survival probabilities for specific time-points (3, 6, 9, 12, 15, 
18, 21, 24, 27 and 30 months). PFS will be calculated at the MTD/RP2D for Phase II Arm 3 
and Phase II Arm A. In addition, for the purposes of the PFS figure, PFS will be calculated for 
Phase Ib treatment arms as well. 
Kaplan-Meier estimates based on all responders with 95% confidence intervals will be 
presented for TTR and DOR. These two analyses based on responders will be used as a 
descriptive analysis. Kaplan-Meier estimates with 95% confidence intervals for median TTR 
and median DOR will be presented. Survival probabilities for specific time-points will include 
3, 6, 9, 12, 15 and 18 months for TTR and 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30 months for 
DOR. 
Details on Kaplan-Meier estimates 
An estimate of the survival function can be constructed using the Kaplan-Meier (product- 
limit) method as implemented in PROC LIFETEST. 
The median survival is obtained along with 95% confidence intervals as calculated from the 
PROC LIFETEST output (using method of [Brookmeyer & Crowley, 1982]). 
Kaplan-Meier estimates with 95% confidence intervals at specific time points can be 
summarized. The confidence intervals are constructed using Greenwood’s formula for the 
standard error of the Kaplan-Meier estimate. When the estimated survival function is close to 
zero or unity, symmetric intervals are inappropriate since they can lead to confidence limits 
that lie outside the interval [0, 1]. Any limit that is greater than unity will be replaced by 1.0. 
Any limit that is less than zero will be replaced by 0.0. 
Hypotheses and test statistics 
Not applicable. 
Hazard ratio 
Not applicable. 
3.5.3.2 
Construction of waterfall graphs 
The waterfall graph is used to depict anti-tumor activity. This plot displays both BOR and the 
best percentage change from baseline in the sum of diameter of all target lesions for each 
patient. 
The assessments with an unknown overall response will not be excluded as long as the sum of 
diameter is correctly computed on the same lesions assessed at baseline. 
The best overall response will be shown above each of the displayed bars in the graph. 
Patients will be ordered in the graph using the following display (from left to right): 
• Bars above the horizontal axis representing tumor growth 
• Bars under the horizontal axis representing tumor shrinkage 


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Waterfall plots will show the cut-off limits for target lesions for PD (+20%) and PR (-30%) as 
dotted lines. 
On the top of the waterfall plot a heatmap will be added in order to display per patient 
(matching with the bar on the waterfall plot) the information regarding BRAF local 
mutational status. 
3.5.3.3 
Construction of swimmer plots 
The plot will show duration of exposure (without display of dose interruption and dose change 
information), BOR status and on-going status or primary reasons for discontinuation by 
patient. 
3.6 
Safety evaluation 
The assessment of safety is based on the type of AEs and frequency of AEs as well as on the 
number of laboratory values that fall outside of pre-determined ranges (Common Toxicity 
Criteria [CTC] version 4.03 grading limits or normal ranges as appropriate). Other safety data 
includes electrocardiogram, vital signs and Ocular. 
The Safety set will be used for summaries and listings of all safety data in Section 14 of the 
CSR with the exception of dose limiting toxicities (DLT) for which the DDS will be used. 
Safety analyses will be performed per treatment received (see Section 2.1.1.2). The FAS will 
be used for Section 16 of the CSR, including for safety listings. These listings will be 
displayed per intended treatment as per all analyses performed on the FAS (see Section 2.2). 
Differences between treatment received and intended treatment, if any, will be provided in a 
listing. 
The safety summary tables will include only assessments collected no later than 30 days after 
study treatment discontinuation. All safety assessments will be listed, and those collected later 
than 30 days after study treatment discontinuation will be flagged. 
3.6.1 
Adverse event 
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA, 
version 18.1) terminology. Although CTCAE version 4.03 grading is by definition a 5-point 
scale generally corresponding to mild, moderate, severe, life threatening and death, CTCAE 
grade 5 (death) will not be used since this information will be collected on the “End of 
Treatment”, “Study evaluation completion” or “Survival information” CRF pages. 
Separate summaries and listing for adverse events, serious AEs (SAEs) and death recorded 
during the study will be provided. Deaths will also be summarized by primary reason. 
Additional summaries and listings events suspected to be related to study drug by treatment, 
events leading to study drug discontinuation, and events requiring dose adjustment or delay 
will be produced. 
Listing and summaries will be produced according to the following rules: 


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• Patients reporting and experiencing multiple occurrences of a specific AE will have 
occurrences listed but will be counted only once in the appropriate event 
category/class and according to the worst observed grade within summary tables. 
• AEs will be summarized by one of the following methods: by presenting the number 
and percentage of patients having at least one AE, having at least one AE in each 
primary system organ class, and having at least one AE for each preferred term or by 
presenting the number and percentage of patients having at least one AE and having at 
least one AE for each preferred term. Within each type of summary, AEs will be 
sorted by descending frequency or alphabetically (system organ class [SOC] and 
preferred term [PT] or PT for summaries that do not include SOC information). 
• Specific groupings of clinically notable adverse events will be considered and the 
number of patients with at least one event in each grouping will be reported. The case 
retrieval sheet for each of study drug (if available) will be used to identify risks of 
special interest. Adverse events of special interest (All and Grade 3/4) will be 
tabulated by groups of special interest and preferred term for each study drug 
separately. In addition, separate listing will be provided for each study drug. 
• AEs with incidence thresholds of ≥20% in the summarized population will be 
tabulated by preferred term. Grade 3/4 AEs with incidence ≥5% will be summarized 
similarly. Treatment-related AEs with an incidence of ≥10% will be summarized 
distinctly for all AE grades and for Grade 3/4. 
3.6.2 
Dermatologic examination 
All dermatological examination data will be listed. 
3.6.3 
Ophthalmic examination 
All ophthalmic examinations (i.e., Tonometry, Visual acuity, Visual field, Fundoscopy, Slit 
lamp, 
Optical 
Coherence 
Tomography 
(OCT), 
Fluorescein 
Angiography 
(FA), 
Electroretinogram (ERG)) will be listed. 
3.6.4 
Laboratory data 
All laboratory values will be converted into SI units when applicable and the severity grade 
calculated using the National Cancer Institutes Common Terminology Criteria for Adverse 
Events (CTCAE, version 4.03) unless otherwise indicated. A severity grade of 0 will be 
assigned when the value is within normal limits. In the case when a local laboratory normal 
range overlaps into the higher (i.e., non-zero) CTC grade, the laboratory value will still be 
considered within normal limits and assigned a CTC grade of zero. 
The following summaries will be produced for the laboratory data by laboratory parameter: 
• Shift tables to the worst post-baseline value from baseline value (both expressed in CTC 
grades) will be produced. 
• Tables of worst post-baseline value by CTC grade. 


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• For laboratory parameters where CTC grades are not defined, shift tables to the worst 
post-baseline value will be produced using the low/normal/high classifications based on 
laboratory reference ranges. 
The following listings will be produced for the laboratory data: 
• Listing of patients with laboratory abnormalities of CTC grade 3 and 4 by parameter, 
cycle and treatment group 
• Listing of laboratory normal ranges by laboratory identification number and laboratory 
group 
• Listing of all laboratory data with values flagged to show corresponding CTC grades 
and/or the classifications relative to the laboratory reference ranges (i.e., High (H) or Low 
(L)) 
Table 3-2 lists all those laboratory parameters for which CTCAE grades are defined, Table 3- 
3 lists the remaining laboratory parameters. 
3.6.4.1 
Hematology 
Differential counts will be converted to absolute values for CTC grade classification. For all 
the differential counts, % will be converted to absolute values, if necessary: 
e.g. Absolute WBCdiff (Wunit) = Absolute WBC (Wunit)*Relative WBCdiff(%)/100 
Normal ranges should not be converted to obtain absolute normal ranges. Absolute normal 
ranges should be provided within lab ranges. If both are reported, absolute values will be left 
unchanged. Grading will be applied to absolute values. 
 
 
Table 3-2 
Laboratory parameters to be presented in grade shift tables based on 
CTC grade 
Hematology and coagulation 
Biochemistry 
Urinalysis 
White Blood Cells 
(WBC) 
↑↓ 
Creatinine 
↑ 
Urine Protein Dipstick 
↑ 
test 
Hemoglobin 
↑↓ 
Sodium (hyper & hypo) 
↑↓ 
Platelets counts 
↓ 
Potassium (hyper & 
↑↓ 
hypo) 
Absolute Neutrophils 
↓ 
Glucose (hyper & hypo) 
↑↓ 
Absolute Lymphocytes 
↑↓ 
Magnesium (hyper & 
↑↓ 
hypo) 
aPTT 
↑ 
Uric acid 
↑ 
Fibrinogen 
↓ 
Albumin 
↓ 
INR 
↑ 
AST (SGOT) 
↑ 
ALT (SGPT) 
↑ 
Alkaline Phosphatase 
↑ 
Total Bilirubin 
↑ 


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Amylase 
↑ 
Lipase 
↑ 
Total cholesterol 
↑ 
Triglycerides 
↑ 
CPK 
↑ 
Phosphate (Inorganic 
↓ 
Phosphorus) 
↑ Indicates that CTC grade increases as the parameter increases, these parameters are to be 
included in the summary of maximum post-baseline lab parameters 
↓ Indicates that CTC grade increases as the parameter decreases, these parameters are to be 
included in the summary of minimum post-baseline lab parameters 
 
 
Table 3-3 
Laboratory parameters to be presented in shift tables based on local 
laboratory normal ranges 
 
Hematology and coagulation 
Biochemistry 
Urinalysis 
Red blood cell count (RBC) 
Urea 
Specific gravity 
Absolute eosinophils 
Total protein 
Glucose 
Absolute basophils 
Indirect bilirubin 
Blood 
Absolute monocytes 
Direct bilirubin 
Bilirubin 
Prothrombin time 
HDL 
Ketones 
Hematocrit 
LDH 
Leukocytes 
Chloride 
Myoglobin 
Bicarbonate 
LDL 
TSH 
Free T3 
Free T4 
Total Calcium 
 
3.6.5 
Vital signs, weight and physical examinations 
All vital signs measures (e.g., oral temperature, respiratory rate, sitting blood pressure, and 
sitting pulse) and weight will be listed by parameter, treatment group, patient and time point 
(cycle) for each patient with at least one notable vital sign abnormality on record. Vital sign 
abnormalities as defined in Table 3-4 will be derived and displayed in the listings. 
The number and percentage of patients with at least one post-baseline vital sign abnormality 
(in both directions, i.e., both clinically notable high and low values) will be tabulated. 
Table 3-4 
Notable vital signs ranges 
Vital sign 
Criteria for clinically notable ranges 
Systolic blood pressure 
≥180 mmHg/≤90 mmHg with increase/decrease from baseline of ≥20 


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[mmHg] 
mmHg 
Diastolic blood pressure 
[mmHg] 
≥105 mmHg/≤50 mmHg with increase/decrease from baseline of ≥15 
mmHg 
Pulse rate [bpm] 
≥120 bpm/≤50 bpm with increase/decrease from baseline of ≥15 bpm 
Oral body Temperature [°C] 
Body temperature: ≤ 35,  39 
Weight [kg] 
≥10% decrease/increase from baseline 
3.6.6 
WHO/ECOG performance status 
Frequencies and percentages for the categories of the WHO performance scale will be 
summarized by visit. 
3.6.7 
Electrocardiograms 
3.6.7.1 
ECG data descriptive statistics 
• Data from electrocardiogram will be listed, notable values will be flagged, and any other 
information collected will be listed. The frequency and percentage of patients with newly 
occurring qualitative ECG abnormalities will be tabulated. Shift table baseline to worst on- 
treatment result for overall assessments will also be summarized. 
• Post-baseline values will also be categorized and tabulated to flag notable values 
according to the following rules: 
 
 
Parameters 
Criteria for ECG notable values 
 
QTcF (ms), QTcB (ms) and QT (ms) 
New: > 450, > 480, > 500 ms 
Increase from baseline > 30 
Increase from baseline > 60 
HR (bpm) 
Increase from baseline > 25% & to a value > 100 
Decrease from baseline < 25% & to a value < 50 
PR (ms) 
Increase > 25% to a value > 200 
QRS (ms) 
Increase > 25% to a value > 110 
3.6.7.2 
PK/QT analyses 
Not applicable. 
3.6.8 
Other safety analyses 
Cardiac imaging with decreased left ventricular ejection fraction (LVEF) will be summarized 
based on worst CTC grade and listed. 
Any other safety information collected will be listed and notable values will be flagged. 
3.6.9 
Tolerability 
Tolerability of study drug treatment will be assessed by summarizing the number of treatment 
dose interruptions and dose reductions. Reasons for dose interruption and dose reductions will 
be listed by patient and summarized. Dose interruption occurs when patient receives 0 mg of 
the study drug. 


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Cumulative dose, dose intensity and relative dose intensity of MEK162, LGX818 and 
LEE011 will be summarized. Categories for relative dose intensity of each study drug will be 
specified as < 0.5, ≥ 0.5 to < 0.75, ≥ 0.75 to < 0.9, ≥ 0.9 to < 1.1 and ≥ 1.1. The number and 
proportion of patients within each category will be presented. 
3.6.10 
COVID-19 Study disruptions 
The following data will be summarized in relevant disposition analyses and will also be listed 
to indicate the extent of COVID-19 study disruptions on the trial participants and study data. 
• 
Protocol deviations related to COVID-19 
• 
COVID-19 related AEs 
• 
COVID-19 related deaths 
• 
Study drug discontinuation due to COVID-19 
• 
Study discontinuation due to COVID-19 
3.7 
Pharmacokinetic data 
3.7.1 
Descriptive statistics 
PK concentration data will be listed and summarized in the interim CSR. PK concentration 
data will be summarized in the final CSR but not listed. 
Plasma concentrations that were excluded for the derivation of PK parameters and labeled as 
such in the listings will also excluded from the summary statistics. 
The PK parameters defined in Table 3-5 will be calculated as appropriate. Steady state (SS) is 
assumed to be reached on Day 15 and the patient should have taken all scheduled doses for at 
least 2 consecutive days prior to Day 15. The PK parameters will be listed and summarized 
using relevant statistics in the interim CSR. The PK parameters will be summarized in the 
final CSR but not listed. Median, minimum, and maximum will be calculated for tmax and 
tlast. For other PK parameters, mean, standard deviation, CV% mean, geometric mean, CV% 
geo-mean, median, minimum, and maximum will be calculated. In addition, in case drug 
accumulation is observed upon multiple dosing, additional PK parameters describing drug 
accumulation will be added to the analysis (i.e. effective half-life). 
Only PK blood samples with date and time and for which at last prior dose dates and times are 
adequately recorded will be included in the PK analyses. Samples taken from patients who 
vomited within 4 hours of dosing will be excluded from the analysis. The FAS will be used. 
Table 3-5 
Definition of PK parameters 
Parameter 
Definition 
 
Cmax 
Maximum observed plasma concentration after drug administration [mass x volume- 
1] 
Tmax 
Time to reach Cmax [time] 
Ctrough 
Predose plasma concentration before drug administration [mass x volume-1] 


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AUClast 
Area under the concentration-time curve from time zero to the last measurable 
concentration sampling time (tlast) [mass x time x volume-1] 
Tlast 
Time at which the last measurable concentration was observed [time] 
AUCinf 
Area under the concentration-time curve from time zero to infinity with extrapolation 
of the terminal phase [mass x time x volume-1] 
AUCtau 
Area under the concentration-time curve from time zero to tau after first dose [mass 
x time x volume-1] 
AUC(0-t) 
Area under the concentration-time curve from time zero to time t after first dose 
[mass x time x volume-1] 
AUC(0-t), ss 
Area under the concentration-time curve from time zero to time t after drug 
administration at steady state [mass x time x volume-1] 
t1/2 
Elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve [time] 
CL/F 
Apparent total plasma clearance of drug after oral administration [volume x time-1] 
Vz/F 
Apparent volume of Distribution at the terminal elimination phase [volume] 
Cmax,ss 
Maximum observed plasma concentration after drug administration at steady state 
[mass x volume-1] 
Tmax,ss 
Time to reach Cmax at steady state [time] 
Ctrough,ss 
Predose plasma concentration before drug administration at steady state [mass x 
volume-1] 
AUCtau,ss 
Area under the concentration-time curve from time zero to tau at steady state [mass 
x time x volume-1] 
t1/2, ss 
Elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve at steady state [time] 
CL,ss/F 
Apparent total plasma clearance of drug after oral administration at steady state 
[volume x time-1] 
Vz,ss/F 
Apparent volume of Distribution at the terminal elimination phase at steady state 
[volume] 
RA* 
Accumulation ratio calculated as AUCtau,ss/AUCtau 
* Steady state is assumed to be reached by Cycle 1 Day 15. 
 
3.7.2 
Modeling of PK data 
Selected primary PK parameters will be analyzed using mixed model to assess the dose 
proportionality, inter- and intra-individual variability, and steady-state attainment. If relevant, 
some of the analyses described below could be repeated by excluding patients receiving 
treatment in an inappropriate dosage or regimen as well as patients receiving concomitant 
therapies that may interact with LGX818 and MEK162 combination. 
These analyses will be documented in separate reports. 
 
 
Dose proportionality 
Dose proportionality for LGX818 and MEK162 (and LEE011 if applicable) will be assessed 
for AUCτ,ss and Cmax,ss. An analysis of variance is performed on log-transformed parameters 
by using a mixed-effect model with patient as random effect and log(dose) as continuous 
fixed effect. 


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Dose prop01tionality will be assessed by estimating the model parameter for log(dose) as well 
as its 90% confidence interval, using the SOLUTION statement in SAS PROC MIXED. 
The general SAS code for the model is the following: 
 
 
These analyses will be documented in separate repo1ts. 
3.7.3 
PK/efficacy analyses 
Not applicable. 
3.8 
Biomarker assessments 
3.8.1 
Introduction 
 
There may be circumstances when a decision is made to stop sample collection, or not 
peifonn or discontinue the analysis of blood/ archival tumor samples / fresh tumor biopsies / 
fine needle aspirates due to either practical or strategic reasons (e.g. issues related to the 
quality and/or quantity of the samples or issues related to the assay). Under such 
circumstances, the number of samples may be inadequate to perfonn a rigorous data analysis 
and the available data will only be listed and potentially summarized. 
3.8.2 
Outline of the data analysis 
Biomarker analyses may be perfo1med after the completion of the end-of-study CSR and will 
be documented in separate repo1ts. These analyses may include but are not limited to the 
meta-analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in an addendum of the 
SAP or in a stand-alone analysis plan document, as appropriate. 
3.8.3 
Biomarker objectives 
See Table 1-1. 
PROC MIXED DATA=dataset METHOD=reml; 
CLASS Patient ID; 
MODEL log_PK_parameter = log_dose / ddfm=kr solution 
alpha=0.1 cl; 
 
 


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3.8.4 
Biomarker analysis data set 
The Full Analysis Set will be used for all biomarker analysis. Unless othe1wise specified, all 
statistical analyses ofbiomarker data will be perfo1med on patients with biomarker data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Definition of baseline and summarizing replicate data values 
The Cycle 1 Day 1 assessment (pre-dose) will be used as the baseline value. 
For assessments perfonned in tumor biopsies, fresh biopsy results will be used for baseline 
when both archived and fresh tumor samples are available. 
When more than one biomarker data value are available for a patient at any time point, the 
mean of the replicate values will be used for all statistical analyses. 


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Table 3-7 
Coding of compartment and staining level for IHC 
 
Compartment 
CELLOC1C 
Staining level 
cytoplasm 
1 
1+ 
2 
2+ 
3 
3+ 
membrane 
4 
1+ 
5 
2+ 
6 
3+ 
nucleus 
7 
1+ 
8 
2+ 
 
9 
3+ 
 
 
Derivation of Change and Percent Change Variables 
Absolute and relative change (percent change) and fold change from baseline will be 
calculated for each patient and or treatment group. 
Percent change is computed as ((visit i - baseline)/ baseline) * 100. To compute the average 
percent change from baseline is to compute the average expression level at each time point 
and then compute the percent change using the average values. Please note the number of 
patients for the average of percent change from baseline might vaiy due to potential missing 
values at respective time points. 
3.8.5.2 
IHC Summary statistics 
For each IHC assay, the mean, standard deviation, %CV, median, minimum, maximum, inter- 
quaiiile range, number, and percent of the H-score values for each treatment group at each 
time point will be reported. Interquaiiile range is the number of data points between the 25th 
and 75th percentile. 


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The summa1y statistics will be repo1ied for each subcellular localization separately for the 
IHC assays where the H-score data is repo1ied by subcellular localization. 
Summary statistics (mean, standard deviation, median, minimum, maximum) for change from 
baseline and/or percent change from baseline and the frequency and associated percentage of 
data points in each treatment group will be repo1ied. 
The derived IHC H-scores and the individual components of the H-scores will be listed for 
each patient for all time points and ordered by the treatment group. 
 
Table 3-8 
Compartment and statistic for IHC 
 
 -
3.8.6.1 
Handling of RT-PCR data 
 
 
 
 
 != ------------- '=--== 
RT-PCR data will be repo1ied as PCR cycle (CT) values, which refer to the cycle number at 
which the amount of amplified target reaches a fixed threshold, or the threshold cycle for 
linear amplification. The higher the raw CT for a target gene, the weaker the level of 
expression for this gene. Raw CT (threshold cycle) results will be nonnalized. Nonnalization 
of the CT value, or .6.CT, is generally the average CT of the control genes minus the raw CT 
of the target gene. .6.CT is, by definition, on the log2 scale. No transformation will be applied 
to these data. Each raw CT value should be checked and if it exceeds the maximum reliable 
CT, then impute those values with the value of the maximum reliable CT. 
Deriving change and percent change variables 
For RT-PCR data, the fold change from baseline is calculated using the fo1mula 2Mcr, where 
.6..6.CT= post.6.CT- pre.6.CT. 
3.8.6.2 
RT-PCR Summary Statistics 
Absolute and/or relative (% and/or fold) changes from baseline will be listed by patient and 
summarized using descriptive statistics by treatment group for baseline and all available post 
baseline visits for each biomarker. The descriptive statistics will include the mean, standard 
deviation, %CV, median, minimum, and maximum for each treatment group at each time 
point. 
The raw CT values will also be listed by patient ordered by time point within treatment 
groups. 
Table 3-9 


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Terminology and definitions: 
• 
Exon - The coding region of DNA 
• 
Intron - The noncoding region of DNA 
• 
Synonymous mutation - A change in an exon of DNA that does not cause a change to the 
resultant amino acid sequence. 
• 
Nonsynonymous - A change in an exon of DNA that causes a change to the resultant 
amino acid sequence. Mutations may or may not produce discemable changes in the 
observable characteristics (phenotype) of an organism. Mutations play a pait in both 
nonnal and abnonnal biological processes, including evolution, cancer, and the 
development of the immune system. 
• 
Mutation - a change in the genetic material of an individual 
• 
Point mutations - often caused by malfunction of DNA replication, exchange a single 
nucleotide for another. 
• 
Silent mutations - code for the same amino acid 
• 
Missense mutations - code for a different amino acid (nonsynonymous) 
• 
Nonsense - code for a "stop" and trnncate the resultant protein 
• 
Inse1tions - add one or more extra nucleotides into the DNA 
• 
Deletion - remove one or more nucleotides from the DNA 
• 
 Fraineshift mutation - a mutation caused by an inse1tion or a deletion of a number of 
nucleotides not evenly divisible by 3 from a DNA sequence. This causes a 
completely different sequence of amino acids to be produced, rendering the original 
protein non-functional 
• 
Amplifications - also known as gene duplications, lead to multiple copies of all 
chromosomal regions, increasing the dosage of the genes located within them 
• 
 Deletions - when lai·ge chromosomal regions are removed, leading to loss of the genes 
within those regions 
• 
Translocations - interchange of genetic paits of different chromosomes 
 
3.8.7.2 
Somatic Mutation summary statistics 
 
Results will be fmther categorized and summai·ized by the type of variant(s) present for each 
biomai·ker (copy number vai·iant, reaiTangement, sequence vai·iant). Exon mutations occuning 


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due to sequence variation will also be categorically summarized for each biomarker.If somatic 
mutations are analyzed in multiple samples from a patient (e.g. biopsy) fresh and/or frozen 
sample, the patient may be considered having a mutation if a mutation is observed in at least 
one of the samples. 
All the mutation data will be listed for each patient ordered by treatment group. 
3.8.8 
Next Generation Sequencing 
NGS data, also known as deep sequencing data will be generated on a panel of ~200 genes. 
As these data are extensive, complex and not fully understood, only the following markers of 
the panel will be shown, if the variant exists at a frequency of> 15% in the trial population. 
Note that a gene will be considered as amplified if six (6) or greater copies of a given gene are 
present in the sample. Loss will be defined if zero (0) copies of a given gene are present in 
the sample. Additional markers assessed using this technology may be described in separate 
analysis plan documentation and displayed external to the main study CSR. 
 
3.8.1O  Relationship between biomarkers and PK parameters 
If deem necessaiy, this paii of analysis may be described in sepai·ate analysis plan 
documentation and displayed external to the main study CSR. 
3.8.11 
Association between biomarkers and clinical outcome 
If deem necessaiy, this paii of analysis may be described in separate analysis plan 
documentation and displayed external to the main study CSR. 
 
 
4 
Final Analysis Appendices 
 
The appendices include a comprehensive list of tables listings, and figures to support the final 
CSR. 
4.1.1 
Tables 
Table Number 
Title 
Analysis Set 
Subset 
Table 14.1.1.1.ld 
Analysis set by treatment group/arm 
Full Analysis Set 
Phase lb/11, Triple 
Combination 
Table 14.l.1.1.2d 
Significant protocol deviations by 
treatment group/arm 
Full Analysis Set 
Phase lb/11, Triple 
Combination 
Table 14.1.1.2.la 
Patient disposition by treatment 
group 
Full Analysis Set 
Phase lb, Dual 
Combination 


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Table 14.1.1.2.1b 
Patient disposition by arm 
Full Analysis Set 
Phase II, Dual 
Combination 
Table 14.1.1.2.1d 
Patient disposition by treatment 
group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Table 14.1.1.2.2a 
Demographics and baseline 
characteristics by treatment group 
Full Analysis Set 
Phase Ib, Dual 
Combination 
Table 14.1.1.2.2b 
Demographics and baseline 
characteristics by arm 
Full Analysis Set 
Phase II, Dual 
Combination 
Table 14.1.1.2.2d 
Demographics and baseline 
characteristics by treatment 
group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Table 14.1.1.2.3d 
Disease history by treatment 
group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Table 14.1.3.1d 
Relevant medical histories, by 
primary system organ class, preferred 
term and treatment group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Table 14.1.3.2d 
Current medical conditions, by 
primary system organ class, preferred 
term and treatment group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Table 14.1.4.1d 
Prior antineoplastic therapy – 
Surgery, by treatment group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Table 14.1.4.2d 
Prior antineoplastic therapy – 
Radiotherapy, by treatment 
group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Table 14.1.4.3d 
Prior antineoplastic therapy – 
Medication, by treatment group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Table 14.1.4.4d 
Prior antineoplastic therapy – 
Medication, by preferred term and 
treatment group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Table 14.1.4.5d 
Prior Medications stopped prior to 
the start of study drug by preferred 
term, and treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.2.1.1d 
Summary of best overall response as 
per local assessment by treatment 
group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Table 14.2.2.1b 
Analysis of overall survival using 
Kaplan-Meier method by arm 
Full Analysis Set 
Phase II, Dual 
Combination 
Table 14.2.2.1d 
Analysis of overall survival using 
Kaplan-Meier method by arm 
Full Analysis Set 
Phase II, Triple 
Combination 
Table 14.2.3.1b 
Analysis of progression free survival 
as per local assessment using Kaplan- 
Meier method by arm 
Full Analysis Set 
Phase II, Dual 
Combination 
Table 14.2.3.1d 
Analysis of progression free survival 
as per local assessment using Kaplan- 
Meier method by arm 
Full Analysis Set 
Phase II, Triple 
Combination 


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Table 14.2.4.1d 
Analysis of time to response as per 
local assessment using Kaplan-Meier 
method by arm 
Full Analysis Set 
Phase II, Triple 
Combination, 
Confirmed 
Responders 
Table 14.2.5.1b 
Analysis of duration of response as 
per local assessment using Kaplan- 
Meier method by arm 
Full Analysis Set 
Phase II, Dual 
Combination, 
Confirmed 
Responders 
Table 14.2.5.1d 
Analysis of duration of response as 
per local assessment using Kaplan- 
Meier method arm 
Full Analysis Set 
Phase II, Triple 
Combination, 
Confirmed 
Responders 
Table 14.3.1.1.1d 
Dose limiting toxicities occurring 
during the first 28 days by primary 
system organ class, preferred term 
and treatment group 
Dose Determining 
Set 
Phase Ib, Triple 
Combination 
Table 14.3.1.2.1d 
Treatment-emergent adverse events 
(all causality) by preferred term, 
maximum grade (grades 1-4) and 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.1.2.2a 
Treatment-emergent adverse events 
(all causality) by preferred term, 
maximum grade (overall and grade 
3/4) and treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
Table 14.3.1.2.2b 
Treatment-emergent adverse events 
(all causality) by preferred term, 
maximum grade (overall and grade 
3/4) and arm 
Safety Set 
Phase II, Dual 
Combination 
Table 14.3.1.2.2d 
Treatment-emergent adverse events 
(all causality by preferred term, 
maximum grade (overall and grade 
3/4), and treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.1.2.3d 
Serious adverse events (all causality) 
by preferred term, maximum grade 
(overall and grade 3/4), and 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.1.2.4a 
Treatment-emergent adverse events 
leading to permanent study drug 
discontinuation (all causality) by 
preferred term, maximum grade 
(grades 1-4) and treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
Table 14.3.1.2.4b 
Treatment-emergent adverse events 
leading to permanent study drug 
discontinuation (all causality) by 
preferred term, maximum grade 
Safety Set 
Phase II, Dual 
Combination 


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(grades 1-4) and arm 
Table 14.3.1.2.4d 
Treatment-emergent adverse events 
leading to permanent study drug 
discontinuation (all causality)by class, 
preferred term, maximum grade 
(grades 1-4) and treatment 
group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.1.2.5d 
Treatment-emergent adverse events 
requiring dose adjustment or delay 
(all causality) by preferred term, 
maximum grade (grades 1-4) and 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.1.2.6a 
Treatment-emergent adverse events 
(all causality) occurring in >= 20% of 
patients by preferred term and 
treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
Table 14.3.1.2.6b 
Treatment-emergent adverse events 
(all causality) occurring in >= 20% of 
patients by preferred term and arm 
Safety Set 
Phase II, Dual 
Combination 
Table 14.3.1.2.6d 
Treatment-emergent adverse events 
(all causality) occurring in >= 20% of 
patients by preferred term and 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.1.2.7a 
Treatment-emergent adverse events 
(all causality) occurring in >= 5% of 
patients by preferred term, grade 3/4 
and treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
Table 14.3.1.2.7b 
Treatment-emergent adverse events 
(all causality) occurring in >= 5% of 
patients by preferred term, grade 3/4 
and arm 
Safety Set 
Phase II, Dual 
Combination 
Table 14.3.1.2.7d 
Treatment-emergent adverse events 
(all causality) occurring in >= 5% of 
patients by preferred term, grade 3/4 
and treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.1.3.1d 
Treatment-emergent adverse events 
(treatment-related) by primary 
system organ class, preferred term, 
maximum grade (grades 1-4) and 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.1.3.2a 
Treatment-emergent adverse events 
(treatment-related) by preferred 
term, maximum grade (overall and 
grade 3/4) and treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
Table 14.3.1.3.2b 
Treatment-emergent adverse events 
Safety Set 
Phase II, Dual 


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(treatment-related) by preferred 
term, maximum grade (overall and 
grade 3/4) and arm 
Combination 
Table 14.3.1.3.2d 
Treatment-emergent adverse events 
(treatment-related) by preferred 
term, maximum grade (overall and 
grade 3/4) and treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.1.3.3a 
Treatment-emergent adverse events 
(treatment related) occurring in >= 
10% of patients by preferred term, 
maximum grade and treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
Table 14.3.1.3.3b 
Treatment-emergent adverse events 
(treatment related) occurring in >= 
10% of patients by preferred term, 
maximum grade and arm 
Safety Set 
Phase II, Dual 
Combination 
Table 14.3.1.3.3d 
Treatment-emergent adverse events 
(treatment related) occurring in >= 
10% of patients by preferred term, 
maximum grade and treatment 
group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.2.2.1a 
Deaths, by preferred term and 
treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
Table 14.3.2.2.1b 
Deaths, by preferred term and arm 
Safety Set 
Phase II, Dual 
Combination 
Table 14.3.2.2.1d 
Deaths, by preferred term and 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
14.3.2.2.2a 
Deaths, by primary reason and 
treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
14.3.2.2.2b 
Deaths, by primary reason and arm 
Safety Set 
Phase II, Dual 
Combination 
14.3.2.2.2d 
Deaths, by primary reason and 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.4.1.1d 
Hematology and coagulation shift 
table based on CTC grade by 
parameter and treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.4.1.2d 
Hematology and coagulation shift 
table based on normal range by 
parameter and treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.4.1.3d 
Biochemistry shift table based on CTC 
grade by parameter and treatment 
group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.4.1.4d 
Biochemistry shift table based on 
normal range by parameter and 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.4.1.5d 
Urinary shift table based on CTC 
Safety Set 
Phase Ib/II, Triple 


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grade by parameter and treatment 
group/arm 
Combination 
Table 14.3.4.1.6d 
Urinary laboratory parameters 
without CTC grades by visit and 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.4.1.7d 
Notable hepatic laboratory values by 
parameter and treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.5.2d 
Notably abnormal vital signs by 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.6.2.1d 
Notable ECG values per central 
analysis by treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.6.2.2d 
New clinically meaningful ECG 
abnormalities per central analysis, by 
evaluation type and treatment 
group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.6.2.3d 
ECG shift table based on notable 
values by treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.7.1d 
Left ventricular ejection fraction 
worst CTC grade by treatment 
group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.3.8.1d 
WHO/ECOG performance status by 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.4.1.1a 
Duration of exposure to study drug 
by treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
Table 14.4.1.1b 
Duration of exposure to study drug 
by arm 
Safety Set 
Phase II, Dual 
Combination 
Table 14.4.1.1d 
Duration of exposure to study drug 
by treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.4.1.2d 
Dose reductions of study treatment 
by treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.4.1.3d 
Dose delays of study treatment by 
treatment group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.4.1.4a 
Summary statistics of exposure of 
study treatment by treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
Table 14.4.1.4b 
Summary statistics of exposure of 
study treatment by arm 
Safety Set 
Phase II, Dual 
Combination 
Table 14.4.1.4c 
Summary statistics of exposure of 
study treatment by treatment 
group/arm 
Safety Set 
Phase Ib/II, Dual 
Combination 
Table 14.4.1.4d 
Summary statistics of exposure of 
study treatment by treatment 
group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.4.2.1d 
Concomitant medications and 
significant non-drug therapies started 
prior to the start of study drug by 
Safety Set 
Phase Ib/II, Triple 
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preferred term and treatment 
group/arm 
Table 14.4.2.2d 
Concomitant medications and 
significant non-drug therapies started 
after the start of study drug by 
preferred term and treatment 
group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.4.2.3a 
Antineoplastic therapy since 
discontinuation of study drug by 
preferred term and treatment group 
Safety Set 
Phase Ib, Dual 
Combination 
Table 14.4.2.3b 
Antineoplastic therapy since 
discontinuation of study drug by 
preferred term and arm 
Safety Set 
Phase II, Dual 
Combination 
Table 14.4.2.3d 
Antineoplastic therapy since 
discontinuation of study drug by 
preferred term and treatment 
group/arm 
Safety Set 
Phase Ib/II, Triple 
Combination 
Table 14.4.4.1.1 
Summary of encorafenib 
concentrations by treatment group 
Full Analysis Set 
Phase Ib 
Table 14.4.4.1.2 
Summary of encorafenib 
concentrations by arm 
Full Analysis Set 
Phase II 
Table 14.4.4.2.1 
Summary of binimetinib 
concentrations by treatment group 
Full Analysis Set 
Phase Ib 
Table 14.4.4.2.2 
Summary of binimetinib 
concentrations by arm 
Full Analysis Set 
Phase II 
Table 14.4.4.3.1 
Summary of AR00426032 
concentrations by treatment group 
Full Analysis Set 
Phase Ib 
Table 14.4.4.3.2 
Summary of AR00426032 
concentrations by arm 
Full Analysis Set 
Phase II 
Table 14.4.4.4.1 
Summary of ribociclib concentrations 
by treatment group 
Full Analysis Set 
Phase Ib, Triple 
Combination 
Table 14.4.4.4.2 
Summary of ribociclib concentrations 
by arm 
Full Analysis Set 
Phase II, Triple 
Combination 
Table 14.4.4.5.1 
Summary of LEQ803 concentrations 
by treatment group 
Full Analysis Set 
Phase Ib, Triple 
Combination 
Table 14.4.4.5.2 
Summary of LEQ803 concentrations 
by arm 
Full Analysis Set 
Phase II, Triple 
Combination 
Table 14.4.5.1.1 
Summary of PK parameters of 
primary interest for encorafenib by 
profile day and treatment group 
Full Analysis Set 
Phase Ib 
Table 14.4.5.1.2 
Summary of PK parameters of 
primary interest for encorafenib by 
profile day and arm 
Full Analysis Set 
Phase II 
Table 14.4.5.2.1 
Summary of PK parameters of 
primary interest for binimetinib by 
Full Analysis Set 
Phase Ib 


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profile day and treatment group 
Table 14.4.5.2.2 
Summary of PK parameters of 
primary interest for binimetinib by 
profile day and arm 
Full Analysis Set 
Phase II 
Table 14.4.5.3.1 
Summary of PK parameters of 
primary interest for AR00426032 by 
profile day and treatment group 
Full Analysis Set 
Phase Ib 
Table 14.4.5.3.2 
Summary of PK parameters of 
primary interest for AR00426032 by 
profile day and arm 
Full Analysis Set 
Phase II 
Table 14.4.5.4.1.1 
Summary of PK parameters of 
primary interest for ribociclib by 
profile day and treatment group 
Full Analysis Set 
Phase Ib, Triple 
Combination 
Table 14.4.5.4.1.2 
Summary of PK parameters of 
primary interest for ribociclib by 
profile day and arm 
Full Analysis Set 
Phase II, Triple 
Combination 
Table 14.4.5.4.2.1 
Summary of PK parameters of 
primary interest for LEQ803 by 
profile day and treatment group 
Full Analysis Set 
Phase Ib, Triple 
Combination 
Table 14.4.5.4.2.2 
Summary of PK parameters of 
primary interest for LEQ803 by 
profile day and arm 
Full Analysis Set 
Phase II, Triple 
Combination 
Table 14.4.5.5.1 
Summary of PK parameters of 
secondary interest for encorafenib by 
profile day and treatment group 
Full Analysis Set 
Phase Ib 
Table 14.4.5.5.2 
Summary of PK parameters of 
secondary interest for encorafenib by 
profile day and arm 
Full Analysis Set 
Phase II 
Table 14.4.5.6.1 
Summary of PK parameters of 
secondary interest for binimetinib by 
profile day and treatment group 
Full Analysis Set 
Phase Ib 
Table 14.4.5.6.2 
Summary of PK parameters of 
secondary interest for binimetinib by 
profile day and arm 
Full Analysis Set 
Phase II 
Table 14.4.5.7.1 
Summary of PK parameters of 
secondary interest for AR00426032 
by profile day and treatment group 
Full Analysis Set 
Phase Ib 
Table 14.4.5.7.2 
Summary of PK parameters of 
secondary interest for AR00426032 
by profile day and arm 
Full Analysis Set 
Phase II 
Table 14.4.5.8.1.1 
Summary of PK parameters of 
secondary interest for ribociclib by 
profile day andv treatment group 
Full Analysis Set 
Phase Ib, Triple 
Combination 
Table 14.4.5.8.1.2 
Summary of PK parameters of 
secondary interest for ribociclib by 
Full Analysis Set 
Phase II, Triple 
Combination 


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profile day and arm 
Table 14.4.5.8.2.1 
Summary of PK parameters of 
secondary interest for LEQ803 by 
profile day and treatment group 
Full Analysis Set 
Phase Ib, Triple 
Combination 
Table 14.4.5.8.2.2 
Summary of PK parameters of 
secondary interest for LEQ803 by 
profile day and arm 
Full Analysis Set 
Phase II, Triple 
Combination 
Table 14.4.5.9.1 
Dose proportionality analysis 
Full Analysis Set 
Phase Ib/II 
Table 14.4.5.10.1 
Statistical Analysis of Accumulation 
for Encorafenib: Cycle 1 
Full Analysis Set 
Table 14.4.5.10.2 
Statistical Analysis of Accumulation 
for Binimetinib: Cycle 1 
Full Analysis Set 
Table 14.4.5.10.3 
Statistical Analysis of Accumulation 
for AR00426032: Cycle 1 
Full Analysis Set 
Table 14.4.5.10.4 
Statistical Analysis of Accumulation 
for Ribociclib: Cycle 1 
Full Analysis Set 
Triple Combination 
Table 14.4.5.10.5 
Statistical Analysis of Accumulation 
for LEQ803: Cycle 1 
Full Analysis Set 
Triple Combination 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.1.2 
Listings 
Listing Number 
Title 
Analysis Set 
Subset 
Listing 16.2.1.1.1 
Analysis sets 
Full Analysis Set 
Listing 16.2.1.1.2 
Dose level and analysis sets 
Full Analysis Set 
Listing 16.2.1.2 
Treatment and study completion 
by treatment 
Full Analysis Set 
Listing 16.2.2.1 
Significant protocol deviations by 
treatment 
Full Analysis Set 
Listing 16.2.2.2 
Study disruption due to COVID-19 
Full Analysis Set 
Listing 16.2.4.1.1 
Patient baseline demographics by 
treatment 
Full Analysis Set 
Listing 16.2.4.1.2 
Baseline disease diagnosis by 
treatment 
Full Analysis Set 
Listing 16.2.5.1.1 
Dosage administration record by 
treatment – encorafenib 
Safety Set 
Listing 16.2.5.1.2 
Dosage administration record by 
treatment – binimetinib 
Safety Set 
Listing 16.2.5.1.3 
Dosage administration record by 
treatment – ribociclib 
Safety Set 
Triple Combination 
Listing 16.2.6.1 
Overall response per patient by 
assessment and treatment 
Full Analysis Set 
Listing 16.2.7.1 
Adverse events by treatment 
Full Analysis Set 
Listing 16.2.7.2 
Dose limiting toxicities (DLT) by 
treatment group 
Full Analysis Set 
Triple Combination 
Listing 16.2.8.1.1 
Hematology: primary hematology 
parameters by treatment group 
Full Analysis Set 
Listing 16.2.8.1.2 
Hematology: WBC and 
Full Analysis Set 
CCI 


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differentials by treatment 
Listing 16.2.8.1.3 
Hematology: coagulation 
parameters by treatment 
Full Analysis Set 
Listing 16.2.8.1.4 
Hematology: others by treatment 
Full Analysis Set 
Listing 16.2.8.1.5 
Biochemistry: liver function test 
and related variables by 
treatment 
Full Analysis Set 
Listing 16.2.8.1.6 
Biochemistry: renal variables by 
treatment 
Full Analysis Set 
Listing 16.2.8.1.7 
Biochemistry: electrolytes by 
treatment group 
Full Analysis Set 
Listing 16.2.8.1.8 
Biochemistry: others by 
treatment 
Safety Set 
Listing 16.2.8.1.9 
Urinary: urinalysis by treatment 
Full Analysis Set 
Listing 16.2.8.1.10 
Thyroid function tests, by 
treatment group 
Full Analysis Set 
Listing 16.2.8.1.11 
Pregnancy test results by 
treatment 
Full Analysis Set 
Listing 16.2.8.1.12 
Patients with newly occurring 
notable hepatic laboratory 
values, by treatment 
Safety Set 
Table 14.3.2.2.1 
Deaths during treatment by 
treatment 
Full Analysis Set 
 
 
4.1.3 
Figures 
Figure Number 
Title 
Analysis Set 
Subset 
Figure 14.2.1.1b 
Best percentage change from baseline in 
sum of longest diameters and best overall 
response as per local assessment by arm 
Full Analysis Set 
Phase II, Dual 
Combination 
Figure 14.2.1.1d 
Best percentage change from baseline in 
sum of longest diameters and best overall 
response as per local assessment by 
treatment group/arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Figure 14.2.1.2b 
Kaplan-Meier plot of progression-free 
survival as per local assessment by arm 
Full Analysis Set 
Phase II, Dual 
Combination 
Figure 14.2.1.2d 
Kaplan-Meier plot of progression-free 
survival as per local assessment by arm 
Full Analysis Set 
Phase Ib/II, Triple 
Combination 
Figure 14.4.4.1a 
Mean Plasma Concentration-time Profiles 
for Encorafenib: Cycle 1 
Full Analysis Set 
Phase Ib 
Figure 14.4.4.1b 
Mean Plasma Concentration-time Profiles 
for Encorafenib: Cycle 1 
Full Analysis Set 
Phase II 
Figure 14.4.4.2a 
Mean Plasma Concentration-time Profiles 
for Binimetinib: Cycle 1 
Full Analysis Set 
Phase Ib 


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Figure 14.4.4.2b 
Mean Plasma Concentration-time Profiles 
for Binimetinib: Cycle 1 
Full Analysis Set 
Phase II 
Figure 14.4.4.3a 
Mean Plasma Concentration-time Profiles 
for AR00426032: Cycle 1 
Full Analysis Set 
Phase Ib 
Figure 14.4.4.3b 
Mean Plasma Concentration-time Profiles 
for AR00426032: Cycle 1 
Full Analysis Set 
Phase II 
Figure 14.4.4.4a 
Mean Plasma Concentration-time Profiles 
for Ribociclib: Cycle 1 
Full Analysis Set 
Phase Ib, Triple 
Combination 
Figure 14.4.4.4b 
Mean Plasma Concentration-time Profiles 
for Ribociclib: Cycle 1 
Full Analysis Set 
Phase II, Triple 
Combination 
Figure 14.4.4.5a 
Mean Plasma Concentration-time Profiles 
for LEQ803: Cycle 1 
Full Analysis Set 
Phase Ib, Triple 
Combination 
Figure 14.4.4.5b 
Mean Plasma Concentration-time Profiles 
for LEQ803: Cycle 1 
Full Analysis Set 
Phase II, Triple 
Combination 
Figure 14.5.1 
Duration of exposure and RECIST status by 
mutation status 
Full Analysis Set 
Phase Ib 
 
 
5 
References 
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41. 
Neuenschwander, Branson and Gsponer (2008). Critical aspects of the Bayesian approach to 
phase I cancer trials, Statistics in medicine 27, 2420-2439 
 
6. 
Change control 
Version 
Date 
Change 
Draft V1.0 
04-JUN-13 
Original version 
Draft V1.1-1.7 
06-JAN-14 to 18-JUN-14 
Changes due to CTT review and additional minor changes 
Final V2.0 
01-JUN-15 
Changes due to protocol amendment 
Draft V2.1 
20-SEP-22 
Changes due to final analysis. 
Draft V2.2 
20-JAN-23 
Changes to adverse event analyses to remove summary by primary 
system organ class to multiple tables and to adjust percentage 
thresholds